Lawrence L. K. Leung MD1
1Professor of Medicine and Chief, Division of Hematology, Department of Medicine, Stanford University School of Medicine
The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Bleeding or bruising that is spontaneous or excessive after tissue injury may be caused by abnormal platelet number or function, abnormal vascular integrity, coagulation defects, fibrinolysis, or a combination of these abnormalities. This chapter addresses hemorrhagic disorders associated with quantitative or qualitative platelet abnormalities and disorders associated with blood vessels. Hemorrhagic disorders associated with abnormalities in coagulation (e.g., von Willebrand disease and hemophilia) are covered elsewhere [see 5:XV Coagulation Disorders].
Approach to the Patient with a Bleeding Disorder
A bleeding disorder may be suspected when a patient complains of excessive bruising or bleeding that often occurs secondary to trauma. The clinical evaluation of a patient with a suspected bleeding disorder begins with a careful history. Assessment of the presenting complaint may suggest where in the hemostatic process a defect is located and whether the defect is inherited or acquired—information that contributes to a rational approach to laboratory evaluation.
Patients suspected of having a bleeding disorder should be questioned about past bleeding problems, bleeding outcomes after surgeries and tooth extractions, character of menses, and dietary habits that might predispose to deficiencies of vitamin K, vitamin B12, and folic acid. The patient should also be questioned about sexual activity, anemia, transfusions, recurrent infections, connective tissue diseases, malignancies, liver and kidney diseases, immunocompromised states, and drug use [see Medication History, below].
Many healthy people consider their bleeding and bruising to be excessive, whereas patients with underlying von Willebrand disease, the most common hereditary bleeding disorder, often fail to identify their bleeding symptoms.1 Given the variability in patients' perceptions of bleeding, as well as the lack of a uniform clinical measure of bleeding severity, a dialogue between the patient and the physician is essential for the evaluation of a bleeding disorder. It is therefore necessary to ask for specific information from patients about bleeding and bruising: (1) If the patient is easily bruised, what size are the bruises? (2) If the patient has had surgery, were blood transfusions needed? (3) If the patient had a wisdom tooth extracted, were return visits required for packing, suturing, or transfusion? The response to trauma is an excellent screening test. A history of surgical procedures, tooth extractions, or significant injury without abnormal bleeding is good evidence against the presence of an inherited hemorrhagic disorder.
The type of bleeding is informative and may suggest the underlying disorder [see Table 1]. Active bleeding can be caused by a localized anatomic lesion or an underlying bleeding diathesis. Mucosal bleeding, with recurrent epistaxis, gum bleeding, ecchymoses, and menorrhagia, is suggestive of von Willebrand disease or other platelet disorders. Deep-tissue bleeding (e.g., hemarthrosis and painful muscle hematomas) is more commonly seen in hemophilia and clotting factor deficiencies. Patients with clotting factor deficiencies may have delayed bleeding, presumably because the initial platelet thrombus provides immediate hemostasis but is not properly stabilized by the fibrin clot.
A careful history of medication use is a critical aspect of the diagnostic evaluation. The patient should be questioned about use of recreational drugs, prescribed medications, over-the-counter medications, and herbal products. Aspirin use is of particular importance. Aspirin can partially impair platelet function and trigger bleeding symptoms in a patient with mild underlying von Willebrand disease. Because several hundred drug formulations contain aspirin (often with no indication of aspirin content in the product name), identification of aspirin as the cause of a hemorrhagic disorder can be difficult.
The laboratory evaluation begins with general screening tests, such as platelet count, bleeding time (BT), prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT). These tests are supplemented with specific tests that define platelet or clotting factor abnormalities. Specific tests include examination of the peripheral blood smear; platelet aggregation in response to adenosine diphosphate (ADP), epinephrine, collagen, and ristocetin; platelet release assays; coagulation factor assays; and assessment of factor XIII activity via clot solubility testing [see 5:XII Hemostasis and Its Regulation].
In many patients with a bleeding disorder, the likely diagnosis will be suggested from the history and physical examination; the diagnosis can then be confirmed with the appropriate specific tests. When the diagnosis is not immediately apparent, three initial tests should be performed: platelet count, PT, and aPTT. The pattern of results provided by these tests suggests a diagnosis that can then be confirmed with specific testing [see Table 2].
Both the PT and aPTT provide a global assessment of the clotting cascade: the PT measures the extrinsic pathway, and the aPTT measures the intrinsic pathway [see 5:XII Hemostasis and Its Regulation]. Prolongations of both the PT and the aPTT suggest a clotting defect in the final common portion of the cascade that involves either factor X, factor V, prothrombin, or fibrinogen.
A prolonged PT with a normal aPTT is most commonly seen in a patient taking warfarin; in the absence of warfarin, these test results will indicate either factor VII deficiency or, more rarely, an inhibitor against factor VII.
A prolonged aPTT with a normal PT has a broader differential diagnosis. This combination of test results may denote the presence of an inhibitor against a clotting factor or a deficiency of one of the clotting factors in the intrinsic pathway. It is important to perform a repeat aPTT with equal volumes of the patient's plasma and normal plasma (a mixing study). If the normal plasma does not correct the prolonged aPTT, an inhibitor exists (e.g., a lupuslike anticoagulant or an inhibitor directed against a specific clotting factor). If the normal plasma corrects the prolonged aPTT, the patient has a clotting factor deficiency involving factor XII, factor XI, factor VIII, factor IX, or, more rarely, prekallikrein or high-molecular-weight kininogen. Because the clinical presentations of these clotting factor deficiencies are quite different (e.g., factor VIII and factor IX deficiencies are X linked, frequently with a positive family history), correlation with the clinical setting should be sought and the specific clotting factor levels subsequently determined [see 5:XV Coagulation Disorders]
Table 1 Clinical Manifestations of Hemorrhagic Disorders
Thrombocytopenia, a decreased platelet count, is a common clinical finding that may be caused by decreased platelet production or accelerated platelet removal. Accelerated platelet removal may result from immunologic mechanisms, nonimmunologic mechanisms, or sequestration of platelets in the spleen [see Table 1]. Thrombocytopenia can range from a transient, isolated finding to a severe, life-threatening condition.
