Rodak's Hematology: Clinical Principles and Applications, 5th Ed.

CHAPTER 40. Thrombocytopenia and thrombocytosis

Larry D. Brace


Thrombocytopenia: Decrease in Circulating Platelets

Impaired or Decreased Platelet Production

Increased Platelet Destruction

Abnormalities in Distribution or Dilution

Thrombocytosis: Increase in Circulating Platelets

Reactive (Secondary) Thrombocytosis

Thrombocytosis Associated with Myeloproliferative Disorders


After completion of this chapter, the reader will be able to:

1. Define thrombocytopenia and thrombocytosis, and state their associated platelet counts.

2. Compare and contrast the clinical symptoms of platelet disorders and clotting factor deficiencies.

3. Explain the primary pathophysiologic processes of thrombocytopenia.

4. Name and list the unique diagnostic features of at least four disorders included in congenital hypoplasia of the bone marrow and describe their inheritance patterns.

5. Differentiate between acute and chronic immune thrombocytopenia.

6. Describe the immunologic and nonimmunologic mechanisms by which drugs may induce thrombocytopenia.

7. Differentiate between neonatal isoimmune thrombocytopenia and neonatal autoimmune thrombocytopenia.

8. Explain the laboratory findings and pathophysiology associated with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.

9. Summarize the pathophysiology of thrombotic complications in heparin-induced thrombocytopenia and describe the sequence of treatment options.

10. Given clinical history and laboratory test results for patients with thrombocytopenia or thrombocytosis, suggest a diagnosis that is consistent with the information provided.


After studying the material in this chapter, the reader should be able to respond to the following case study:

An 18-month-old African-American girl sustained severe burns over 40% to 50% of her body, including both lower extremities. Within 1 month, she underwent a below-knee amputation of the left lower extremity. Over the next several years, she underwent skin-grafting surgeries, central venous line placement, and other burn-related surgeries. During these procedures, the patient was exposed to heparinized saline irrigation. Four years after the burn injury, thrombosis was noted in the right femoral artery during a grafting surgery. Unfractionated heparin was used during the surgery. Surgeons were unable to save the leg, and an above-knee amputation was necessary. At this time, hypercoagulability studies were ordered. Results were as follows:


Patient Results

Reference Range

Protein C antigen


70% to 137%

Protein S antigen


63% to 156%

Antithrombin activity


76% to 136%

The patient’s results were normal on tests for the factor V Leiden and prothrombin G20210A mutations, and she was found not to have antiphospholipid antibody syndrome. Her platelet count had been decreasing steadily for 7 days before surgery but was still within the reference range.

1. Is the heparin used during the grafting surgeries significant in this patient’s case?

2. What test should be ordered next?

Bleeding disorders resulting from platelet abnormalities, whether quantitative or qualitative, usually are manifested by bleeding into the skin or mucous membranes or both (mucocutaneous bleeding). Common presenting symptoms include petechiae, purpura, ecchymoses, epistaxis, and gingival bleeding. Similar findings also are seen in vascular disorders, but vascular disorders (e.g., Ehlers-Danlos syndrome, hereditary hemorrhagic telangiectasia) are relatively rare. In contrast, deep tissue bleeding, such as hematoma and hemarthrosis, is associated with clotting factor deficiencies.

Thrombocytopenia: Decrease in circulating platelets

Although the reference range for the platelet count varies among laboratories, it is generally considered to be approximately 150,000 to 450,000/μL (150,000 to 450,000/mm3 or 150 to 450 × 109/L). Thrombocytopenia (platelet count of fewer than 100,000/μL) is the most common cause of clinically important bleeding. True thrombocytopenia has to be differentiated from the thrombocytopenia artifact that can result from poorly prepared blood smears or automated cell counts when platelet clumping or platelet satellitosis are present (Chapters 15 and 16). The primary pathophysiologic processes that result in thrombocytopenia are decreased platelet production, accelerated platelet destruction, and abnormal platelet distribution (sequestration) (Box 40-1).

BOX 40-1

Classification of Thrombocytopenia

Impaired or decreased production of platelets


May-Hegglin anomaly

Bernard-Soulier syndrome

Fechtner syndrome

Sebastian syndrome

Epstein syndrome

Montreal platelet syndrome

Fanconi anemia

Wiskott-Aldrich syndrome

Thrombocytopenia with absent radii (TAR) syndrome

Congenital amegakaryocytic thrombocytopenia

Autosomal dominant and X-linked thrombocytopenia




Drug induced

Increased platelet destruction


Acute and chronic immune thrombocytopenic purpura

Drug induced: immunologic

Heparin-induced thrombocytopenia

Neonatal alloimmune (isoimmune neonatal) thrombocytopenia

Neonatal autoimmune thrombocytopenia

Posttransfusion isoimmune thrombocytopenia

Secondary autoimmune thrombocytopenia


Thrombocytopenia in pregnancy and preeclampsia

Human immunodeficiency virus infection

Hemolytic disease of the newborn

Thrombotic thrombocytopenia purpura

Disseminated intravascular coagulation

Hemolytic uremic syndrome

Drug induced

Abnormalities of distribution or dilution

Splenic sequestration

Kasabach-Merritt syndrome


Loss of platelets: massive blood transfusions, extracorporeal circulation

From Colvin BT: Thrombocytopenia, Clin Haematol 14:661-681, 1985; and Thompson AR, Harker LA: Manual of hemostasis and thrombosis, ed 3, Philadelphia, 1983, FA Davis.

Small-vessel bleeding in the skin attributed to thrombocytopenia is manifested by hemorrhages of different sizes (). Figure 40-1Petechiae are small pinpoint hemorrhages about 1 mm in diameter, purpura are about 3 mm in diameter and generally round, and ecchymoses are 1 cm or larger and usually irregular in shape. Ecchymosis corresponds with the lay term bruise. Other conditions such as defective platelet function, vascular fragility, and trauma contribute to the hemorrhagic state.




FIGURE 40-1 A, Petechiae, B, purpura, and C, ecchymoses indicate the various patterns of systemic (mucocutaneous) hemorrhage. (Fig. 40-1A and 40-1C from Gary P. Williams, MD, University of Wisconsin Clinical Science Center, Madison, WI.) (Fig. 40-1B from Kitchens CS, Alving BM, Kessler CM: Consultative hemostasis and thrombosis, Philadelphia, 2002, Saunders.)

Clinical bleeding varies and often is not closely correlated with the platelet count. It is unusual for clinical bleeding to occur when the platelet count is greater than 50,000/μL, but the risk of clinical bleeding increases progressively as the platelet count decreases from 50,000/μL. Patients with platelet counts of 20,000/μL or sometimes lower may have little or no bleeding symptoms. In general, patients with platelet counts of fewer than 10,000/μL are considered to be at high risk for a serious hemorrhagic episode.

Impaired or decreased platelet production

Abnormalities in platelet production may be divided into two categories: One type is associated with megakaryocyte hypoplasia in the bone marrow, and the other type is associated with ineffective thrombopoiesis, as may be seen in disordered proliferation of megakaryocytes.

Inherited thrombocytopenia/congenital hypoplasia

It is increasingly apparent that most inherited thrombocytopenias can be linked to fairly specific chromosomal abnormalities or specific genetic defects. Table 40-1 provides a list of inherited thrombocytopenias associated with specific gene and chromosomal abnormalities, mode of inheritance, and associated features.

TABLE 40-1

List of Inherited Thrombocytopenias

Disease (abbreviation, OMIM entry)

Frequency*/Spontaneous Bleeding


Gene (chromosome localization)

Other Features


Wiskott-Aldrich syndrome (WAS, 301000)



WAS (Xp11)

Severe immunodeficiency leading to death in infancy; small platelets

X-linked thrombocytopenia (XLT, 313900)


Mild immunodeficiency; small platelets

MYH9-related disease (MYH9-RD, nd)



MYH9 (22q12-13)

Cataracts, nephropathy and/or deafness; giant platelets; also non-syndromic

Paris-Trousseau thrombocytopenia (TCPT, 188025/600588), Jacobsen syndrome (JBS, 147791)



Large deletion (11q23-ter)

Cardiac and facial defects, developmental delay and/or other defects; large platelets

Thrombocytopenia with absent radii (TAR, 274000)



RBM8A (1q21.1)

Platelet count tends to rise and often normalizes in adulthood; reduced megakaryocytes; normal-sized platelets. Bilateral radial aplasia and/or other malformations

GATA1-related disease (GATA1-RD) (Dyserythropoietic anemia with thrombocytopenia-nd, 300367- X-linked thrombocytopenia with thalassemia-XLTT, 314050)



GATA1 (Xp11)

Hemolytic anemia, possible unbalanced globin chain synthesis, possible congenital erythropoietic porphyria; large platelets

Congenital thrombocytopenia with radio-ulnar synostosis (CTRUS, 605432)



HOXA11 (7p15-14)

Radio-ulnar synostosis and/or other defects; possible evolution into aplastic anemia; normal sized platelets

Thrombocytopenia associated with sitosterolemia (STSL, 210250)



ABCG5, ABCG8 (2p21)

Anemia, tendon xanthomas, atherosclerosis; large platelets; also non-syndromic

FLNA-related thrombocytopenia (FLNA-RT, nd)



FLNA (Xq28)

Periventricular nodular heterotopia (MIM 300049); large platelets; also non-syndromic


Bernard-Soulier syndrome (BSS, 231200)





GP1BA (17p13),

Giant platelets




GP1BB (22q11), GP9(3q21)

Large platelets

Congenital amegakaryocytic thrombocytopenia (CAMT, 604498)



MPL (1p34)

Always evolves into bone marrow aplasia in infancy; normal-sized platelets

Familial platelet disorder and predisposition to acute myelogenous leukemia (FPD/AML, 601399)



RUNX1 (21q22)

High risk of developing leukemia or MDS; normal-sized platelets

Gray platelet syndrome (GPS, 139090)



NBEAL2 (3p21.1)

High risk of developing evolutive myelofibrosis and splenomegaly; giant platelets

ANKRD26-related thrombocytopenia (THC2, 313900)



ANKRD26 (10p11-12)

May be at risk of leukemia; normal-sized platelets

ITGA2B/ITGB3-related thrombocytopenia (ITGA2B/ITGB3-RT, nd)



ITGA2B (17q21.31), ITGB3(17q21.32)

Large platelets

TUBB1-related thrombocytopenia (TUBB1-RT, nd)



TUBB1 (6p21.3)

Giant platelets

CYCS-related thrombocytopenia (THC4, 612004)



CYCS (7p15.3)

Normal-sized platelets

From: Balduini CL, Savoia A, Seri M. Inherited thrombocytopenias frequently diagnosed in adults. J Thromb Haemost 2013; 11:1006-1019.

AD, Autosomal dominant; AR, autosomal recessive; MDS, myelodysplastic syndrome; nd, not defined; OMIM, Online Mendelian Inheritance in Man; XL, X-linked. Some forms are categorized as both syndromic and non-syndromic. *++++, > 100 families; +++, > 50 families; ++ > 10 families; +, < 10 families.

Lack of adequate bone marrow megakaryocytes (megakaryocytic hypoplasia) is seen in a wide variety of congenital disorders, including Fanconi anemia (pancytopenia), thrombocytopenia with absent radius (TAR) syndrome, Wiskott-Aldrich syndrome, Bernard-Soulier syndrome, May-Hegglin anomaly, and several other less common disorders. Although thrombocytopenia is a feature of Bernard-Soulier syndrome and Wiskott-Aldrich syndrome, the primary abnormality in these disorders is a qualitative defect, and these disorders are discussed in Chapter 41.

May-hegglin anomaly. 

May-Hegglin anomaly is a rare autosomal dominant disorder; the exact frequency is unknown. Large platelets (20 μm in diameter) are present on the peripheral blood film, and Döhle-like bodies are present in neutrophils () and occasionally in monocytes. Other than the increase in size, platelet morphology is normal. Thrombocytopenia is present in about one third to one half of affected patients. Platelet function in response to platelet-activating agents is usually normal. In some patients, megakaryocytes are increased in number and have abnormal ultrastructure. Mutations in the Figure 40-2MYH9 gene that encodes for nonmuscle myosin heavy chain (a cytoskeletal protein in platelets) have been reported.1 This mutation may be responsible for the abnormal size of platelets in this disorder. Most patients are asymptomatic unless severe thrombocytopenia is present, but bleeding times may be prolonged in some patients in the absence of bleeding complications (Table 40-1).


FIGURE 40-2 Döhle body in segmented neutrophil and giant platelets associated with May-Hegglin anomaly (peripheral blood, ×1000). Source: (From Carr JH, Rodak BF: Clinical hematology atlas, ed 4, Philadelphia, 2013, Saunders.)