Patients with thrombocytopenia may be asymptomatic; in these patients, the finding of a low platelet count may be first detected on a routine complete blood count. The most common symptomatic presentation of thrombocytopenia is bleeding—characteristically, mucosal and cutaneous. The hallmark of thrombocytopenia is nonpalpable petechiae, which reflect bleeding probably from capillaries or postcapillary venules [see Table 1]. Petechiae usually are only a few millimeters in diameter and occur at sites of increased intravascular pressure, such as over the lower extremities and on the oral mucosa, and at sites constricted by certain types of clothing, such as brassiere straps. Purpura, more extensive subcutaneous bleeding, may occur with a confluence of petechial lesions. Palpable purpura indicates an additional component of vascular inflammation and suggests underlying systemic vasculitis, such as cryoglobulinemia. Thrombocytopenia also leads to mucosal bleeding; deep-tissue bleeding is less common.
Blood count and peripheral smear
Laboratory examination should start with the complete blood count and examination of the peripheral smear. The importance of examination of the peripheral smear for estimation of platelet numbers, morphology, and the presence or absence of platelet clumping, as well as evaluation of associated white and red blood cell changes, cannot be overemphasized.
Normally, there are eight to 12 platelets per high-power field (×1,000 magnification), corresponding to a normal platelet count of 15,000 to 30,000/µl. There is no clearly demarcated level of platelets above which patients can be considered safe from bleeding. In general, a platelet count greater than 20,000/µl is considered safe; platelet counts of 10,000/µl or below may be tolerated in nonsurgical patients [see5:X Transfusion Therapy]. Patients with idiopathic thrombocytopenic purpura bleed less at a given platelet level than patients with aplastic anemia [see Idiopathic Thrombocytopenic Purpura, below]. Presumably, the larger, younger platelets are more effective in hemostasis. The risk of intracranial hemorrhage usually directs therapy.
Elderly patients and patients with coexistent illnesses bleed more than young patients and patients with thrombocytopenia alone. An associated disorder, such as liver dysfunction or connective tissue disease, increases the risk of serious bleeding.
In the initial laboratory evaluation, the complete blood count will establish whether the thrombocytopenia is a single disorder or is associated with anemia or leukopenia, which suggests a production defect as the underlying cause [see Platelet Production Defects, below]. If thrombocytopenia is an isolated finding, the physician should confirm the platelet count by repeating the complete blood count. A falsely low platelet count can be the result of in vitro platelet clumping caused by the presence of cold-dependent or ethylenediamenetetraacetic acid-dependent agglutinins. Examination of the blood smear and a repeat platelet count in a citrated or heparin-anticoagulated blood sample will resolve this problem.2
The peripheral smear may reveal morphologic abnormalities in platelets and indicate the presence of polychromatophilia, neutropenia, lymphopenia, spherocytosis, blastomycosis, or fragmented microangiopathic erythrocytes. The mean platelet volume, as determined by automated blood cell counters, may provide an additional clue to the cause of the thrombocytopenia. Low platelet volumes (< 6.4 femtoliters) suggest poor production, whereas larger volumes suggest rapid platelet regeneration or dysplastic platelet production.
Bone marrow aspirate and biopsy
When accelerated plate let removal appears to be the cause of the patient's thrombocytopenia, a rapid differential diagnosis should be made [see Table 3]. A bone marrow aspirate and biopsy will be very helpful in narrowing the diagnosis. Usually, thrombocytopenia with an abundance of normal megakaryocytes in the marrow is the result of accelerated platelet removal.3 Normally, platelets survive for 10 days and have a half-life of about 4 days; in accelerated-removal states, such as idiopathic thrombocytopenic purpura, the platelet half-life may be as short as 30 to 60 minutes. The platelet count will then reflect the balance between accelerated platelet removal and compensatory megakaryopoiesis.
Table 2 Typical Results of Tests for Hemostatic Function in Bleeding Disorders
Platelet survival studies are not generally available and are not usually necessary to determine whether accelerated platelet removal is occurring. Infusion of random-donor platelets can be used as a diagnostic and therapeutic procedure. When accelerated platelet removal is responsible for the thrombocytopenia, transfusion with six platelet packs only slightly elevates the platelet count, which then returns to baseline values in less than 24 hours. This therapeutic test becomes unreliable, however, if the patient has been previously alloimmunized by blood or platelet transfusions or by multiple pregnancies.
PLATELET PRODUCTION DEFECTS
Inadequate Platelet Production Due to Stem Cell Destructon
Disorders that injure stem cells or prevent their proliferation frequently cause thrombocytopenia. These disorders affect multiple hematopoietic cell lines, and the resulting thrombocytopenia is accompanied by varying degrees of anemia and leukopenia.
Table 3 Causes of Thrombocytopenia
Diagnosis of a platelet production defect is readily established by examination of a bone marrow aspirate and biopsy. The finding of a hypoplastic marrow in which the total cellularity is reduced, along with a decrease in megakaryocytes, implies aplastic or hypoplastic anemia. The first presumption of a cause in these cases is drug toxicity. A marrow that is fibrosed or infiltrated with leukemic or other malignant cells represents the syndrome of pancytopenia from infiltrated marrow.
A marrow aspirate and biopsy sample showing normal cellularity and normal maturation of the erythroid and myeloid precursors, with decreased numbers of apparently normal megakaryocytes, suggest that the patient has ingested a drug, such as ethanol, that specifically affects the megakaryocytic progenitor cells.4 Ethanol also produces ineffective megakaryopoiesis. In vitamin B12 deficiency and folate deficiency, all three marrow cell lines are affected. The marrow smear shows many large hyperlobated megakaryocytes. Some myeloproliferative disorders are characterized by ineffective megakaryopoiesis with bizarre binucleate megakaryocytes.