Three other disorders involving mutations of the MYH9 gene have been reported: Sebastian syndrome, Fechtner syndrome, and Epstein syndrome.2 Sebastian syndrome is inherited as an autosomal dominant disorder characterized by large platelets, thrombocytopenia, and granulocytic inclusions. Similar abnormalities are observed in Fechtner syndrome and are accompanied by deafness, cataracts, and nephritis. In Epstein syndrome, large platelets are associated with deafness, ocular problems, and glomerular nephritis.3 These disorders are discussed in more detail in Chapter 41.

Tar syndrome. 

TAR syndrome is a rare autosomal recessive disorder characterized by severe neonatal thrombocytopenia and congenital absence or extreme hypoplasia of the radial bones of the forearms with absent, short, or malformed ulnae and other orthopedic abnormalities. TAR syndrome is associated with a mutation in the RBM8A gene located on the long arm of chromosome 1 or a 200 Kb deletion involving the RBM8A gene (1q21.1). TAR can result from two deletions of the RBM8A gene, two mutations of the RBM8A gene, or, most commonly, a combination of the two (Table 40-1). In addition to bony abnormalities, patients tend to have cardiac lesions and a high incidence of transient leukemoid reactions with elevated white blood cell (WBC) counts (sometimes with counts above 100,000/μL) in 90% of patients.4 Platelet counts are usually 10,000 to 30,000/μL in infancy. Interestingly, platelet counts usually increase over time, with normal levels often achieved within 1 year of birth.

Fanconi anemia. 

Fanconi anemia is also associated with thrombocytopenia, although other abnormalities are extensive, including bony abnormalities, abnormalities of visceral organs, and pancytopenia. Chapter 22 contains a more detailed description.

Congenital amegakaryocytic thrombocytopenia

Congenital amegakaryocytic thrombocytopenia is an autosomal recessive disorder reflecting bone marrow failure.5 Affected infants usually have platelet counts of fewer than 20,000/μL at birth, petechiae and evidence of bleeding at or shortly after birth, and frequent physical anomalies. About half of the infants develop aplastic anemia in the first year of life, and there are reports of myelodysplasia and leukemia later in childhood. Allogeneic stem cell transplantation is considered curative for infants with clinically severe disease or aplasia.6 This disorder is caused by mutations in the MPL gene on chromosome 1 (1p34), resulting in complete loss of thrombopoietin receptor function (Table 40-1). This loss of function results in reduced megakaryocyte progenitors and high thrombopoietin levels.7

Autosomal dominant thrombocytopenia

Autosomal dominant thrombocytopenia has been mapped to a mutation(s) in the ANKRD26 gene on the short arm of chromosome 10 (10p11-12). Mutations in this gene appear to lead to incomplete megakaryocyte differentiation and the resultant thrombocytopenia. Platelet morphology and size are usually normal. Until recently, autosomal dominant thrombocytopenia was considered a very rare disorder. However, ANKRD26 mutations have recently been found in 21 of 210 thrombocytopenic pedigrees. This indicates that ANKRD26 mutations may be responsible for approximately 10% of inherited thrombocytopenias and is a relatively frequent form of autosomal dominant thrombocytopenia.8 Bleeding in these patients is usually absent or mild, and platelet function is usually normal (Table 40-1).910

X-linked thrombocytopenia

X-linked thrombocytopenia can result from mutations in the WAS (Wiskott-Aldrich syndrome) gene on the X chromosome (Xp11) or mutations in the GATA1 gene, also on the X chromosome at Xp11.11-13 X-linked thrombocytopenias range from mild thrombocytopenia and small platelets and absent or mild bleeding to macrothrombocytopenia with severe bleeding (Table 40-1).

Other inherited thrombocytopenias

In addition to the inherited thrombocytopenias discussed above, there are several others that are due to gene mutations, including HOXA11, ABCG5 and ABCG8, FLNA, RUNX1, ITGA2B, ITGB3, TUBB1, andCYCS(Table 40-1).

Neonatal thrombocytopenia

Neonatal thrombocytopenia (platelet count < 150,000/μL) is present in 1% to 5% of infants at birth. The causes of neonatal thrombocytopenia are numerous as illustrated in . In 75% of cases, the thrombocytopenia is present at or within 72 hours of birth. Only a minority of these patients have immunologic disorders or coagulopathy causing thrombocytopenia. Table 40-2

TABLE 40-2

Classification of Fetal and Neonatal Thrombocytopenias



Congenital infection (e.g., CMV, toxoplasma, rubella, HIV) 

Aneuploidy (e.g., trisomies 18, 13, 21, or triploidy) 

Autoimmune (e.g., ITP, SLE) 

Severe Rh hemolytic disease 

Congenital/inherited (e.g., Wiskott-Aldrich syndrome)

Early onset neonatal (< 72 hours)

Placental insufficiency (e.g., preeclampsia, IUGR, diabetes) 

Perinatal asphyxia 

Perinatal infection (e.g., E. coli, group B streptococcus, Haemophilus influenzae) 



Autoimmune (e.g., ITP, SLE) 

Congenital infection (e.g., CMV, toxoplasma, rubella, HIV) 

Thrombosis (e.g., aortic, renal vein) 

Bone marrow replacement (e.g., congenital leukemia) 

Kasabach-Merritt syndrome 

Metabolic disease (e.g., propionic and methylmalonic acidemia) 

Congenital/inherited (e.g., TAR, CAMT)

Late onset neonatal (> 72 hours)

Late onset sepsis 


Congenital infection (e.g., CMV, toxoplasma, rubella, HIV) 


Kasabach-Merritt syndrome 

Metabolic disease (e.g., propionic and methylmalonic acidemia) 

Congenital/inherited (e.g., TAR, CAMT)

From: Roberts I, Murray NA. Neonatal thrombocytopenia: causes and management. Arch Dis Child Fetal Neonatal Ed 2003; 88:F359-F364.

CAMT, Congenital amegakaryocytic thrombocytopenia; CMV, cytomegalovirus; DIC, disseminated intravascular coagulation; ITP, immune thrombocytopenic purpura; IUGR, intrauterine growth restriction; NEC, necrotizing enterocolitis; SLE, systemic lupus erythematosus; TAR,thrombocytopenia with absent radii.

Causes of neonatal thrombocytopenia include infection with Toxoplasma, rubella, cytomegalovirus (CMV), herpes (TORCH), and human immunodeficiency virus (HIV), and in utero exposure to certain drugs, particularly chlorothiazide diuretics and the oral hypoglycemic tolbutamide and other agents. TORCH infections cause thrombocytopenia with characteristically small platelets. CMV is the most common infectious agent causing congenital thrombocytopenia, with an overall incidence of 0.5% to 1% of all births,14 but only 10% to 15% of infected infants have symptomatic disease,15 which suggests that the incidence of significant neonatal thrombocytopenia caused by CMV is about 1 in 1000 infants. Although the mechanism of thrombocytopenia is not well understood, reports suggest that CMV inhibits megakaryocytes and their precursors, which results in impaired platelet production.16 About 1 in 1000 to 1 in 3000 infants are affected by congenital toxoplasmosis. About 40% of such infants develop thrombocytopenia.17 While persistent thrombocytopenia is a prominent feature in infants with congenital rubella syndrome, it is now rare in countries with organized immunization programs.1819 Thrombocytopenia also is a feature of maternal transmission of HIV to the neonate and is a sign of intermediate to severe disease.20

Maternal ingestion of chlorothiazide diuretics or tolbutamide can have a direct cytotoxic effect on the fetal marrow megakaryocytes. Thrombocytopenia may be severe, with platelet counts of 70,000/μL and sometimes lower. Bone marrow examination reveals a marked decrease or absence of megakaryocytes. The thrombocytopenia develops gradually and is slow to regress when the drug is stopped. Recovery usually occurs within a few weeks after birth.102122

While infectious agents and certain drugs are well-known causes of neonatal thrombocytopenia, the overwhelming cause is impaired production. Most patients are preterm neonates born after pregnancies complicated by placental insufficiency and/or fetal hypoxia (preeclampsia and intrauterine growth restriction). These neonates have early-onset thrombocytopenia and impaired megakaryopoiesis in spite of increased levels of thrombopoietin (Table 40-2).

Increased platelet consumption/sequestration is another mechanism of neonatal thrombocytopenia accounting for approximately 2% to 25% of neonatal thrombocytopenia. Of these, 15% to 20% result from transplacental passage of maternal alloantibodies and autoantibodies (see neonatal alloimmune thrombocytopenia and neonatal autoimmune thrombocytopenia later in this chapter). Another 10% to 15% of cases are due to disseminated intravascular coagulation (DIC), almost always in very ill infants, particularly those with perinatal asphyxia or infections. Other examples include thrombosis, platelet activation, or immobilization at sites of inflammation (e.g., necrotizing enterocolitis). In very sick infants, splenic sequestration may be a contributing factor to thrombocytopenia.

Inherited thrombocytopenic syndromes are increasingly being recognized as causes of neonatal thrombocytopenia (Tables 40-1 and 40-2). Although considered to be rare, they may be more common than once believed.

Acquired (drug-induced) hypoplasia

A wide array of chemotherapeutic agents used for the treatment of hematologic and nonhematologic malignancies suppress bone marrow megakaryocyte production and the production of other hematopoietic cells. Examples include the commonly used agents methotrexate, busulfan, cytosine arabinoside, cyclophosphamide, and cisplatin. The resulting thrombocytopenia may lead to hemorrhage, and the platelet count should be monitored closely. Drug-induced thrombocytopenia is often the dose-limiting factor for many chemotherapeutic agents. Recombinant interleukin-11 has been approved for treatment of chemotherapy-induced thrombocytopenia, and thrombopoietin may prove to be useful for this purpose.23-25 Zidovudine (used for the treatment of HIV infection) is also known to cause myelotoxicity and severe thrombocytopenia.26

Several drugs specifically affect megakaryocytopoiesis without significantly affecting other marrow elements. Anagrelide is one such agent, although its mechanism of action is unknown. This characteristic has made anagrelide useful for treating the thrombocytosis of patients with essential thrombocythemia and other myeloproliferative disorders.27

Ingestion of ethanol for long periods (months to years) may result in persistent severe thrombocytopenia. Although the mechanism is unknown, studies indicate that alcohol can inhibit megakaryocytopoiesis in some individuals. Mild thrombocytopenia is a common finding in alcoholic patients, but other causes unrelated to ethanol use, such as portal hypertension, splenomegaly, and folic acid deficiency, should be excluded. The platelet count usually returns to normal within a few weeks of alcohol withdrawal, but thrombocytopenia may persist for longer periods. A transient rebound thrombocytosis may develop when alcohol ingestion is stopped.10

Interferon therapy commonly causes mild to moderate thrombocytopenia, although under certain circumstances, the thrombocytopenia can be severe and life-threatening. Interferon-α and interferon-γ inhibit stem cell differentiation and proliferation in the bone marrow, but the mechanism of action is unclear.28

Thrombocytopenia presumably caused by megakaryocyte suppression also has been reported to follow the administration of large doses of estrogen or estrogenic drugs such as diethylstilbestrol. Other drugs, such as certain antibacterial agents (e.g., chloramphenicol), tranquilizers, and anticonvulsants, also have been associated with thrombocytopenia caused by bone marrow suppression.29-31

Ineffective thrombopoiesis

Thrombocytopenia is a usual feature of the megaloblastic anemias (pernicious anemia, folic acid deficiency, and vitamin B12 deficiency). Quantitative studies indicate that, as with erythrocyte production in these disorders, platelet production is ineffective. Although the bone marrow generally contains an increase in the number of megakaryocytes, the total number of platelets released into the circulation is decreased. Thrombocytopenia is caused by impaired DNA synthesis, and the bone marrow may contain grossly abnormal megakaryocytes with deformed, dumbbell-shaped nuclei, sometimes in large numbers. Stained peripheral blood films reveal large platelets that may have a decreased survival time and may have abnormal function. Thrombocytopenia is usually mild, and there is evidence of increased platelet destruction. Patients typically respond within 1 to 2 weeks to vitamin replacement.2232-34

Miscellaneous conditions

Viruses are known to cause thrombocytopenia by acting on megakaryocytes or circulating platelets, either directly or in the form of viral antigen-antibody complexes. Live measles vaccine can cause degenerative vacuolization of megakaryocytes 6 to 8 days after vaccination. Some viruses interact readily with platelets by means of specific platelet receptors. Other viruses associated with thrombocytopenia include CMV, varicella-zoster virus, rubella virus, Epstein-Barr virus (which causes infectious mononucleosis), and the virus that causes Thai hemorrhagic fever.10

Certain bacterial infections commonly are associated with the development of thrombocytopenia. This may be the result of toxins of bacterial origin, direct interactions between bacteria and platelets in the circulation, or extensive damage to the endothelium, as in meningococcemia. Many cases of thrombocytopenia in childhood result from infection. Purpura may occur in many infectious diseases in the absence of thrombocytopenia, presumably because of vascular damage (Chapter 41).1035

A common cause of unexplained thrombocytopenia is infiltration of the bone marrow by malignant cells with a progressive decrease in marrow megakaryocytes as the abnormal cells replace normal marrow elements. Inhibitors of thrombopoiesis may be produced by these abnormal cells and may help to account for the thrombocytopenia associated with conditions such as myeloma, lymphoma, metastatic cancer, and myelofibrosis.223236

Increased platelet destruction

Thrombocytopenia as a result of increased platelet destruction can be separated into two categories: increased platelet destruction caused by immunologic responses and increased destruction caused by mechanical damage or consumption or both. Regardless of the process, increased production is required to maintain a normal platelet count, and the patient becomes thrombocytopenic only when production capacity is no longer adequate to compensate for the increased rate of destruction.

Immune mechanisms of platelet destruction

Immune (idiopathic) thrombocytopenic purpura: Acute and chronic. 

The term idiopathic thrombocytopenic purpura (ITP) was used previously to describe cases of thrombocytopenia arising without apparent cause or underlying disease state. Although the acronym for the disorder remains the same, the word idiopathic has been replaced by immune because of the realization that acute and chronic ITP are immunologically mediated.

Acute ITP. 

This is primarily a disorder of children, although a similar condition is seen occasionally in adults. The disorder is characterized by the abrupt onset of bruising, petechiae, and sometimes mucosal bleeding (e.g., epistaxis) in a previously healthy child. The primary hematologic feature is thrombocytopenia, which frequently occurs 1 to 3 weeks after an infection.

The infection is most often a nonspecific upper respiratory tract or gastrointestinal tract viral infection, but acute ITP also may occur after rubella, rubeola, chickenpox, or other viral illnesses and may follow live virus vaccination.37 The incidence of acute ITP is estimated to be 4 in 100,000 children, with a peak frequency in children between 2 and 5 years of age. There is no sex predilection. In about 10% to 15% of the children initially thought to have acute ITP, the thrombocytopenia persists for 6 months or longer, and these children are reclassified as having chronic ITP.38 The observation that acute ITP often follows a viral illness suggests that some children produce antibodies and immune complexes against viral antigens and that platelet destruction may result from the binding of these antibodies or immune complexes to the platelet surface.

The diagnosis of acute ITP in a child with severe thrombocytopenia almost always can be made without a bone marrow examination. If the child has recent onset of bleeding signs and symptoms, otherwise normal results on complete blood count (for all red and white blood cell parameters and cell morphology), and normal findings on physical examination (except for signs of bleeding), there is a high likelihood that the child has ITP. In addition, if the bleeding symptoms develop suddenly and there is no family history of hemorrhagic abnormalities or thrombocytopenia, the diagnosis of ITP is almost certain. There is, at present, no specific test that is diagnostic of acute or chronic ITP.

In mild cases of acute ITP, patients may have only scattered petechiae. In most cases of acute ITP, however, patients develop fairly extensive petechiae and some ecchymoses and may have hematuria or epistaxis or both. About 3% to 4% of acute ITP cases are considered severe, and typically generalized purpura is present, often accompanied by gastrointestinal bleeding, hematuria, mucous membrane bleeding, and retinal hemorrhage. Of patients with severe disease, 25% to 50% are considered to be at risk for intracranial hemorrhage, which is the primary complication that contributes to the overall 1% to 2% mortality rate for patients with acute ITP.38 Most patients with life-threatening hemorrhage have a platelet count of less than 4000/μL.39 Hemorrhage is rarely experienced by patients whose platelet count exceeds 10,000/μL.

Most patients with acute ITP recover with or without treatment in about 3 weeks, although for some, recovery may take 6 months. In a few children, recurrent episodes of acute ITP are occasionally seen after complete recovery from the first episode.40 Most patients with acute ITP have relatively mild symptoms, and no treatment is needed. The most severe cases may need to be treated, however, and intravenous immunoglobulin (IVIG), platelet transfusions, and splenectomy (or some combination of these) seem to offer the most immediate benefit.3738

Chronic ITP. 

This disorder can be found in patients of any age, although most cases occur in patients between the ages of 20 and 50 years. Females with this disorder outnumber males 2:1 to 3:1, with the highest incidence in women between 20 and 40 years of age. The incidence of chronic ITP ranges from 3.2 to 6.6 cases per 100,000 per year.41 Chronic ITP usually begins insidiously, with platelet counts that are variably decreased and sometimes normal for periods of time. Presenting symptoms are those of mucocutaneous bleeding, with menorrhagia, recurrent epistaxis, and easy bruising (ecchymoses) being most common.

Platelet destruction in chronic ITP is the result of an immunologic process. The offending antibodies attach to platelets, and as a result, the antibody-labeled platelets are removed from the circulation by reticuloendothelial cells, primarily in the spleen. Autoantibodies that recognize platelet surface glycoproteins such as glycoprotein IIb (GP IIb) and GP IIIa (αIIb/β3), GP Ia/IIa, and others can be demonstrated in 50% to 60% of ITP patients.4243 Because megakaryocytes also express GP IIb/IIIa and GP Ib/IX on their membranes, these cells are obvious targets of the antibodies. Platelet turnover studies have shown impaired platelet production in ITP. Overall, the life span of the platelet is shortened from the normal 7 to 10 days to a few hours, and the rapidity with which platelets are removed from the circulation correlates with the degree of thrombocytopenia. If plasma from a patient with ITP is infused into the circulation of a normal recipient, the recipient develops thrombocytopenia. The thrombocytopenia-producing factor in the plasma of the ITP patient is an immunoglobulin G (IgG) antibody that can be removed from serum by adsorption with normal human platelets. In addition, cytotoxic T cell-mediated lysis of platelets has been shown in vitro using CD3+CD8+ lymphocytes from patients with active chronic ITP, although the in vivo significance of this mechanism is not known.44

The only abnormalities in the peripheral blood of patients with ITP are related to platelets. In most cases, platelets number between 30,000/μL and 80,000/μL. Patients with ITP undergo periods of remission and exacerbation, however, and their platelet counts may range from near normal to fewer than 20,000/μL during these periods (). Morphologically, platelets appear normal, although larger in diameter than usual. This is reflected in an increased mean platelet volume as measured by electronic cell counters. The marrow typically is characterized by megakaryocytic hyperplasia. Megakaryocytes are increased in size, and young forms with a single nucleus, smooth contour, and diminished cytoplasm are commonly seen. In the absence of bleeding, infection, or other underlying disorder, erythrocyte and leukocyte precursors are normal in number and morphology. Coagulation tests showing abnormal results include tests dependent on platelet function. Although platelet-associated IgG levels are increased in most patients,Figure 40-31021,45 it has not been shown conclusively that any method of testing for platelet antibodies is sensitive or specific for ITP.


FIGURE 40-3 Typical peripheral blood cell morphology in immune thrombocytopenic purpura. Note scarce platelets and increased platelet size but normal red blood cell and leukocyte morphology (peripheral blood, ×500).

The initial treatment of chronic ITP depends on the urgency for increasing the platelet count. In ITP patients with platelet counts greater than 30,000/μL who receive no treatment, the expected mortality rate is equal to that of the general population. Unless there are additional risk factors, ITP patients with platelet counts greater than 30,000/μL should not be treated. If additional risk factors are present, such as old age, coagulation defects, recent surgery, trauma, or uncontrolled hypertension, the platelet count should be kept at 50,000/μL or higher, depending on the clinical situation. In patients in whom the need is considered urgent, IVIG remains the treatment of choice. For most patients, however, the initial treatment of chronic ITP consists principally of prednisone. About 70% to 90% of patients respond to this therapy, with an increase in platelet count and a decrease in hemorrhagic episodes. Although reported response rates vary widely, about 50% of patients have a long-term beneficial effect from corticosteroid treatment.46 If the response to corticosteroids is inadequate or no response is seen, steroid therapy can be supplemented with IVIG or, in some cases, anti-D immunoglobulin.47 For patients in whom prednisone is ineffective, intravenous rituximab should be tried. Responses to rituximab are usually seen within 3 to 4 weeks. In some patients splenectomy may become necessary. Splenectomy eliminates the primary site of platelet removal and destruction, but it also removes an organ containing autoantibody-producing lymphocytes. Splenectomy is an effective treatment for adult chronic ITP, with 88% of patients showing improvement and 66% having a complete and lasting response.48 Vaccination with pneumococcal, meningococcal, and Haemophilus influenzae vaccines should be performed at least 2 weeks prior to surgery. The use of laparoscopic surgery speeds recovery and shortens hospitalization and is generally preferred to open splenectomy. In the most severe refractory cases, immunosuppressive (chemotherapeutic) agents such as azathioprine given alone or with steroids may be necessary. In such patients, platelet transfusions may be of transient benefit in treating severe hemorrhagic episodes but should not be given routinely.45 IVIG given alone or just before platelet transfusion also may be beneficial.3745

Chronic ITP occurring in association with HIV infection, with hemophilia, or with pregnancy presents special problems in diagnosis and therapy. Unexplained thrombocytopenia in otherwise healthy members of high-risk populations may be an early manifestation of acquired immune deficiency syndrome (AIDS).3645

Differentiation of acute versus chronic immune thrombocytopenic purpura. 

The differences between acute and chronic ITP are summarized in . Acute ITP occurs most frequently in children 2 to 9 years of age and in young adults, whereas chronic ITP occurs in patients of all ages, although most frequently in adults aged 20 to 50 years, and more commonly in women. Of patients with acute ITP, 60% to 80% have a history of infection, usually viral (rubella, rubeola, chickenpox, and nonspecific respiratory tract infection), occurring 2 to 21 days before ITP onset. Acute ITP also may occur after immunization with live vaccine for measles, chickenpox, mumps, and smallpox. Table 40-3

TABLE 40-3

Clinical Picture of Acute and Chronic Immune Thrombocytopenic Purpura




Age at onset

2–6 yr

20–50 yr

Sex predilection


Female over male, 3:1

Prior infection



Onset of bleeding



Platelet count

< 20,000/μL



2–6 wk

Months to years

Spontaneous remission

90% of patients


Seasonal pattern

Higher incidence in winter and spring





70% response rate

30% response rate


Rarely required

< 45 yr, 90% response rate 

> 45 yr, 40% response rate

From Triplett DA, editor: Platelet function: laboratory evaluation and clinical application, Chicago, 1978, American Society of Clinical Pathologists; Quick AJ: Hemorrhagic diseases and thrombosis, ed 2, Philadelphia, 1966, Lea & Febiger; and Bussel J, Cines D: Immune thrombocytopenia, neonatal alloimmune thrombocytopenia, and post-transfusion purpura. In Hoffman R, Benz EJ Jr, Shattil SJ, et al, editors: Hematology: basic principles and practice, ed 3, New York, 2000, Churchill Livingstone, pp 2096-2114.

Acute ITP usually is self-limited, and spontaneous remissions occur in 80% to 90% of patients, although the duration of the illness may range from days to months. In chronic ITP, there is typically a fluctuating clinical course, with episodes of bleeding that last a few days or weeks, but spontaneous remissions are uncommon and usually incomplete.45

Symptoms of acute ITP vary, but petechial hemorrhages, purpura, and often bleeding from the gums and gastrointestinal or urinary tract typically begin suddenly, sometimes over a few hours. Hemorrhagic bullae in the oral mucosa are often prominent in patients with severe thrombocytopenia of acute onset. Usually the severity of bleeding is correlated with the degree of thrombocytopenia.45 In contrast, presenting symptoms of chronic ITP begin with a few scattered petechiae or other minor bleeding manifestations. Occasionally, a bruising tendency, menorrhagia, or recurrent epistaxis is present for months or years before diagnosis. Platelet counts range from 5000/μL to 75,000/μL and are generally higher than those in acute ITP. Giant platelets are commonly seen. Platelet-associated immunoglobulin levels are elevated in most patients, but the test lacks sensitivity and specificity.45

Treatment also varies for acute and chronic ITP. In chronic ITP, initial therapy often consists of glucocorticoids (corticosteroids), which interfere with splenic and hepatic macrophages to increase platelet survival time. If the ITP does not respond to corticosteroids or the patient cannot tolerate them because of the resultant immunosuppression and toxicity, splenectomy may be necessary. In acute ITP, treatment for all but the most severely thrombocytopenic and hemorrhagic patients is contraindicated. When treatment is necessary, a good response to IVIG or corticosteroids or both usually can be obtained, and splenectomy is rarely required.3738

Immunologic drug-induced thrombocytopenia. 

As can be seen from , many drugs can induce acute thrombocytopenia. Drug-induced immune-mediated thrombocytopenia can be divided into several types based on the interaction of the antibody with the drug and platelets. Mechanisms of drug-antibody binding are shown in Box 40-2Figure 40-4.


FIGURE 40-4 Immunoglobulin binds a platelet membrane antigen or antigen and drug combination. Macrophage Fc receptors bind the Fc portion of the immunoglobulin. This may result in platelet removal and thrombocytopenia. IgG, immunoglobulin G. Source: (From Rapaport SI: Introduction to hematology, ed 2, Philadelphia, 1987, JB Lippincott, p. 489.)