If a drug is the suspected cause of the thrombocytopenia, it should be discontinued. Specific replacement is required for deficiencies of vitamin B12 and folate. When the thrombocytopenia is causing significant bleeding, platelet transfusion will be required until the situation resolves [see 5:X Transfusion Therapy].
Interleukin-11 (IL-11), which plays a contributory role in megakaryopoiesis, has been approved for secondary prophylaxis against thrombocytopenia after chemotherapy5; however, it has limited efficacy and is associated with moderate toxicity.6 Two forms of recombinant thrombopoietin—one full length and one with a truncated form—have undergone extensive clinical trials. Both types are potent stimulators of megakaryocyte growth and platelet production and are effective in reducing the thrombocytopenia after nonmyeloablative chemotherapy. They have, however, elicited antibody formation; even more worrisome, use of the truncated form has led to the development of functionally neutralizing antibodies that cross-react with the endogenous thrombopoietin.6 Thrombopoietin mimetics are now in clinical trials.
Inadequate Platelet Production Due to Low Thrombopoietin Level
Moderate thrombocytopenia, generally in the 50,000 to 100,000/µl range, is commonly seen in patients with cirrhosis, which has been conventionally ascribed to platelet sequestration caused by hypersplenism. In addition, there is evidence that low-grade disseminated intravascular coagulation (DIC) occurs in cases of severe liver disease. Impaired clearance of fibrin degradation products may interfere with platelet function and fibrin polymerization. In one study, patients with advanced cirrhosis and thrombocytopenia were found to have low-normal serum levels of thrombopoietin (TPO). Serum TPO levels increased rapidly after orthotopic liver transplantation, and normalization of thrombocytopenia occurred within 14 days after transplantation, irrespective of the change in spleen size.7 The data indicate that the liver is a major site of TPO production, and decreased hepatic TPO production accounts for a significant part of the thrombocytopenia in liver disease.
ACCELERATED PLATELET REMOVAL DUE TO IMMUNE DESTRUCTION
Idiopathic Thrombocytopenic Purpura
The estimated incidence of idiopathic thrombocytopenic purpura (ITP) is 50 to 100 new cases per million persons per year, equally distributed between children and adults.8,9 ITP typically appears in young women. Predisposing diseases and contributing factors may include infectious mononucleosis and other acute viral illnesses, Graves disease, and Hashimoto thyroiditis,10 as well as antiphospholipid antibody syndrome.11 For ITP patients who have antiphospholipid antibody, the outcomes, courses, and response to therapy do not differ from those of other ITP patients.
ITP is an autoimmune disorder characterized by rapid platelet destruction that is caused by the presence of antibodies against the patient's own platelets. These autoantibodies bind to specific proteins on the platelet surface, and the antibody-coated platelets are removed by the reticuloendothelial system, especially in the spleen. The immunoglobulin on the platelet membrane is usually IgG (most commonly, IgG1). In some patients, only IgG2, IgG3, or IgG4 is present on the platelet surface, suggesting oligoclonality.12 Immunoglobulin on the plate let membrane is frequently directed against the platelet glycoprotein (GP) IIb-IIIa, the receptor complex that mediates fibrin-ogen binding and platelet aggregation; fortunately, most of these antibodies are not capable of functionally neutralizing the GPIIb-IIIa complex. Less frequently, the immunoglobulin is directed against the GPIb complex.13 Thrombopoietin levels are normal in ITP, indicating a normal or increased megakaryocyte mass (in contrast to a high thrombopoietin level in aplastic anemia).14 The marrow may respond to the thrombocytopenia by increasing platelet production. In many cases, however, the marrow response is suboptimal, probably because the antiplatelet antibodies also react with megakaryocyte cell surface antigens. The platelets produced in ITP are usually large and functional, which may account for the clinical observation that most patients with ITP do not have significant clinical bleeding.
The onset of ITP is usually insidious. History and physical examination are usually negative except for the presence of petechiae, most commonly in the lower extremities. Clinical bleeding is usually mild, consisting of purpura, epistaxis, gingival bleeding, and menorrhagia. Blood blisters (wet purpura) in the mouth indicate the presence of severe thrombocytopenia. Retinal hemorrhages are uncommon. The spleen is usually not palpable. The presence of a palpable spleen raises the possibility of systemic lupus erythematosus (SLE), lymphoma, infectious mononucleosis, or hypersplenism from underlying chronic liver disease.
The peripheral smear is usually normal; the few platelets that are present are large and well granulated. The presence of hypochromia suggests iron deficiency from chronic blood loss; spherocytes raise the possibility of associated autoimmune hemolysis (Evans syndrome); and red blood cell fragments (schistocytes) suggest DIC, thrombotic thrombocytopenic purpura (TTP), or hemolytic-uremic syndrome (HUS). The marrow shows abundant megakaryocytes; erythroid and myeloid precursors remain normal. Results of tests for SLE are negative. Platelet-associated IgG (PA-IgG) levels are elevated; however, because platelets normally contain IgG in their α-granules, PA-IgG does not distinguish between antiplatelet antibodies, immune complexes deposited on plate let surfaces, and antibodies released from the platelet granules and bound on its surface. Therefore, tests for PA-IgG are not useful in the diagnosis of ITP, unless the tests are performed by special research laboratories that measure platelet antigen-specific antibodies.15
The differential diagnosis of ITP includes a falsely low platelet count resulting from ethylenediamenetetraacetic acid (EDTA)-dependent or cold-dependent agglutinins that cause in vitro platelet clumping (diagnosed by reexamination of the platelet count in a citrated or heparin-anticoagulated blood sample); the gestational thrombocytopenia of pregnancy (usually a mild problem that is not associated with increased bleeding risk [see Idiopathic Thrombocytopenic Purpura in Pregnancy, below]); myelodysplastic syndrome (usually associated with anemia and leukopenia); and underlying lymphoproliferative disease.