BOX 40-2

Common Drugs Causing Immune Thrombocytopenia









Aminosalicylic acid



Various sulfa drugs (chlorthalidone, furosemide)




Sedatives, anticonvulsants








Oral hypoglycemics



Heavy metals




Organic arsenicals





From Triplett DA, editor: Platelet function: laboratory evaluation and clinical application, Chicago, 1978, American Society of Clinical Pathologists; and Quick AJ: Hemorrhagic diseases and thrombosis, ed 2, Philadelphia, 1966, Lea & Febiger.

Drug-dependent antibodies. 

One mechanism of drug-dependent antibodies is typified by quinidine- and quinine-induced thrombocytopenia and has been recognized for more than 100 years. The antibody induced by drugs of this type interacts with platelets only in the presence of the drug. Drug-dependent antibodies typically occur after 1 to 2 weeks of exposure to a new drug. Many drugs can induce such antibodies, but quinine, quinidine, and sulfonamide derivatives do so more often than other drugs. When antibody production has begun, the platelet count falls rapidly and often may be fewer than 10,000/μL. Patients may have abrupt onset of bleeding symptoms. If this type of drug-induced thrombocytopenia develops in a pregnant woman, both she and her fetus may be affected. Quinine previously was used to facilitate labor but is no longer used for this purpose.

The initial studies of quinidine-induced thrombocytopenia suggested that the drug first combines with the antibody and that the antigen-antibody (immune) complex then attaches to the platelet in an essentially nonspecific manner (the “innocent bystander” hypothesis). It now seems clear, however, that the antibodies responsible for drug-induced thrombocytopenia bind to the platelets by their Fab regions, rather than by attaching nonspecifically as immune complexes. The innocent bystander/immune complex explanation for this type of drug-induced thrombocytopenia should be abandoned. The Fab portion of the antibody binds to a platelet membrane constituent, usually the GP Ib/IX/V complex or the GP IIb/IIIa complex, only in the presence of drug.4950 The mechanism by which the drug promotes binding of a drug-dependent antibody to a specific target on the platelet membrane without covalently linking to the target or the antibody remains to be determined, however. Because the Fc portion of the immunoglobulin is not involved in binding to platelets, it is still available to the Fc receptors on phagocytic cells. This situation may contribute to the rapid onset and relatively severe nature of the thrombocytopenia. Most drug-induced platelet antibodies are of the IgG class, but in rare instances, IgM antibodies are involved.45

A similar pattern is seen with the antiplatelet/antithrombotic agents abciximab, tirofiban, and eptifibatide, although with these drugs thrombocytopenia tends to occur within several hours of exposure. Such immediate reactions are due to naturally occurring antibodies to the murine structural elements of abciximab (a mouse/human monoclonal antibody fragment) or to structural changes induced by binding of eptifibatide or tirofiban to platelet GP IIb/IIIa.

Hapten-induced antibodies. 

A second mechanism of drug-induced thrombocytopenia is induction of hapten-dependent antibodies. Some drug molecules are too small by themselves to trigger an immune response, but they may act as a hapten and combine with a larger carrier molecule (usually a plasma protein or protein constituent of the platelet membrane) to form a complex that can act as a complete antigen.45 Penicillin and penicillin derivatives are the primary offending agents causing drug-induced thrombocytopenia by this mechanism. Drug-induced thrombocytopenia of this type is often severe. The initial platelet count may be fewer than 10,000/μL and sometimes fewer than 1000/μL. The number of bone marrow megakaryocytes is usually normal to elevated.45 Bleeding is often severe and rapid in onset, and hemorrhagic bullae in the mouth may be prominent.

Drug-induced autoantibodies. 

Drug-induced autoantibodies represent a third mechanism of drug-induced thrombocytopenia. In this case, the drugs stimulate the formation of an autoantibody that binds to a specific platelet membrane glycoprotein with no requirement for the presence of free drug. Gold salts and procainamide are two examples of such drugs. Levodopa also may cause thrombocytopenia in the same way. The precise mechanism by which these drugs induce autoantibodies against platelets is not known with certainty.

Treatment for any drug-induced thrombocytopenia is first to identify the offending drug, immediately discontinue its use, and substitute another suitable therapeutic agent. This is often difficult to accomplish. Many patients are taking multiple drugs, and it is not always easy to determine which of the drugs is at fault for causing thrombocytopenia. Under these conditions, identifying the causative agent may be a trial-and-error procedure in which the most likely drugs are eliminated one at a time. In addition, even if the patient is taking only one agent, there may not be a suitable replacement, or a prolonged period may be required for the alternative drug to become effective. Drugs usually are cleared from the circulation rapidly, but dissociation of drug-antibody complexes may require longer periods, perhaps 1 to 2 weeks.10 In some cases, such as those caused by gold salts, thrombocytopenia may persist for months. Platelet transfusions may be necessary for patients with life-threatening bleeds. Although it is true that the transfused platelets are destroyed rapidly, they may function to halt bleeding effectively before they are destroyed. In addition, high-dose IVIG may be used and is generally an effective treatment for most drug-induced immune thrombocytopenias. Laboratory testing to identify the specific drug involved is usually beyond the capabilities of most laboratories. This type of testing is performed by many reference laboratories, however.

Immune complex–induced thrombocytopenia. 

Heparin-induced thrombocytopenia (HIT) is a good example of another type of drug-induced thrombocytopenia. Heparin binds to platelet factor 4 (PF4), a heparin-neutralizing protein made and released by platelets (Figure 40-5). Binding of heparin by plasma PF4 or platelet membrane–expressed PF4 causes a conformational change in PF4, resulting in the exposure of neoepitopes. Exposure of these neoepitopes (“new antigens”) stimulates the immune system of some individuals, which leads to the production of an antibody to one of the neoepitopes. In HIT, heparin and PF4 form a complex on the platelet surface or circulating free complexes to which the antibody binds. The Fab portion of the immunoglobulin molecule binds to an exposed neoepitope in the PF4 molecule; this leaves the Fc portion of the IgG free to bind with the platelet FcγIIa receptor, which causes platelet activation.5152 Because the Fc portions of the IgG molecules bind to platelet FcγIIa receptor, they are not available to the Fc receptors of the cells of the reticuloendothelial system. This may explain the less severe decline in platelet count in this thrombocytopenia. That does not mean, however, that the consequences are less serious. The opposite may be true. Because platelets are activated by occupancy of their FcγIIa receptor, in vivo platelet aggregation with thrombosis is possible. HIT sometimes is referred to as heparin-induced thrombocytopenia and thrombosis(Chapter 39)Heparin binding to PF4 is required to expose the neoepitope to which the antibody binds. The treatment for HIT is to discontinue heparin administration and replace it with another suitable anticoagulant. Low-molecular-weight heparin should not be used as a heparin replacement for this purpose, because the antibody cross-reacts with low-molecular-weight heparin and PF4 to result in platelet activation and aggregation.53


FIGURE 40-5 Heparin-induced thrombocytopenia with thrombosis. An antibody (Ab) binds the heparin–platelet factor 4 (PF4) complex in plasma or on the platelet surface. The Fc portion binds platelet Fc receptors and activates the platelet. The activated platelets aggregate to form platelet thrombi in the arterial circulation. Thrombi can also occur in the venous system.

Heparin-induced thrombocytopenia. 

HIT is a relatively common side effect of unfractionated heparin administration, with about 1% to 5% of patients developing this complication. Despite the thrombocytopenia, patients with HIT usually are not at significant risk of bleeding, because the platelet count typically does not fall below 40,000/μL. Ten percent to 30% of patients with HIT develop thrombotic complications, however. In patients who develop HIT, heparin therapy should be stopped as soon as the diagnosis is made, because continued heparin therapy can lead to significant morbidity and mortality, including gangrene of the extremities, amputation, and death. After discontinuation of heparin, the platelet count begins to increase and should return to normal within a few days.54

Because the immune system is involved in the development of HIT, the clinical signs of HIT typically are not seen until 7 to 14 days after the initiation of heparin therapy (the time necessary to mount an immune response on first exposure to an antigen). If the patient has been exposed to heparin previously, however, symptoms of HIT may be seen in 1 to 3 days. Because the platelet count may fall sharply in 1 day, it is recommended that platelet counts be measured daily in patients receiving unfractionated heparin therapy (). Table 40-4

TABLE 40-4

Laboratory Tests for Heparin-Induced Thrombocytopenia

Laboratory Test


Platelet count

A > 30% decrease from baseline may signal HIT, even if still within the reference interval.

Antigen Tests



Stago H:PF4* 

Hyphen BioMed 

Rapid tests (point-of-care): 

Akers PIFA* 

DiaMed Pa-GIA 

Coagulation instrument based tests:

Milenia Biotec LFI-HIT 

HemosIL HIT-Ab

Use with a clinical scoring system (Table 39-17). Can be used as a first lab test to screen for the presence of HIT antibodies; due to high frequency of false positive results, functional tests should be performed to confirm a positive antigen test. False negative results can also occur.

Functional Tests

Platelet Aggregation HIPA 

Lumi-Aggregation HIPA 

Serotonin Release Assay

Important to perform functional testing that detects platelet activation by HIT antibodies to confirm a diagnosis of HIT; sensitivities and specificities differ among tests with the SRA (washed platelet assay) being the most sensitive. 

Require skill and experience of the operator to obtain quality results.

* FDA-cleared.

HIPA, Heparin-induced platelet aggregation.

One other sign of impending HIT in some patients is the development of heparin resistance. This is the clinical situation in which a patient who had experienced adequate anticoagulation at a certain heparin dosage suddenly requires increasing amounts of heparin to maintain the same level of anticoagulation. This situation can result from in vivo activation of platelets and release of PF4 and β-thromboglobulin from platelet α-granules. Both of these substances neutralize heparin, which leads to a normalization of results on the partial thromboplastin time test that is used to monitor heparin therapy. Heparin resistance often is seen before the development of thrombocytopenia.55

A common benign form of HIT that occurs on heparin administration is type I (non–immune mediated) HIT. It is important to distinguish benign type I from type II HIT. Type I HIT is associated with a rapid decrease in the platelet count after administration of heparin, but the thrombocytopenia is mild (the platelet count rarely decreases to fewer than 100,000/μL) and transient, and the platelet count returns rapidly to the preheparin level even if heparin therapy is continued. Careful attention should be paid to the platelet count and other signs of HIT so that this form of thrombocytopenia is not confused with the clinically significant type II HIT. Although the mechanism of type I HIT has not been completely described, it may be related to the well-documented proaggregatory effects of heparin.5356 Because activated or aggregated platelets are cleared from the circulation, these effects may explain the mild decrease in the platelet count that occurs during the first few days of heparin administration. This has not been clearly documented, however.

The binding of heparin and related compounds depends on polysaccharide chain length, composition, and degree of sulfation. Short-chain heparin polysaccharides (low-molecular-weight heparin) have lower affinity to PF4 and are less prone to cause type II HIT. Pentasaccharide and its synthetic derivatives (e.g., fondaparinux) do not seem to bind PF4 and are unlikely to cause type II HIT.

The detection of clinically significant HIT occurs by laboratory testing using immunoassays and platelet function tests (Table 40-4 and Chapter 42). Laboratory testing, however, is problematic because all tests lack sensitivity. Three methods are commonly used, but all depend on the presence of free heparin–induced antiplatelet antibodies in the patient’s serum or plasma in sufficient quantity to cause a positive test result. HIT can be detected by a platelet aggregation technique.57 In this method, serum from the patient is added to platelet-rich plasma from normal donors, heparin is added to the mixture, and platelet aggregation is typically monitored for 20 minutes. The specificity of the method is excellent (near 100%), but the sensitivity is quite low (about 50%). The sensitivity of the test can be improved, but this requires the use of several heparin concentrations and platelet-rich plasma from two or more blood donors, preferably of the same ABO blood type as the patient. In addition, the individuals donating blood for platelet-rich plasma must not have taken aspirin for 10 to 14 days before platelet donation because platelets from donors who have ingested aspirin produce a false-negative result for HIT.53 In the author’s experience, patients who develop HIT while receiving aspirin therapy rarely develop thrombotic complications, and the drop in their platelet counts is less precipitous, gradually decreasing over the course of several days(unpublished observations). Given the efficacy of aspirin therapy in primary and secondary prevention of myocardial infarction and thrombotic stroke, it is increasingly difficult to find a sufficient pool of suitable (and willing) blood donors. Although the platelet aggregation procedure is time consuming, reasonable sensitivity can be obtained with sufficient attention to the details of the technique.27

Dense granules of platelets contain serotonin, and platelets have an active mechanism for rapid uptake and storage of serotonin in dense granules. This property of platelets is used in another test for HIT, theserotonin release assay (SRA), in which washed normal platelets from a donor are incubated with radioactive serotonin (Figure 40-6).58 Radioactive serotonin is taken up rapidly and stored in the dense granules of the donor platelets, which are washed and resuspended. In the presence of heparin-dependent antiplatelet antibody and heparin, the donor platelets become activated and release the contents of their dense granules when the concentration of heparin in the test suspension is near the therapeutic range. The reappearance of radioactive serotonin in the plasma indicates the presence of a heparin-dependent antiplatelet antibody (i.e., HIT). Under these same conditions, supratherapeutic concentrations of heparin do not activate platelets, however, and if platelets release the contents of dense granules at both therapeutic and supratherapeutic concentrations of heparin, the test result is not positive for HIT. A similar phenomenon is observed in the test that uses platelet aggregometry.5359 The SRA is considered the gold standard for detection of HIT. Its major drawback is the requirement for radiolabeled serotonin. Most clinical laboratories no longer use isotopic techniques. As a result, this test is performed only in a few specialized centers. In addition, it has some of the same methodologic drawbacks as the platelet aggregation technique, in particular the need for platelets from drug-free donors. Nonetheless, when properly performed, this technique has similar specificity and superior sensitivity compared with the platelet aggregation method.


FIGURE 40-6 The serotonin release assay (SRA) for heparin-induced thrombocytopenia (HIT). Donor platelets in platelet-rich plasma (PRP) are labeled with tritiated (3H) serotonin, washed, and suspended in a buffer to which patient plasma is added. Heparin in therapeutic and saturating doses is added to two aliquots. Release of radioactive serotonin in the therapeutic aliquot in combination with no release in the supratherapeutic system indicates HIT.

More recently, enzyme-linked immunosorbent assays (ELISAs) have been developed based on the knowledge that the antigenic target of the heparin-dependent antiplatelet antibody is a PF4-heparin complex (Figure 40-7). In this assay, PF4 and heparin (or a related compound) are coated to the surfaces of microplate wells. The serum or plasma from the patient suspected to have HIT is added to wells of the microtiter plate. If the antibody is present, it adheres to the PF4-heparin (or heparin-like compound) complex. The plate wells are washed, and enzyme-labeled monoclonal antibodies against human IgG and IgM are added. After an appropriate incubation period, the plate is washed, and a chromogenic substrate for the enzyme is added. Color development in the assay well indicates the presence of the heparin-dependent antiplatelet antibody in the patient specimen.60 This assay has greater sensitivity than the platelet aggregation method and similar sensitivity to the SRA, but it has lower specificity than the serotonin release assay or the platelet aggregation method. Unlike the functional HIT assays (SRA and platelet aggregation), the ELISA can detect anti–PF4-heparin antibodies that are not pathologic; that is, the test result is positive, but the patient does not have clinical HIT. Some ELISA assays can detect both IgG and IgM antibodies to heparin-PF4 complexes. More recently, ELISA kits that detect only IgG antibodies have been developed and have a better correlation with the SRA. The ELISA method is considerably less labor intensive, does not require blood from healthy drug-free donors, and can be performed in most laboratories.


FIGURE 40-7 Enzyme immunoassay for heparin-induced thrombocytopenia (HIT). The solid-phase target antigen is a complex of platelet factor 4 (PF4) and heparin or a heparin surrogate. Anti–heparin-PF4 antibody in patient serum binds the antigen and is bound by enzyme-labeled anti–human antibody (Ab), a “sandwich” assay. The enzyme catalyzes the release of a chromophore from its substrate.

For patients who develop type II HIT, it is essential that heparin therapy be withdrawn immediately. It is not prudent, however, to discontinue administration of an anticoagulant/antithrombotic without substituting a suitable alternative. It is clear from the literature that under these circumstances, withdrawal of heparin treatment without replacement anticoagulant therapy results in an unacceptably high rate of thrombotic events. In the recent past, good alternatives for heparin were not available. Today, several alternative agents are suitable substitutes (although considerably more expensive), including direct thrombin inhibitors such as the intravenous use of argatroban and bivalirudin (Angiomax) (Chapter 43). Fondaparinux (Arixtra) is a synthetic heparin pentasaccharide, identical in chemical structure to the antithrombin binding sequence in heparin and heparin-derived agents such as low-molecular-weight heparins. Fondaparinux is given subcutaneously, and while its use in patients with HIT is “off-label” (not FDA approved), it is gaining favor in the clinical community as a second-line agent for the management of suspected HIT to avoid progression into acute HIT.

Neonatal alloimmune thrombocytopenia. 

Neonatal alloimmune thrombocytopenia (NAIT) develops when the mother lacks a platelet-specific antigen (usually human platelet antigen 1a, or HPA-1a [P1A1]) that the fetus has inherited from the father. HPA-1a is the most often involved (80% of cases), and HPA-5b accounts for another 10% to 15% of cases. Fetal platelet antigens may pass from the fetal to the maternal circulation as early as the fourteenth week of gestation.61 If the mother is exposed to a fetal antigen she lacks, she may make antibodies to that fetal antigen. These antibodies cross the placenta, attach to the antigen-bearing fetal platelets, and result in thrombocytopenia in the fetus. In this regard, the pathophysiology of NAIT is the same as that of hemolytic disease of the newborn.

The most frequent cause of NAIT in whites is the HPA-1a antigen expressed on GP IIIa of the surface membrane GP IIb/IIIa complex, followed by HPA-5b (Bra). The antigen HPA-3a (Baka) is present on GP IIb and is an important cause of neonatal thrombocytopenia in Asians. Platelet antigen HPA-4 (Penn and Yuk) accounts for the disorder in a few affected neonates.

Clinically significant thrombocytopenia develops in an estimated 1 in 1000 to 2000 newborns.62 With the first pregnancy, about 50% of neonates born to mothers lacking a specific platelet antigen are affected, whereas with subsequent pregnancies the risk is 75% to 97%.62 The incidence of intracranial hemorrhage or death or both in affected offspring is about 25%, and about half of the intracranial hemorrhages occur in utero in the second trimester.

Affected infants may appear normal at birth but soon manifest scattered petechiae and purpuric hemorrhages. In many infants with NAIT, serious hemorrhage does not develop, however, and the infants recover over a 1- to 2-week period as the level of passively transferred antibody decreases.1038 In symptomatic cases, platelet levels are usually below 30,000/μL and may diminish even further in the first few hours after birth.

The diagnosis of NAIT is one of exclusion of other causes of neonatal thrombocytopenia, including maternal ITP and maternal ingestion of drugs known to be associated with drug-induced thrombocytopenia. The presence of thrombocytopenia in a neonate with a HPA-1a–negative mother or a history of the disorder in a sibling is strong presumptive evidence in favor of the diagnosis. Confirmation should include platelet typing of both parents and testing for evidence of a maternal antibody directed at paternal platelets.37

In situations in which suspicion of NAIT is high or there is a history of NAIT in a first pregnancy, it may be necessary to test or treat the fetus to prevent intracranial hemorrhage in utero. Fetal genotypes now can be determined at 10 to 18 weeks of gestation using polymerase chain reaction methods on cells obtained by chorionic villus sampling or amniocentesis.63 Periumbilical sampling to determine the fetal platelet count can be performed at about 20 weeks of gestation. When the fetus is thrombocytopenic, weekly maternal infusions of IVIG have been shown to be effective in increasing the fetal platelet count in most cases.64 In cases in which the fetal platelet count does not increase with IVIG therapy, washed maternal platelets have been infused into the fetus with good results.65 Treatment of the mother with high-dose corticosteroids (to decrease maternal antibody production) is not recommended because of potential fetal toxicity. In situations in which the diagnosis of NAIT is known or highly suspected, delivery should be by cesarean section to avoid fetal trauma associated with vaginal delivery. After delivery, the affected infant may be treated with transfusion of the appropriate antigen-negative platelets (usually maternal). In addition, IVIG can be used alone or in combination with platelet transfusion. IVIG should not be used as the sole treatment in a bleeding infant, because response to this therapy usually takes 1 to 3 days.62

Neonatal autoimmune thrombocytopenia. 

The diagnosis of ITP or systemic lupus erythematosus in the mother is a prerequisite for the diagnosis of neonatal autoimmune thrombocytopenia. Neonatal autoimmune thrombocytopenia is due to passive transplacental transfer of antibodies from a mother with ITP or, occasionally, systemic lupus erythematosus. The neonate does not have an ongoing autoimmune process per se, but rather is an incidental target of the mother’s autoimmune process. During pregnancy, relapse is relatively common for women with ITP in complete or partial remission; this has been attributed to the facilitation of reticuloendothelial phagocytosis by the high estrogen levels in pregnant women. Women commonly develop chronic ITP during pregnancy. ITP in the mother tends to remit after delivery. Corticosteroids are the primary treatment for pregnant women with ITP, and at the dosages used, there is a relatively low incidence of adverse fetal side effects.66 Neonatal autoimmune thrombocytopenia develops in only about 10% of the infants of pregnant women with autoimmune thrombocytopenia, and intracranial hemorrhage occurs in 1% or less. It is no longer recommended that high-risk infants be delivered by cesarean section to avoid the trauma of vaginal delivery and accompanying risk of hemorrhage in the infant, regardless of maternal platelet count.67

Affected newborns may have normal to decreased platelet numbers at birth and have a progressive decrease in the platelet count for about 1 week before the platelet count begins to increase. It has been speculated that the falling platelet count is associated with maturation of the infant’s reticuloendothelial system and accelerated removal of antibody-labeled platelets by cells of the reticuloendothelial system. Neonatal thrombocytopenia typically persists for about 1 to 2 weeks but sometimes lasts for several months. It usually does not require treatment. Severely thrombocytopenic infants generally respond quickly to IVIG treatment. If an infant develops hemorrhagic symptoms, platelet transfusion, IVIG treatment, or corticosteroid therapy should be started immediately.37

Posttransfusion purpura. 

Posttransfusion purpura (PTP) is a relatively rare disorder that typically develops about 1 week after transfusion of platelet-containing blood products, including fresh or frozen plasma, whole blood, and packed or washed RBCs. PTP is manifested by the rapid onset of severe thrombocytopenia and moderate to severe hemorrhage that may be life-threatening. The recipient’s plasma is found to contain alloantibodies to antigens on the platelets or platelet membranes of the transfused blood product, directed against an antigen the recipient does not have. In more than 90% of cases, the antibody is directed against the HPA-1a antigen; in most of the remaining cases, the antibodies are directed against PlA2 or other epitopes on GP IIb/IIIa.37 Involvement of other alloantigens, such as HPA-3a (Bak), HPA-4 (Penn), and HPA-5b (Br), has been reported. The mechanism by which the recipient’s own platelets are destroyed is unknown. Most patients with this type of thrombocytopenia are multiparous middle-aged women. Almost all the other patients have a history of blood transfusion. PTP seems to be exceedingly rare in men who have never been transfused and in women who have never been pregnant or never been transfused.68 PTP seems to require prior exposure to foreign platelet antigens and behaves in many respects like an anamnestic immune response.

No clinical trials have been conducted on the treatment of PTP, primarily because of the small number of cases. If PTP is untreated or treatment is ineffective, mortality rates may approach 10%.69 In addition, untreated or unresponsive patients have a protracted clinical course, with thrombocytopenia typically lasting 3 weeks but in some cases up to 4 months. Plasmapheresis and exchange transfusion have been used with some success in the past, but the treatment of choice is now IVIG. Many patients with PTP respond to a 2-day course of IVIG, generally within the first 2 to 3 days, although a second course occasionally is necessary.69 IVIG also is much easier to administer, and the response rates are higher than for plasmapheresis or exchange transfusion. Corticosteroid therapy is not particularly efficacious when used alone but may be beneficial in combination with other, more effective treatments.37

Secondary thrombocytopenia, presumed to be immune mediated. 

Severe thrombocytopenia has been observed in patients receiving biologic response modifiers such as interferons, colony-stimulating factors, and interleukin-2.70-72 The thrombocytopenia associated with use of these substances is reversible and, at least for interferon, may be immune mediated, because increased levels of platelet-associated IgG have been measured. Immune thrombocytopenia develops in about 5% to 10% of patients with chronic lymphocytic leukemia and in a smaller percentage of patients with other lymphoproliferative disorders.7374 Thrombocytopenia also is noted in 14% to 26% of patients with systemic lupus erythematosus.75 The clinical picture is similar to that of ITP: the bone marrow has a larger than normal number of megakaryocytes, and increased levels of platelet-associated IgG frequently are found.36Parasitic infections also are known to cause thrombocytopenia. Malaria is the most studied in this group and is regularly accompanied by thrombocytopenia, the onset of which corresponds to the first appearance of antimalarial antibodies, a decrease in serum complement, and control of parasitemia. There is evidence for the adsorption of microbial antigens to the platelet surface and subsequent antibody binding via the Fab terminus.76 Immune destruction of platelets seems to be the most likely mechanism for the thrombocytopenia.