Course and prognosis
ITP is a relatively benign disorder that has a mortality of approximately 1% to 5%; most deaths in adult cases result from intracranial bleeding. Acute ITP is usually confined to children and young adults and is frequently preceded by a viral illness. Permanent spontaneous remission occurs in less than 3 months. Chronic ITP, the usual adult variety, refers to disease that persists for more than 3 months. Although spontaneous remissions and relapses do occur in chronic ITP, long-term spontaneous remissions are uncommon. On the other hand, the long-term prognosis of ITP is benign, even in refractory cases, when these patients are managed properly.16
The treatment of ITP depends on the age of the patient; disease severity; whether petechiae are present alone or with moderate or severe mucosal or central nervous system bleeding; and whether the patient is pregnant.17
The American Society of Hematology has released an evidence-based practice guideline for the management of ITP,15 which can be summarized as follows:
Patients with asymptomatic mild or moderate thrombocyto penia (i.e., platelet count > 50,000/µl) do not require active therapy. They may be followed and simply alerted to report any mucosal bleeding or crops of new petechiae. Avoidance of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is strongly advised. The role of Helicobacter pylori eradication in the management of ITP is controversial. It may have a limited value in improving the thrombocytopenia in young patients who have evidence of H. pylori infection and have relatively mild thrombocytopenia (i.e., 30,000 to 70,000/µl) of short duration (< 2 years). H. pylori eradication is not useful in patients with chronic severe ITP.18
For patients with moderate mucosal bleeding, therapy is begun with prednisone at a dosage of 60 to 100 mg/day in divided doses. Corticosteroids interfere with the macrophage attack on platelets and eventually reduce the amount of antiplatelet antibody produced by splenic and marrow lymphoid cells. A study showed that a 4-day course of high-dose dexamethasone (40 mg daily) achieved a high remission rate (85%) in newly diagnosed ITP patients; of those patients who responded to therapy, 50% had a sustained response.19 This remarkably high rate of long-term response after a single course of dexamethasone will require confirmation and longer follow-up.
Unless bleeding is severe, the patient need not be hospitalized. Heavy physical activity, particularly any activity that involves the Valsalva maneuver, should be avoided so as not to increase intracranial pressure. The avoidance of aspirin and other NSAIDs should be emphasized. If required, red blood cell transfusions can be given; however, it is rarely necessary to transfuse platelets in such cases.
The platelet count usually rises several days to 2 to 3 weeks after the start of therapy. When the platelet count reaches normal levels, the prednisone dose can be tapered over a 3- to 4-week period. Although complete long-term remissions with prednisone alone have been reported, sustained complete response after therapy occurs in fewer than 10% of patients.
Splenectomy, usually performed by laparoscopy, is indicated if platelet counts remain below 30,000/µl after 4 to 6 weeks of steroid therapy or when the platelet count begins to fall again after the tapering of steroid. The procedure produces long-standing remission in about 65% of patients with ITP. It is best to administer intravenous immune globulin (IVIg) a few days before splenectomy so that the patient will have a platelet count of at least 30,000 to 50,000/µl at the time of surgery. Generally, a full course of IVIg therapy (1 g/kg/day for 2 days or 0.4 g/kg/day for 5 days) is not required when given as preparation for splenectomy. IVIg will produce a transient increase in the platelet count in the majority of patients, but it is a very expensive therapy. The platelet count usually begins to rise on the first postoperative day, often overshooting normal values by the second week. Pneumococcal, Haemophilus influenzae, and meningococcal vaccines should be administered 1 to 2 weeks before surgery.
If the patient is elderly or frail and hence may not survive splenectomy, the disease may be controlled by administration of the minimum amount of corticosteroids required to raise the platelet count to 30,000 to 50,000/µl, a level above which severe bleeding rarely occurs. Because patients with ITP who are classified as therapeutic failures generally do well clinically, the role of such potentially dangerous agents as cyclophosphamide and azathioprine in the management of such cases should be evaluated on a case-by-case basis.
Severe mucosal or CNS bleeding is a true medical emergency requiring hospitalization. Red cells are transfused as required, and prednisone is administered immediately, beginning with a 100 mg dose and then continuing at a level of 25 mg every 6 hours. A full course of IVIg should be administered, and transfusion with 8 to 10 units of random-donor platelets should be carried out when the infusion of the first dose of IVIg, usually given over approximately 60 minutes, is complete. The platelet transfusion after the infusion of IVIg produces a greater and more durable increase in the platelet count. Side effects include generalized aches, headache, flushing, fever, and chills. When severe uterine bleeding occurs, a single 25 mg dose of conjugated estrogen can be administered intravenously to control the hemorrhage. It should be emphasized that the benefit of IVIg is usually transitory and lasts only a few days. Plans for splenectomy should follow this emergency therapy.
The mechanism of action of IVIg is not completely understood. It may produce reticuloendothelial blockade by blocking the IgG-Fc sites on the monocyte-macrophages. Highly specific anti-idiotype antibodies may also block the binding of platelet autoantibodies to the platelet GPIIb-IIIa antigen.20 Studies indicate that the catabolic rate of IgG is mediated by a new receptor for the Fc component of IgG, termed FcRn (neonatal Fc receptor, so named because it was initially identified in neonatal intestinal epithelium), on the vascular endothelial cells. Normally, IgG, but not IgM, that enters the cell through the process of pinocytosis is protected from catabolic breakdown by binding to the FcRn. After the administration of high-dose IVIg, this receptor is presumably saturated, permitting the degradation of the pathologic antibody to occur in proportion to its concentration in plasma.21
Refractory Idiopathic Thrombocytopenic Purpura
About 40% of ITP patients are characterized as refractory; they either remain severely thrombocytopenic after splenectomy and corticosteroid therapy or go into remission but later experience a relapse. Approximately 25% to 40% of patients will have a relapse 5 to 10 years after an initially successful splenectomy.16 Because serious hemorrhage is uncommon with platelet counts above 30,000/µl, it is often prudent to accept an incomplete response and not proceed to more toxic forms of management. Immunosuppressive agents are generally the mainstay of therapy at this stage. However, it should be emphasized that there are no large randomized studies to address this difficult problem and that generally these patients should be referred to a hematologist.
There are several major treatment alternatives for refractory patients. Rituximab, a chimeric anti-CD20 monoclonal antibody, when administered at 375 mg/m2 I.V. once weekly for 4 weeks, produces a lasting and substantial response in approximately one third of patients with chronic refractory ITP; however, long-term follow-up is limited.22 The majority of the responses occur within 8 weeks after the first infusion. The therapy is generally well tolerated, with most of the side effects (i.e., fever, chills, mild hypotension, and bronchospasm) being infusion related and occurring during or after the first infusion. Rituximab produces a profound and prolonged peripheral B cell depletion in all patients, which can last for more than a year, but serious infection is rare. Azathioprine (100 to 150 mg/day orally) or, alternatively, cyclophosphamide (100 to 150 mg/day orally) plus prednisone (40 to 60 mg/day orally) can be given, but this therapy requires weekly monitoring of complete blood count and platelet count. Prednisone may be tapered and azathioprine or cyclophosphamide adjusted to avoid severe leukopenia. A frequent mistake is to discontinue the therapeutic trial prematurely. Both azathioprine and cyclophosphamide are myelosuppressive and should be given in sufficient dosages to cause a mild leukopenia, with a white blood cell count of approximately 3,000/µl, and both have been associated with development of myelodysplastic syndrome and acute myeloid leukemia. After 1 month, alternate-day prednisone therapy should be considered to avoid steroid side effects. Because of the concern of long-term marrow toxicity associated with azathioprine and cyclophosphamide, rituximab should be considered the first-line therapy in refractory ITP patients, if treatment is indicated.
Another alternative is antibody therapy with intermittent courses of IVIg at the dosage schedules described (see above). The cost of this therapy and the usual short-lived response make it an unattractive choice. Anti-D antibody has been used successfully in Rh+(D+) patients with ITP; in the presumed mechanism of action, the antibody-coated red blood cells block Fc receptors on macrophages and prevent the accelerated removal of platelets. Other therapeutic options include vincristine, vinblastine,23 danazol,24 high-dose dexamethasone, cyclosporine, interferon alfa, and plasmapheresis.
In the refractory splenectomized patient, it is important to check for the continued presence of Howell-Jolly bodies and the possibility of an accessory spleen. The disappearance of Howell-Jolly bodies suggests the presence of a remaining accessory spleen or a regenerated spleen.
Patients with clinically significant thrombocytopenic bleeding can also benefit from fibrinolysis inhibitor ε-aminocaproic acid (EACA). EACA can be given at 2 to 3 g orally four times daily until hemostasis is achieved.
HIV-Related Idiopathic Thrombocytopenic Purpura
HIV-1-related ITP appears to have a pathophysiology that is somewhat different from that of non-HIV-associated ITP, in that the antigenic specificity for the antiplatelet antibody is different. Two major antigenic determinants have been identified—a linear peptide in the platelet membrane GPIIIa and a cleavage product of talin, a platelet cytoskeletal protein, that can be generated by HIV-1 protease.25,26 In patients with HIV infection, plate lets also contain increased amounts of IgG, IgM, complement, and immune complexes. Platelet survival is moderately short, and platelet production is impaired, especially at the later stages of the disease.27
The use of immunosuppressive agents in HIV-infected patients is hazardous. If the drop in the platelet count is modest, no therapy is needed. When the thrombocytopenia is severe, a short course of prednisone can be administered, followed by splenectomy.
Acute thrombocytopenic hemorrhage in HIV-associated ITP may be managed with high-dose IVIg, similar to the management of other ITPs. Chronic HIV-associated ITP may respond to oral zidovudine (AZT) or other antiviral therapies [see 7:XXXIII HIV and AIDS]. Anti-D antibody, dapsone, and interferon have also been used with some success.28,29,30 Patients who refuse splenectomy or who are thought to be poor surgical candidates may respond to low-dose splenic irradiation.31
Idiopathic Thrombocytopenic Purpura in Pregnancy
Mild thrombocytopenia, generally in the range of 110,000 to 150,000/µl and seldom below 70,000/µl, occurs in 5% of healthy pregnant women. When thrombocytopenia is observed for the first time during pregnancy, the differential diagnosis must include preeclampsia [seeTable 3]. If other diagnoses can be excluded, the diagnosis is gestational thrombocytopenia (incidental thrombocytopenia of pregnancy); it requires no management.32 If the diagnosis of ITP is made, the the patients is considered to be at high risk for complications. The platelet counts should be monitored regularly and closely, especially in the third trimester, because in many pregnant women with ITP, thrombocytopenia progressively worsens over the course of the pregnancy. The therapeutic choices are limited because splenectomy may cause spontaneous abortion and immunosuppressive agents may damage the developing fetus; therefore, therapy is usually limited to corticosteroids or IVIg. Because corticosteroids increase the risk of preeclampsia and gestational diabetes, IVIg is the drug of choice. Generally, no treatment is required until the platelet count has fallen to 20,000 to 30,000/µl or there is clinical bleeding. Typically, a single dose of IVIg (1 g/kg I.V. over 6 hours) will raise the platelet count to above 50,000/µl in the majority of patients, which will last for 3 to 4 weeks. Repeated doses can be given if necessary. In cases of severe thrombocytopenic hemorrhage, however, all of the available therapies should be used to protect the life and well-being of the mother.
Because the antiplatelet autoantibody in ITP has broad specificity and is almost always an IgG, it can cross the placenta and produce thrombocytopenia in the fetus. During a vaginal delivery, the pressure applied to the head of a thrombocytopenic fetus may induce an intracranial hemorrhage. Concern about this occurrence led many experts in the past to recommend early cesarean sections in women with a history of ITP or active disease. No data exist, however, to support this recommendation, and a much more conservative approach is now generally accepted. Most pregnant women with ITP undergo vaginal deliveries; cesarean sections are performed only for obstetric indications.