Nonimmune mechanisms of platelet destruction

Nonimmune platelet destruction may result from exposure of platelets to nonendothelial surfaces, from activation of the coagulation process, or from platelet consumption by endovascular injury without measurable depletion of coagulation factors.36

Thrombocytopenia in pregnancy and preeclampsia

Incidental thrombocytopenia of pregnancy. 

Incidental thrombocytopenia of pregnancy also is known as pregnancy-associated thrombocytopenia and gestational thrombocytopenia. This disorder is the most common cause of thrombocytopenia in pregnancy. Random platelet counts in pregnant and postpartum women are slightly higher than normal, but about 5% of pregnant women develop a mild thrombocytopenia (100,000 to 150,000/μL), with 98% of such women having platelet counts greater than 70,000/μL. These women are healthy and have no prior history of thrombocytopenia. They do not seem to be at increased risk for bleeding or for delivery of infants with neonatal thrombocytopenia. The cause of this type of thrombocytopenia is unknown. Maternal platelet counts return to normal within several weeks of delivery. These women commonly experience recurrence in subsequent pregnancies.

Preeclampsia and other hypertensive disorders of pregnancy. 

Approximately 20% of cases of thrombocytopenia of pregnancy are associated with hypertensive disorders. These disorders include the classifications preeclampsia, preeclampsia-eclampsia, preeclampsia with chronic hypertension, chronic hypertension, and gestational hypertension. Preeclampsia complicates about 5% of all pregnancies and typically occurs at about 20 weeks of gestation. The disorder is characterized by the onset of hypertension and proteinuria and may include abdominal pain, headache, blurred vision, or mental function disturbances.77 Thrombocytopenia occurs in 15% to 20% of patients with preeclampsia, and about 40% to 50% of these patients progress to eclampsia (hypertension, proteinuria, and seizures).7879

Some patients with preeclampsia have microangiopathic hemolysis, elevated liver enzymes, and a low platelet count, termed HELLP syndrome. HELLP syndrome affects an estimated 4% to 12% of women with severe preeclampsia458081 and seems to be associated with higher rates of maternal and fetal complications. This disorder may be difficult to differentiate from thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and disseminated intravascular coagulation (DIC).

The development of thrombocytopenia in these patients is thought to be due to increased platelet destruction. The mechanism of platelet destruction is unclear, however. Some evidence (elevated D-dimer) suggests that these patients have an underlying low-grade DIC.82 Elevated platelet-associated immunoglobulin is commonly found in these patients, however, which indicates immune involvement.83 Early reports suggested that there may be a component of in vivo platelet activation because low-dose aspirin therapy has been shown to prevent preeclampsia in high-risk patients.8485 When aspirin is used to prevent preeclampsia, however, reduction in risk is only 15%.

The treatment of preeclampsia is delivery of the infant whenever possible. After delivery, the thrombocytopenia usually resolves in a few days. In cases in which delivery is not possible (e.g., the infant would be too premature), bed rest and aggressive treatment of the hypertension may help to increase the platelet count in some patients. Such treatments include magnesium sulfate and other antiepileptic therapies to inhibit eclamptic seizures.

Other causes of thrombocytopenia during pregnancy. 

As has been discussed previously, ITP is a relatively common disorder in women of childbearing age, and pregnancy does nothing to ameliorate the symptoms of this disorder. ITP should be a part of the differential diagnosis of thrombocytopenia in a pregnant woman. There is little or no correlation between the level of maternal autoantibodies and the fetal platelet count. Other causes of thrombocytopenia during pregnancy include HIV infection, systemic lupus erythematosus, antiphospholipid syndromes, TTP, and HUS. Of all women who develop TTP, 10% to 25% manifest the disease during pregnancy or in the postpartum period, and TTP tends to recur in subsequent pregnancies.8687 Plasmapheresis is the treatment of choice, and the maternal mortality is 90% or greater without such treatment.

Hemolytic disease of the newborn. 

Thrombocytopenia, usually moderate in degree, occurs frequently in infants with hemolytic disease of the newborn. Although the RBC destruction characteristic of this disorder is antibody induced, the antigens against which the antibodies are directed are not expressed on platelets. Platelets may be destroyed as a result of their interaction with products of RBC breakdown, rather than their direct participation in an immunologic reaction.36

Thrombotic thrombocytopenic purpura. 

TTP, sometimes referred to as Moschcowitz syndrome, is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and neurologic abnormalities.88 In addition, fever and renal dysfunction (forming a pentad) are often present. Additional symptoms are present in most patients at the time of diagnosis and include diarrhea, anorexia, nausea, weakness, and fatigue. TTP is uncommon but not rare, and its incidence may be increasing. About twice as many women as men are affected, and it is most common in women 30 to 40 years of age.3489 About half of the patients who develop TTP have a history of a viral-like illness several days before the onset of TTP.

There seem to be at least four types of TTP. In most patients, TTP occurs as a single acute episode, although a small fraction of these patients may have recurrence at seemingly random intervals. Recurrent TTP occurs in 11% to 28% of TTP patients.9091 A third type of TTP is drug induced. The primary agents involved are the purinoreceptor (adenosine diphosphate) blocking agents ticlopidine (Ticlid) and clopidogrel (Plavix) used for inhibition of platelet function. Ticlopidine seems to cause TTP in about 0.025% of patients, whereas the incidence of clopidogrel-induced TTP is approximately four times less frequent.89 The fourth type is chronic relapsing TTP, a rare form of TTP, in which episodes occur at intervals of approximately 3 months starting in infancy.9293

Although it is unclear what triggers their deposition, hyaline thrombi are found in the end arterioles and capillaries. These hyaline thrombi are composed of platelets and von Willebrand factor (VWF) but contain very little fibrin or fibrinogen. As these platelet-VWF thrombi are deposited, thrombocytopenia develops. The degree of thrombocytopenia is directly related to the extent of microvascular platelet aggregation. RBCs flowing under arterial pressure are prone to fragmentation and hemolysis when they encounter the strands of these thrombi.

Hemolysis is usually quite severe, and most patients have less than 10 g/dL hemoglobin at the time of diagnosis. Examination of the peripheral blood film reveals a marked decrease in platelets, RBC polychromasia, and RBC fragmentation (microspherocytes, schistocytes, keratocytes), a triad of features characteristic of microangiopathic hemolytic anemias (Figure 40-8). Nucleated RBC precursors also may be present, depending on the degree of hemolysis. Other laboratory evidence of intravascular hemolysis includes reduction of haptoglobin, hemoglobinuria, hemosiderinuria, increased serum unconjugated bilirubin, and increased lactate dehydrogenase activity. Bone marrow examination reveals erythroid hyperplasia and a normal to increased number of megakaryocytes. The partial thromboplastin time, prothrombin time, fibrinogen, fibrin degradation products, and D-dimer test results are usually normal and may be useful in differentiating this disorder from DIC.


FIGURE 40-8 Microangiopathic hemolytic anemia. A,Thrombotic thrombocytopenic purpura (TTP); B, Hemolytic uremic syndrome (HUS). Abundant schistocytes (arrows) reflect the platelet rich clots in the microvasculature that occur with TTP and HUS. TTP and HUS have similar blood morphologies. Source: (From Carr JH, Rodak BF: Clinical hematology atlas, ed 4, Philadelphia, 2013, Saunders.)

The thrombotic lesions also give rise to the other characteristic manifestations of TTP, because they are deposited in the vasculature of all organs. The thrombi occlude blood flow and lead to organ ischemia. Symptoms depend on the severity of ischemia in each organ. Neurologic manifestations range from headache to paresthesia and coma. Visual disturbances may be of neurologic origin or may be due to thrombi in the choroid capillaries of the retina or hemorrhage into the vitreous. Renal dysfunction is common and present in more than half of patients.9091 Symptoms of renal dysfunction include proteinuria and hematuria. Overwhelming renal damage with anuria and fulminant uremia usually does not occur, however, which helps to distinguish TTP from HUS.10 Gastrointestinal bleeding occurs frequently in severely thrombocytopenic patients, and abdominal pain is occasionally present due to occlusion of the mesenteric microcirculation.

Adamts-13 and thrombotic thrombocytopenic purpura. 

The development of TTP seems to be directly related to the accumulation of ultra-large von Willebrand factor (ULVWF) multimers in the plasma of patients with TTP. VWF multimers are made by megakaryocytes and endothelial cells. The primary source of plasma VWF seems to be endothelial cells. Endothelial cells secrete VWF into the subendothelium and plasma and store it in Weibel-Palade bodies (storage granules). Endothelial cells and megakaryocytes make even larger VWF multimers (ULVWF multimers) than those found in plasma, and these are even more effective than the normal plasma VWF multimers at binding platelet GP Ib/IX or GP IIb/IIIa complexes under fluid shear stresses ().Figure 40-992 In the plasma, the ULVWF multimers are rapidly cleaved into the smaller VWF multimers normally found in the plasma by a VWF-cleaving protease, called a disintegrin and metalloprotease with a thrombo spondin type 1 motif, member 13 (ADAMTS-13). This metalloprotease seems to be more effective when VWF multimers are partially unfolded by high shear stress.9495


FIGURE 40-9 Mechanism for thrombotic thrombocytopenic purpura (TTP). Unusually large von Willebrand factor (ULVWF) multimers are normally digested by the VWF–cleaving protease ADAMTS-13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13). In TTP, the absence of ADAMTS-13 allows the release of ULVWF, triggering platelet activation.

Familial chronic relapsing TTP is a form characterized by recurrent episodes of thrombocytopenia with or without ischemic organ damage. In this type of TTP, the VWF-cleaving metalloprotease is completely deficient. The more common form of TTP (usually not familial) does not tend to recur, but patients also are deficient in the metalloprotease. In this more common form of TTP, the metalloprotease deficiency occurs through removal of the enzyme (or blockade of its function) by a specific autoantibody that is present during TTP but disappears during remission.9697 An assay to measure the VWF-cleaving enzyme has been introduced.98 However, the test may take several days, and treatment decisions must usually be made before test results are available. In addition, the assay lacks sensitivity and specificity for TTP. Additional tests for ADAMTS-13 (and TTP) are in development and hold the promise for rapid diagnosis of TTP.

In patients with TTP, ULVWF multimers tend to be present in the plasma at the beginning of the episode. These ULVWF multimers, and usually the normal-sized plasma multimers, disappear as the TTP episode progresses and the thrombocytopenia worsens. Platelets and VWF are consumed during deposition of the microvascular hyaline thrombi characteristic of this disorder.99 If the patient survives an episode of TTP and does not experience relapse, the plasma VWF multimers are usually normal after recovery. If ULVWF multimers are found in the plasma after recovery, however, it is likely that the patient will have recurrent episodes of TTP. The episodes may be infrequent and at irregular intervals (intermittent TTP) or frequent and at regular intervals, as is often the case when TTP episodes occur in early childhood or infancy.

The most effective treatment for TTP is plasma exchange using fresh-frozen plasma or cryoprecipitate-poor plasma (plasma lacking most of the fibrinogen, fibronectin, and VWF).100 Either of these approaches may produce dramatic effects within a few hours. Because plasmapheresis is not available in all centers, the patient should be given corticosteroids and infusions of fresh-frozen plasma immediately. Plasma exchange should be arranged as quickly as possible. Plasmapheresis and replacement/infusion of plasma is effective on two fronts. First, some of the ULVWF multimers will be removed by apheresis, and plasma (fresh-frozen plasma or cryoprecipitate-poor plasma) supplies the deficient protease, which is able to degrade the ULVWF multimers in the blood of the patient. Because some patients with TTP have recovered while receiving immunosuppressive treatment (corticosteroids) alone, it is recommended that all patients with TTP be given high-dose corticosteroids in addition to undergoing plasma exchange. Plasma exchange typically is continued over a 5-day period. If a response is not seen within 5 days, or if the condition of the patient worsens during the first few days of plasma exchange, additional treatment is instituted. Such therapies include administering vincristine or azathioprine (or other immunosuppressive agents), performing splenectomy, or passing the patient’s plasma over a staphylococcal A column to remove immune complexes. The use of antiplatelet agents, prostacyclin, heparin, or fibrinolytic agents is controversial and has not clearly been shown to be helpful. Platelet transfusions should be avoided unless intracranial bleeding or other serious hemorrhagic problems arise.45

Before 1990, TTP was fatal in more than 80% of patients. With the means for rapid diagnosis and the advent of exchange plasmapheresis, now 80% of patients who are treated early can be expected to survive. Because patients are known to experience relapse, however, platelet counts should be monitored on a regular basis until patients are in remission. The detection of ULVWF multimers in patient samples after complete remission has predicted relapse accurately in 90% of the patients tested101; this may prove to be useful in the long-term management of TTP.

Hemolytic uremic syndrome. 