There is no correlation between maternal platelet count and the infant's platelet count. A mother with a history of ITP who has a normal platelet count can deliver a thrombocytopenic neonate (~10% incidence). Alternatively, a thrombocytopenic mother can have an infant with a normal platelet count. Measurement of maternal antiplatelet antibody is of no clinical utility. The best predictor of thrombocytopenia in a neonate is the mother's previous experience of giving birth to an infant with neonatal thrombocytopenia.33 Neonatal severe thrombocytopenia—defined as a platelet count at birth that is less than 20,000/µl—is uncommon (1% to 5% of births), and severe bleeding complications are rare (< 1%).34,35 The occurrence of neonatal severe thrombocytopenia is also unpredictable. The risk of intracranial hemorrhages in these infants is low (< 1%), and it cannot be reduced by cesarean section.36 Percutaneous umbilical blood sampling is generally not recommended. Many infants who are born to mothers with ITP will have a decrease in platelet count after delivery, with a nadir on day 2; the infant's platelet count should be monitored daily for several days.32 Maternal ITP is not a contraindication to breast-feeding.
Thrombocytopenic Purpura with Lymphomas and Systemic Lupus Erythematosus
Patients with SLE, Hodgkin disease, or non-Hodgkin lymphoma can present with a clinical picture identical to that seen in ITP. The diagnostic approach and therapy are the same in these cases as they are in ITP. Splenomegaly with splenic sequestration, marrow infiltration with malignant cells, and recent antineoplastic or immunosuppressive therapy should be excluded. Patients with SLE or lymphoma may have Evans syndrome, in which ITP is associated with autoimmune hemolytic anemia. The management of Evans syndrome is the same as that of ITP and autoimmune hemolytic anemia.
Posttransfusion purpura (PTP) is characterized by acute onset of severe thrombocytopenia, often with a platelet count below 10,000/µl, accompanied by clinical bleeding. It may occur from 2 to 10 days after a transfusion of packed red blood cells or platelet-containing components. Almost all of the affected patients are multiparous women. Such disorders as septic thrombocytopenia, DIC, and heparin-induced thrombocytopenia must be considered in the differential diagnosis. The thrombocytopenia usually lasts for about 4 weeks. Because platelet transfusions are usually futile and sometimes precipitate severe systemic responses, they should be avoided if possible.
The pathophysiology of PTP is not completely understood. In most cases, the patient has been exposed to platelet alloantigens during pregnancy or as a result of a transfusion. Most patients with this disorder have antibodies to the human platelet antigen-1 (HPA-1), a polymorphic epitope present on platelet surface GPIIIa. The HPA-1 has two isoforms, HPA-1a and HPA-1b (previously PLA-1 and PLA-2). In the United States, approximately 98% of the white population, 99% of the African-American population, and 99% of the Asian-American population are homozygous for HPA-1. Patients in whom PTP develops are usually HPA-1a negative and HPA-1b positive. The patient has been sensitized to the HPA-1a antigen, most frequently during pregnancy, and reexposure to HPA-1a platelets during red cell transfusion leads to an anamnestic response and the destruction of the foreign platelets. It is puzzling that alloantibody directed against an antigen present on foreign platelets results in destruction of the patient's autologous platelets, which do not express the HPA-1a antigen. There is evidence suggesting that the HPA-1a antigen becomes soluble and attaches to the HPA-1a-negative platelets. Alternatively, exposure to foreign platelets may induce the formation of a true autoantibody against the endogenous platelets. The HPA-1a/HPA-1b polymorphism accounts for 80% to 90% of PTP. However, the presence of an alloantibody is necessary but insufficient for the development of PTP. Some patients with anti-HPA-1a antibodies become refractory to platelet transfusions but do not have PTP.37 In addition, the incidence of PTP is far less common than might be predicted by the 1% to 2% of the general population who are homozygous for HPA-1b.
Confirmation of the diagnosis of PTP requires serologic studies demonstrating the presence of anti-HPA-1a antibody and a homozygous HPA-1b genotype. Several rapid platelet genotyping techniques based on the polymerase chain reaction have been developed. Homozygous deficiency of platelet CD36 (glycoprotein IV) occurs in 3% to 5% of Asians and Africans, and alloantibody against CD36 has also been found to be associated with PTP.38 There are no controlled clinical trials evaluating therapy for PTP because of the limited number of cases. IVIg, used at doses similar to those used in the treatment of ITP, is efficacious in about 80% of cases. Plasmapheresis is also efficacious, but it is more cumbersome than IVIg administration. Use of high doses of corticosteroids is not consistently effective.39 Transfusion of HPA-1a-negative platelets may provide some transient benefit in life-threatening bleeding situations.40
Drug-Induced Immune Platelet Destruction
Drug-induced immune platelet destruction is indistinguishable from ITP. The bone marrow shows abundant megakaryo cytes, and special laboratories can detect the presence of antidrug antibodies.
Quinidine and quinine purpura
The pathogenic antibodies in cases of quinidine and quinine purpura develop as early as 12 days after exposure to the offending agent. In most cases, drug-dependent antibodies to platelet surface GPIb-IX have been identified in patients' sera.41 The antibodies are drug dependent because they bind to the platelets only in the presence of quinine or quinidine. Presumably, the binding of the drugs to these platelet surface glycoproteins induces new antigenic sites on the proteins that are recognized by the antibodies.
The agent (quinidine or quinine) should be withdrawn in such cases. Neither corticosteroid therapy nor emergency splenectomy is of documented benefit in purpura induced by these agents. Plasmapheresis to remove the drug and antibodies would appear to be a logical treatment, but there are no systematic studies of its effectiveness. Transfused platelets are removed as rapidly as the recipient's own platelets. Treatment with prednisone and IVIg in a dose similar to that used in ITP is recommended. Platelet transfusion after IVIg infusion may be given to control life-threatening bleeding.
A quinine-induced thrombocytopenia that is closely followed by the development of HUS has been recognized. Quinine-dependent antibodies to platelets, as well as to endothelial cells, have been found in patients' sera.42 Even the small amount of quinine in tonic water seems to be sufficient to trigger recurrent bouts of the syndrome. Other drugs that may occasionally produce drug-dependent thrombocytopenia include dipyridamole and trimethoprim-sulfamethoxazole.43
Heparin-induced thrombocytopenia (HIT) is a frequent cause of drug-induced thrombocytopenia in hospitalized patients. Despite the presence of modest to moderate thrombocytopenia, HIT is rarely associated with bleeding but is associated with significant and sometimes fatal thrombosis [see 5:XIV Thrombotic Disorders].
Gold salt therapy for rheumatoid arthritis produces thrombocytopenia, which is sometimes severe, in 1% to 3% of patients. There are drug-induced autoantibodies that target platelet membrane GPV, but the presence of gold is not required for their reactivity.44 Most patients respond to therapy with 60 mg of prednisone daily. IVIg is also efficacious.
An ITP-like syndrome has been reported in intravenous cocaine users. They have been shown to respond to an approach similar to that employed in patients with ITP.45
Thrombocytopenia caused by GPIIb-IIIa receptor antagonists
Three parenteral GPIIb-IIIa antagonists—abciximab, eptifibatide, and tirofiban—have been approved for use in the treatment of acute coronary artery syndrome and as adjunctive therapy in coronary angioplasty. In contrast to the low platelet counts in other types of drug-induced thrombocytopenia, patients who have low platelet counts resulting from GPIIb-IIIa receptor antagonists can develop acute, often profound thrombocytopenia within a few hours after drug administration. In patients receiving abciximab, thrombocytopenia occurs in about 1% after the first exposure. After a second exposure, the incidence of thrombocytopenia rises to 4%.46 The incidence of drug-induced thrombocytopenia associated with eptifibatide and tirofiban is probably also about 1% after first exposure.47
The abrupt development of severe thrombocytopenia in patients who have never been exposed to these drugs initially suggested that platelets were being destroyed by a nonimmune mechanism. However, accumulating evidence indicates that drug-dependent antibodies, which occur naturally, are the underlying cause. Preexisting anti-GPIIb-IIIa autoantibodies are present in these patients, and after the administration of the anti-GPIIb-IIIa antagonist, the binding of the drug to GPIIb-IIIa induces conformational changes in GPIIb-IIIa such that new epitopes are exposed that are recognized by the autoantibodies. These actions would explain the acute onset of profound thrombocytopenia.47
When thrombocytopenia develops (i.e., when platelet counts drop below 100,000/µl), the GPIIb-IIIa antagonist and any other potentially offending medications (e.g., heparin) should be discontinued immediately. Depending on the platelet count, it may not be advisable to discontinue antiplatelet agents such as aspirin or clopidogrel, because in such cases, patients are at high risk for acute coronary artery or stent thrombosis. If the platelet count drops below 10,000/µl, strong consideration should be given to platelet transfusion. In general, only one single-platelet transfusion is sufficient. There are anecdotal reports of acute coronary thrombosis associated with platelet transfusion in this setting when the platelet count climbs over 50,000/µl and the patient is off all antiplatelet agents. Thus, antiplatelet agents may need to be reinstituted. Because eptifibatide and tirofiban have very short half-lives and are cleared from the circulation within hours, the duration of thrombocytopenia is short, once the offending drugs have been discontinued. However, because abciximab has a much longer half-life—with inhibition of platelet function reported up to 1 week after drug discontinuance—thrombocytopenia can persist for 5 to 7 days. Platelet counts should be obtained in all patients before, as well as within 2 to 4 hours after, the initiation of an intravenous GPIIb-IIIa antagonist. It should be noted that a subgroup of patients develop delayed thrombocytopenia 5 to 8 days after abciximab administration. On the basis of limited published experience, it appears to be safe to administer eptifibatide or tirofiban to patients who are sensitive to abciximab, and vice versa.47
Thrombocytopenia caused by metabolites of naproxen and acetaminophen
Five patients have experienced thrombocytopenia after taking naproxen and acetaminophen. In each case, antibodies that reacted with normal platelets in the presence of a known drug metabolite of naproxen or acetaminophen were identified.48 Therefore, the sensitizing agents are drug metabolites that formed in vivo.
ACCELERATED REMOVAL OF PLATELETS BY NONIMMUNOLOGIC MECHANISMS
There are several nonimmunologic causes for thrombocytopenia. Blood vessel wall injury with increased thrombin generation and increased platelet activation and consumption occurs in several of these conditions.
Thrombotic Thrombocytopenic Purpura and Adult Hemolytic-Uremic Syndrome
TTP and HUS encompass a group of clinical syndromes characterized by widespread platelet-fibrin thrombi deposition in the small arteries and arterioles and capillaries. Thrombotic microangiopathy is a distinct feature of both TTP and HUS; however, the underlying pathogenetic processes in TTP and HUS may differ [see Pathogenesis, below]. Familial TTP/HUS is rare and usually occurs in the immediate postnatal period or infancy, although there are reported cases of delayed onset until the second to third decade of life. More frequently, TTP is either idiopathic or secondary to a variety of conditions [see Etiology, below].
TTP/HUS occurs spontaneously and is also associated with pregnancy, cancer, bone marrow transplantation, autoimmune diseases, and various drugs. In pregnancy, it resembles severe preeclampsia. In the postpartum period, the CNS manifestations may initially be confused with postpartum depression, with tragic results. Cases have been reported after a normal delivery and with abruptio placentae and preeclampsia.