Clinically, HUS resembles TTP except that it is found predominantly in children 6 months to 4 years of age and is self-limiting. Approximately 90% of cases are caused by Shigella dysenteriae serotypes or enterohemorrhagic Escherichia coli OH serotypes, particularly O157:H7.102 These organisms sometimes can be cultured from stool samples. The bloody diarrhea typical of childhood HUS is caused by colonization of the large intestine with the offending organism, which causes erosive damage to the colon. S. dysenteriae produces Shiga toxin, and enterohemorrhagic E. coli produces either Shiga-like toxin-1 (SLT-1) or SLT-2, which can be detected in fecal samples from patients with HUS. The toxins enter the bloodstream and attach to renal glomerular capillary endothelial cells, which become damaged and swollen and release ULVWF multimers.102103 This process leads to formation of hyaline thrombi in the renal vasculature and the development of renal failure, thrombocytopenia, and microangiopathic hemolytic anemia, although the RBC fragmentation is usually not as severe as that seen in TTP (this is, however, not a differentiating feature). The extent of renal involvement correlates with the rate of recovery. In more severely affected children, renal dialysis may be needed. The mortality rate associated with HUS in children is much lower than that for TTP, but there is often residual renal dysfunction that may lead to renal hypertension and severe renal failure. Because HUS in children is essentially an infectious disorder, it affects boys and girls equally and is often found in geographic clusters of cases rather than in random distribution.

The adult form of HUS is associated most often with exposure to immunosuppressive agents or chemotherapeutic agents or both, but it also may occur during the postpartum period. Usually the symptoms of HUS do not appear until weeks or months after exposure to the offending agent.104 This disorder most likely results from direct renal arterial endothelial damage caused by the drug or one of its metabolic products. The damage to endothelial cells results in release of VWF (including ULVWF multimers), turbulent flow in the arterial system with increased shear stresses on platelets, and VWF-mediated platelet aggregation in the renal arterial system. The renal impairment in adults seems to be more severe than that in childhood HUS, and dialysis is usually required. The cause of HUS associated with pregnancy or oral contraceptive use is unclear, but it may be related to development of an autoantibody to endothelial cells. In outbreaks of HUS associated with consumption of E. coli–contaminated water, both children and adults have developed HUS.

The cardinal signs of HUS are hemolytic anemia, renal failure, and thrombocytopenia. The thrombocytopenia is usually mild to moderate in severity. Renal failure is reflected in elevated blood urea nitrogen and creatinine levels. The urine nearly always contains RBCs, protein, and casts. The hemolytic process is shown by a hemoglobin level of less than 10 g/dL, elevated reticulocyte count, and presence of schistocytes in the peripheral blood.

Differentiating the adult form of HUS from TTP may be difficult. The lack of neurologic symptoms, the presence of renal dysfunction, and the absence of other organ involvement suggest HUS. Also, in HUS the thrombocytopenia tends to be mild to moderate (platelet consumption occurs primarily in the kidneys), whereas in TTP the thrombocytopenia is usually severe. Similarly, fragmentation of RBCs and the resultant anemia tend to be milder than that observed in TTP, because RBCs are being fragmented primarily in the kidneys. In some cases of HUS, other organs become involved, and the differentiation between HUS and TTP becomes less clear. In such cases, it is prudent to treat as though the patient has TTP.

Disseminated intravascular coagulation. 

A common cause of destructive thrombocytopenia is activation of the coagulation cascade (by a variety of agents or conditions), resulting in a consumptive coagulopathy that entraps platelets in intravascular fibrin clots. This disorder is described in more detail in Chapter 39 but is discussed here briefly for the sake of completeness. DIC has many similarities to TTP, including microangiopathic hemolytic anemia and deposition of thrombi in the arterial circulation of most organs. In DIC, however, the thrombi are composed primarily of platelets and fibrinogen, whereas in TTP the thrombi are composed primarily of platelets and VWF.

One form of DIC is acute with rapid platelet consumption and results in severe thrombocytopenia. In addition, levels of factor V, factor VIII, and fibrinogen are decreased as a result of in vivo thrombin generation. The test for D-dimer (a breakdown product of stabilized fibrin) almost always yields positive results. This form of DIC is life-threatening and must be treated immediately.

In chronic DIC, there is an ongoing, low-grade consumptive coagulopathy. Clotting factors may be slightly reduced or normal, and compensatory thrombocytopoiesis results in a moderately low to normal platelet count.34 D-dimer may not be detectable or may be slightly to moderately increased. Chronic DIC is not generally life-threatening, and treatment usually is not urgent. Chronic DIC is almost always due to some underlying condition. If that condition can be corrected, the DIC usually resolves without further treatment. Chronic DIC should be followed closely, however, because it can convert into the life-threatening acute form.

Drug-induced thrombocytopenia. 

A few drugs directly interact with platelets to cause thrombocytopenia. Ristocetin, an antibiotic no longer in clinical use, facilitates the interaction of VWF with platelet membrane GP Ib and leads to in vivo platelet agglutination and thrombocytopenia. Hematin, used for the treatment of acute intermittent porphyria, may give rise to a transient thrombocytopenia that seems to be caused by stimulation of platelet secretion and aggregation. Protamine sulfate and bleomycin may induce thrombocytopenia by a similar mechanism.45

Abnormalities in distribution or dilution

An abnormal distribution of platelets also may cause thrombocytopenia. The normal spleen sequesters approximately one third of the total platelet mass. Mild thrombocytopenia may be present in any of the “big spleen” syndromes. The total body platelet mass is often normal in these disorders, but numerous platelets are sequestered in the enlarged spleen, and consequently the venous blood platelet count is low. Disorders such as Gaucher disease, Hodgkin disease, sarcoidosis, lymphoma, cirrhosis of the liver, and portal hypertension may result in splenomegaly and lead to thrombocytopenia.

Lowering the body temperature to less than 25° C, as is routinely done in cardiovascular surgery, results in a transient but mild thrombocytopenia secondary to platelet sequestration in the spleen and liver. An associated transient defect in function also occurs with hypothermia. Platelet count and function return to baseline values on return to normal body temperature.32

Thrombocytopenia often follows surgery involving extracorporeal circulatory devices, as a consequence of damage and partial activation of platelets in the pump. In a few cases, severe thrombocytopenia, marked impairment of platelet function, and activation of fibrinolysis and intravascular coagulation may develop.45

The administration of massive amounts of stored whole blood may produce a temporary thrombocytopenia. This phenomenon is explained by the fact that stored blood contains platelets whose viability is severely impaired by the effects of storage and temperature. Under these conditions, the dead or damaged platelets are rapidly sequestered by the reticuloendothelial system of the patient. If this problem is encountered, it may be minimized by administering platelet concentrates or units of fresh whole blood along with the stored blood. This situation is only rarely encountered, however, because the practice of transfusing whole blood has been replaced almost completely by the use of specific components. Finally, mild thrombocytopenia may be encountered in patients with chronic renal failure, severe iron deficiency, megaloblastic anemia, postcompression sickness, and chronic hypoxia.

Thrombocytosis: Increase in circulating platelets

Thrombocytosis is defined as an abnormally high platelet count, typically more than 450,000/μL. The term reactive thrombocytosis is used to describe an elevation in the platelet count secondary to inflammation, trauma, or other underlying and seemingly unrelated conditions. In reactive thrombocytosis, the platelet count is elevated for a limited period and usually does not exceed 800,000/μL, although platelet counts greater than 1 million/μL are occasionally seen (Figure 40-10). A marked and persistent elevation in the platelet count is a hallmark of myeloproliferative disorders such as polycythemia vera, chronic myelogenous leukemia, and myelofibrosis with myeloid metaplasia (or primary myelofibrosis). In these conditions, the platelet count often exceeds 1 million/μL. Although the terms thrombocythemia andthrombocytosis are often used interchangeably, in this text the term thrombocythemia is used only as part of the description of the myeloproliferative disorder known as essential thrombocythemia (Figure 40-11). In essential thrombocythemia, platelet counts typically exceed 1 million/μL and may reach levels of several million.34105106 Processes resulting in thrombocytosis are summarized in Box 40-3.


FIGURE 40-10 Peripheral blood film showing cell morphology in reactive thrombocytosis. Note the increased number of platelets but reasonably normal platelet morphology, characteristic of reactive thrombocytosis.


FIGURE 40-11 Peripheral blood film showing cell morphology in essential thrombocythemia. Note the increased number of platelets and wide variation in platelet size characteristic of essential thrombocythemia. Red and white blood cell morphology is characteristically normal. Source: (From Carr JH, Rodak BF: Clinical hematology atlas, ed 4, Philadelphia, 2013, Saunders.)

BOX 40-3

Processes Resulting in Thrombocytosis

Conditions associated with reactive thrombocytosis

Blood loss and surgery


Iron deficiency anemia

Inflammation and disease

Stress or exercise

Myeloproliferative disorders associated with thrombocytosis

Polycythemia vera

Chronic myelogenous leukemia

Myelofibrosis with myeloid metaplasia

Thrombocythemia: essential or primary

From Colvin BT: Thrombocytopenia, Clin Haematol 14:661-681, 1985; and Thompson AR, Harker LA: Manual of hemostasis and thrombosis, ed 3, Philadelphia, 1983, FA Davis.

Reactive (secondary) thrombocytosis

Platelet counts between 450,000/μL and 800,000/μL with no change in platelet function can result from acute blood loss, splenectomy, childbirth, and tissue necrosis secondary to surgery, chronic inflammatory disease, infection, exercise, iron deficiency anemia, hemolytic anemia, renal disorders, and malignancy. Occasionally, patients manifest a platelet count of 1 to 2 million/μL (Figure 40-10). In reactive thrombocytosis, platelet production remains responsive to normal regulatory stimuli (e.g., thrombopoietin, a humoral factor that is produced in the kidney parenchyma), and morphologically normal platelets are produced at a moderately increased rate. This is in contrast to essential thrombocythemia, which is characterized by unregulated or autonomous platelet production and platelets of variable size.105106

Examination of the bone marrow from patients with reactive thrombocytosis reveals a normal to increased number of megakaryocytes that are normal in morphology. Results of platelet function tests, including aggregation induced by various agents, and bleeding time are usually normal in reactive thrombocytosis but also may be normal in patients with elevated platelet counts accompanying myeloproliferative disorders.

Reactive thrombocytosis is not associated with thrombosis, hemorrhage, or abnormal thrombopoietin levels. It seldom produces symptoms per se and disappears when the underlying disorder is brought under control.105106

Reactive thrombocytosis associated with hemorrhage or surgery

After acute hemorrhage, the platelet count may be low for 2 to 6 days (unless platelets have been transfused) but typically rebounds to elevated levels for several days before returning to the prehemorrhage level. A similar pattern of thrombocytopenia and thrombocytosis is seen after major surgical procedures in which there is significant blood loss. In both cases, the platelet count typically returns to normal 10 to 16 days after the episode of blood loss.

Postsplenectomy thrombocytosis

Removal of the spleen typically results in platelet counts that can reach or exceed 1 million/μL regardless of the reason for splenectomy. The spleen normally sequesters about one third of the circulating platelet mass. After splenectomy, one would expect an initial increase in the platelet count of approximately 30% to 50%. The platelet count, however, far exceeds levels that could result from rebalancing of the circulating platelet pool to incorporate the splenic platelet pool. The cause of the accelerated platelet production is unknown. Unlike after blood loss from hemorrhage or other types of surgery, the platelet count reaches a maximum 1 to 3 weeks after splenectomy and remains elevated for 1 to 3 months. In some patients who undergo splenectomy for treatment of chronic anemia, the count can remain elevated for several years.

Thrombocytosis associated with iron deficiency anemia

Mild iron deficiency anemia secondary to chronic blood loss is associated with thrombocytosis in about 50% of cases. Thrombocytosis can be seen in severe iron deficiency anemia, but thrombocytopenia also has been reported. In some cases of iron deficiency, the platelet count may be 2 million/μL. After iron therapy is started, the platelet count usually returns to normal within 7 to 10 days. It is believed that iron plays some role in regulating thrombopoiesis, because treatment of the iron deficiency with iron replacement has resulted in a normalization of the platelet count in thrombocytopenic patients and has been reported to induce thrombocytopenia in patients with normal platelet counts. Not enough research has been done, however, to elucidate the role of iron in thrombopoiesis.

Thrombocytosis associated with inflammation and disease

Similar to elevations in C-reactive protein, fibrinogen, VWF, and other acute phase reactants, thrombocytosis may be an indication of inflammation. Thrombocytosis may be found in association with rheumatoid arthritis, rheumatic fever, osteomyelitis, ulcerative colitis, acute infections, and malignancy. In rheumatoid arthritis, the presence of thrombocytosis can be correlated with activation of the inflammatory process.

Kawasaki disease (Kawasaki syndrome) causes inflammation of the walls of small and medium-sized arteries throughout the body. It is also known as mucocutaneous lymph node syndrome because it affects lymph nodes, skin, and mucous membranes in the mouth, nose, and throat. It is an acute febrile illness of infants and young children. Boys are more likely than girls to develop the disease, and children of Japanese and Korean descent have higher rates of Kawasaki disease. It is a self-limited acute vasculitic syndrome of unknown origin, although an infectious etiology has been suspected. Although the disease is self-limiting, there can be lifelong sequelae, including coronary artery thrombosis and aneurysms. The acute febrile stage of the disease lasts 2 weeks or longer, with a fever of 40° C or higher, and is unresponsive to antibiotic therapy. The longer the fever continues, the higher the risk of cardiovascular complications. The subacute phase lasts an additional week to 10 days. During this phase, the platelet count usually is elevated, and counts of 2 million/μL have been reported. In addition, acute phase reactants such as C-reactive protein and sedimentation rate are elevated, consistent with an inflammatory component. The WBC count can be moderately to markedly elevated with a left shift, and many patients develop a mild normochromic, normocytic anemia. During this phase, cardiovascular complications and aneurysms develop. The higher the platelet count, the higher the risk of cardiovascular complication. After the subacute phase comes the convalescent phase, during which all signs of illness disappear and the acute phase reactants subside to normal. The highest incidence of Kawasaki disease is found in Japan and in individuals of Japanese descent, although the disease seems to occur in most, if not all, ethnic groups. There is no specific test for Kawasaki disease. Diagnosis is primarily by excluding other diseases that cause similar signs and symptoms (e.g., scarlet fever, juvenile rheumatoid arthritis, Stevens-Johnson syndrome, and toxic shock syndrome). The treatment for Kawasaki disease is administration of antiplatelet agents and immunoglobulin.

An elevated platelet count also may be early evidence of a tumor (e.g., Hodgkin disease) and various carcinomas. Finally, hemophilic patients often have platelet counts above normal limits, even in the absence of active bleeding.

Exercise-induced thrombocytosis

Strenuous exercise is a well-known cause of relative thrombocytosis and is likely due to the release of platelets from the splenic pool or hemoconcentration by transfer of plasma water to the extravascular compartment or both. Normally, the platelet count returns to its preexercise baseline level 30 minutes after completion of exercise.

Rebound thrombocytosis

Thrombocytosis often follows the thrombocytopenia caused by marrow-suppressive therapy or other conditions. “Rebound” thrombocytosis usually reaches a peak 10 to 17 days after withdrawal of the offending drug (e.g., alcohol or methotrexate) or after institution of therapy for the underlying condition with which thrombocytopenia is associated (e.g., vitamin B12 deficiency).45

Thrombocytosis associated with myeloproliferative disorders

Primary or autonomous thrombocytosis is a typical finding in four chronic myeloproliferative disorders: polycythemia vera, chronic myelogenous leukemia, myelofibrosis with myeloid metaplasia (primary myelofibrosis), and essential thrombocythemia. Depending on the duration and stage of the myeloproliferative disorder at the time of diagnosis, it may be difficult to differentiate among these diseases. Chapter 33provides a more complete description of these disorders. In the other types of myeloproliferative disorders, the platelet count seldom reaches the extreme values characteristic of essential thrombocythemia. Diagnosis of essential thrombocythemia should not be based on the platelet count alone but should also take into account the physical examination findings, history, and other laboratory data.34106

Essential (primary) thrombocythemia

Essential thrombocythemia is a clonal disorder related to other chronic myeloproliferative diseases and is the most common cause of primary thrombocytosis. It is characterized by peripheral blood platelet counts exceeding 1 million/μL and uncontrolled proliferation of marrow megakaryocytes. Although the platelet count may (or may not) be markedly elevated in other myeloproliferative disorders, persistent marked elevation of the platelet count is an absolute requirement for the diagnosis of essential thrombocythemia (Figure 40-11). There is evidence that essential thrombocythemia is caused by a clonal proliferation of a single abnormal pluripotential stem cell that eventually crowds out normal stem cells. As with most myeloproliferative disorders, essential thrombocythemia is neither congenital nor hereditary, is prevalent in middle-aged and older patients, and affects equal numbers of men and women. In contrast to other myeloproliferative disorders, however, the other marrow cell lines are not involved at the time of diagnosis.

The clinical manifestations of essential thrombocythemia are hemorrhage, platelet dysfunction, and thrombosis. Bleeding times are usually normal. There is no specific clinical sign, symptom, or laboratory test that establishes the diagnosis of essential thrombocythemia. The diagnosis must be made by ruling out the other myeloproliferative disorders and systemic illnesses that produce reactive thrombocytosis.

Thrombosis in the microvasculature is relatively common in essential thrombocythemia, and the incidence at the time of diagnosis is 10% to 20%. This thrombosis can lead to digital pain, digital gangrene, or erythromelalgia (throbbing, aching, and burning sensation in the extremities, particularly in the palms and soles).106 The symptoms of erythromelalgia can be explained by arteriolar inflammation and occlusive thrombosis mediated by platelets and can be relieved for several days by a single dose of aspirin.107 Thrombosis of large veins and arteries also may occur in essential thrombocythemia. The arteries most commonly involved are those in the legs, the coronary arteries, and the renal arteries, but involvement of the mesenteric, subclavian, and carotid arteries is not infrequent (in fact, neurologic complications are relatively common). Venous thrombosis may involve the large veins of the legs and pelvis, hepatic veins, or splenic veins.108 The platelets of some patients who have experienced thrombotic episodes have been shown to have increased binding affinity for fibrinogen and to generate more than the usual quantities of thromboxane B2, and these patients have elevated levels of thromboxane B2 and β-thromboglobulin in the blood. These findings suggest enhanced in vivo platelet activation and perhaps an explanation for the thrombotic tendencies of patients with essential thrombocythemia. The primary cause of death of patients with essential thrombocythemia seems to be thrombosis. Hemorrhagic episodes occur less frequently than thrombotic episodes in patients with essential thrombocythemia.

As with bleeding secondary to platelet function disorders, the hemorrhagic manifestations of essential thrombocythemia are mucocutaneous in nature, with gastrointestinal tract bleeding occurring most frequently. Other sites of bleeding include the mucous membranes of the nose and mouth, the urinary tract, and the skin. Symptoms may be aggravated by aspirin use. In an occasional patient with essential thrombocythemia, there is a paradoxical combination of thromboembolic (clotting) and hemorrhagic episodes in association with this condition. A patient with essential thrombocythemia who has had a thrombotic event may have a hemorrhagic event later.109

The bleeding manifestations may be related to a variety of qualitative abnormalities in the platelets, including deficiencies in epinephrine receptors and ultrastructural defects in granules, mitochondria, and microfilaments. Platelets may be agranular or hypogranular and have a clear, light blue appearance on a routine Wright-stained film of the peripheral blood. Although platelet size is heterogeneous, giant and bizarrely shaped platelets are characteristic of myeloproliferative diseases, and megakaryocyte fragments or nuclei are commonly encountered in the peripheral blood. Platelets may be notably clumped on blood films, exhibiting marked variation in size and shape. The number and volume of megakaryocytes are increased in the bone marrow, and they are predominantly large, show some cellular atypia, and tend to form clusters. Often the platelets are functionally defective when tested in vitro. Aggregation is usually absent in response to epinephrine and may be decreased with adenosine diphosphate but is usually normal with collagen. Lack of an epinephrine response may help to differentiate essential thrombocythemia from reactive thrombocytosis, because this response is usually normal in reactive thrombocytosis but absent in most cases of essential thrombocythemia. Platelet adhesion also may be decreased.106

The degree of thrombocytosis has not been found to predict hemorrhagic or thrombotic events reliably. The role of lowering platelet counts as a prophylactic treatment in this disease is not established. The risks from exposure to mutagenic alkylating agents used to decrease the platelet count may be greater than the risk of thrombosis or hemorrhage. When treatment is deemed necessary because of thrombotic tendencies or splenomegaly, a variety of myelosuppressive agents (e.g., melphalan, busulfan, hydroxyurea, or even radioactive phosphorus) can be used.106 In patients with life-threatening hemorrhage or thrombosis and an extremely high platelet count, platelet apheresis may be used to reduce the platelet count rapidly. In these situations, a myelosuppressive agent is added for longer-term control of the platelet count.110 Interferon-α has been used to treat essential thrombocythemia and is associated with an approximately 60% rate of complete remission, but 28% of patients given the drug cannot tolerate the dosages required.111-113 A newer agent that has shown great promise in the treatment of essential thrombocythemia is anagrelide. The drug acts by inhibiting megakaryocyte maturation and platelet release.114 In one large study, anagrelide decreased the platelet count in 93% of patients.115 Many patients cannot tolerate anagrelide, however, and in these patients other, more traditional chemotherapeutic agents seem to be more effective. Despite the availability of newer treatments for essential thrombocythemia, whether a patient with essential thrombocythemia and an elevated platelet count who is asymptomatic should or should not be treated remains controversial.

In patients with essential thrombocythemia there is a low incidence of transformation to acute leukemia or fatal thrombotic or hemorrhagic complications. Therapy to prevent thrombotic complications seems to be effective in preventing morbidity but does not seem to improve survival, at least in high-risk patients.


• Thrombocytopenia is the most common cause of clinically significant bleeding.

• Thrombocytopenia may be a result of decreased platelet production, increased destruction, or abnormal distribution of platelets and manifests with small-vessel bleeding in the skin.

• Decreased production of platelets can be attributed to megakaryocyte hypoplasia, ineffective thrombopoiesis, or replacement of marrow by abnormal cells.

• Patients experiencing increased platelet destruction become thrombocytopenic only when the rate of platelet production can no longer increase enough to compensate.

• Pathologic destruction of platelets can be caused by both immunologic and nonimmunologic mechanisms.

• Acute ITP commonly occurs in children after a viral illness, and there is usually spontaneous remission. Chronic ITP is more commonly seen in women and requires treatment if the platelet count decreases to fewer than 30,000/μL.

• Treatment of drug-induced thrombocytopenia must begin with identification of the causative drug and discontinuation of its use.

• TTP presents with a triad of symptoms that includes microangiopathic hemolytic anemia, thrombocytopenia, and neurologic abnormalities; these may be accompanied by fever and renal dysfunction.

• Abnormal distribution of platelets can be caused by splenic sequestration.

• Reactive thrombocytosis is secondary to inflammation, trauma, or a variety of underlying conditions. Platelet counts are increased for a limited time. The thrombocytosis seen in myeloproliferative disorders is marked and persistent.

Now that you have completed this chapter, go back and read again the case study at the beginning and respond to the questions presented.

Review questions

Answers can be found in the Appendix.

1. The autosomal dominant disorder associated with decreased platelet production is:

a. Fanconi anemia

b. TAR syndrome

c. May-Hegglin anomaly

d. Wiskott-Aldrich anomaly

2. Which of the following is not a hallmark of ITP?

a. Petechiae

b. Thrombocytopenia

c. Large overactive platelets

d. Megakaryocyte hypoplasia

3. The specific antigen most commonly responsible for the development of NAIT is:

a. Bak

b. HPA-1a

c. GP Ib

d. Lewis antigen a

4. A 2-year-old child with an unexpected platelet count of 15,000/μL and a recent history of a viral infection most likely has:

a. HIT


c. Acute ITP

d. Chronic ITP

5. What is the first step in the treatment of HIT?

a. Start low-molecular-weight heparin therapy

b. Stop heparin infusion immediately

c. Switch to warfarin (Coumadin) immediately

d. Initiate a platelet transfusion

6. A defect in primary hemostasis (platelet response to an injury) often results in:

a. Musculoskeletal bleeding

b. Mucosal bleeding

c. Hemarthroses

d. None of the above

7. When a drug acts as a hapten to induce thrombocytopenia, an antibody forms against which of the following?

a. Typically unexposed, new platelet antigens

b. The combination of the drug and the platelet membrane protein to which it is bound

c. The drug alone in the plasma, but the immune complex then binds to the platelet membrane

d. The drug alone, but only when it is bound to the platelet membrane

8. TAR refers to:

a. Abnormal platelet morphology in which the radial striations of the platelets are missing

b. Abnormal appearance of the iris of the eye in which radial striations are absent

c. Abnormal bone formation, including hypoplasia of the forearms

d. Neurologic defects affecting the root (radix) of the spinal nerves

9. Neonatal autoimmune thrombocytopenia occurs when:

a. The mother lacks a platelet antigen that the infant possesses, and she builds antibodies to that antigen, which cross the placenta

b. The infant develops an autoimmune process such as ITP secondary to in utero infection

c. The infant develops an autoimmune disease such as lupus erythematosus before birth

d. The mother has an autoimmune antibody to her own platelets, which crosses the placenta and reacts with the infant’s platelets

10. HUS in children is associated with:

a. Diarrhea caused by Shigella species

b. Meningitis caused by Haemophilus species

c. Pneumonia caused by Mycoplasma species

d. Pneumonia caused by respiratory viruses


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