Several drugs appear to cause TTP/HUS. These include chemotherapeutic drugs (e.g., mitomycin C, bleomycin, and cisplatin), immunosuppressive agents (e.g., cyclosporine and FK506), the antiplatelet agent ticlopidine, oral contraceptives, and quinine. Anecdotal cases of TTP/HUS associated with clopidogrel, which is related to ticlopidine, have also been reported.49
There have been significant recent advances in the understanding of TTP, showing that the proper processing of von Willebrand factor (vWF) multimers plays a key role in its pathogenesis. vWF is an abundant plasma protein that mediates platelet adhesion to the subendothelium and serves as a carrier molecule for factor VIII [see 5:XII Hemostasis and Its Regulation]. vWF is synthesized by both megakaryocytes and endothelial cells. Monomers of vWF (280,000 daltons) are cross-linked by disulfide bonds to form vWF multimers, which are released into the circulation by endothelial cells and are stored within platelet α-granules and the Weibel-Palade bodies in endothelial cells. The stored vWF multimers can be released upon platelet or endothelial stimulation. These released vWF multimers are larger than plasma vWF multimers and are referred to as ultra-large vWF (ULvWF) multimers, with a molecular size up to 20 million daltons. Functionally, these are the most reactive vWF multimers. In 1982, ULvWF multimers were found in the plasma of patients with chronic relapsing TTP, giving rise to the hypothesis that TTP may result from the deficiency of a vWF-cleaving protease (depolymerase), which causes ULvWF multimers to circulate, contributing to the development of thrombosis.50 This hypothesis has been proved largely correct with the recent identification of the vWF-cleaving protease and the demonstration that deficiency of the vWF-cleaving protease activity is associated with TTP.
The vWF-cleaving protease has been identified as ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif13).51 It is a novel metalloprotease that cleaves vWF monomer at a specific site (842Tyr-843Met) in the A2 domain. Current data indicate that ULvWF multimers are secreted from stimulated endothelial cells as a long “string” anchored on the endothelial cell surface. Plasma ADAMTS13 may attach, under flowing conditions within the blood, to the cell surface-bound ULvWF multimers (via the A3 domain in the vWF monomer) and cleave them into the vWF multimers that are normally found in plasma.52 Partial unfolding of the ULvWF multimers by shear stress forces in the blood presumably enhances the enzymatic cleavage process. Patients with familial TTP have hereditary deficiency of ADAMTS13,53 whereas patients with acquired idiopathic TTP have antibodies that inhibit the ADAMTS13 activity.54,55 In either case, the persistence of ULvWF multimers on the stimulated surface of the endothelial cell leads to the adhesion and subsequent aggregation of platelets, which in turn lead to the formation of platelet thrombi [see Figure 1]. (Presumably, platelets do not bind to the smaller plasma vWF multimers, because the platelet binding sites are not exposed in these vWF multimers). In addition to causing ischemic injury at the site of thrombi formation, it is likely that platelet thrombi resulting from aggregation of ULvWF multimers will break up and embolize downstream, resulting in further ischemic tissue damage.
Figure 1. ADAMTS13 activity in normal and thrombotic thrombocytopenia purpura plasma. (a) In normal persons, ADAMTS13 enzyme molecules from the plasma attach to and then cleave the unusually large von Willebrand factor (ULvWF) multimers that are secreted in long strings from stimulated endothelial cells. (b) In patients with thrombotic thrombocytopenic purpura (TTP), a deficiency of ADAMTS13 prevents the cleavage of ULvWF multimers secreted by endothelial cells. Platelets carried by flowing blood adhere to the uncleaved ULvWF multimers, resulting in the development of platelet thrombi.
The gene encoding ADAMTS13 is located on chromosome 9q34. More than 50 mutations in this gene have been identified in patients with familial TTP, most of which result in greatly reduced ADAMTS13 secretion in vitro.51 In many cases of acquired idiopathic TTP, an IgG autoantibody against ADAMTS13 is produced transiently, leading to severe deficiency of ADAMTS13 activity. ULvWF multimers are detectable in the plasma in some patients during the acute episodes but not after recovery.50
Although the role of ADAMTS13 in the pathogenesis of TTP has been established, it appears that the majority of patients with HUS do not have severe ADAMTS13 deficiency, strongly suggesting that the pathogenesis of HUS is different.
ADAMTS13 as a screening assay
The clinical utility of measuring ADAMTS13 is not established. In part, this is because there is no gold standard for its measurement; most of the current assays have long turnaround times and are not readily available. Furthermore, the sensitivity and specificity of ADAMTS13 deficiency for the diagnosis of TTP remains unclear. Decreased vWF-cleaving activity is found in many clinical conditions that are not associated with TTP, including cirrhosis, chronic renal insufficiency, ITP, DIC, SLE, leukemia, pregnancy, and the postoperative state; it is also associated with advancing age.56,57 In a prospective study involving 37 patients, severe deficiency in the ADAMTS13 level (< 5%) was found in 80% of patients with idiopathic TTP but in none of the patients with TTP associated with hematopoietic stem cell transplantation, cancer, drugs, or pregnancy.58 Thus, acquired TTP may be considered as either idiopathic or secondary; the former is generally associated with severe ADAMTS13 deficiency, whereas the latter is not. Among the patients with idiopathic TTP and severe ADAMTS13 deficiency, 44% had inhibitors. Other studies found an incidence of inhibitors in idiopathic TTP of 65% to 95%; however, part of the variation in study results may have to do with patient selection.59,60
The reason why an inhibitor is not detectable in a substantial number of the idiopathic TTP patients is unclear. It is possible that the current assay is not sufficiently sensitive; alternatively, the assay may involve a nonneutralizing antibody that binds to ADAMTS13 and accelerates its clearance. New assays using a recombinant vWF fragment as the substrate for the ADAMTS13 protease are in development and should help clarify some of these issues.61,62
Clinical features and diagnosis
The five major manifestations (pentad) of TTP are (1) severe microangiopathic hemolytic anemia associated with a very high serum lactic dehydrogenase (LDH) level and a blood smear showing the characteristic schistocytes and helmet cells; (2) moderate to severe thrombocytopenia with increased marrow megakaryocytes, which indicates intravascular platelet activation and consumption; (3) fever, which is occasionally quite high; (4) CNS signs and symptoms that can be quite mild initially with transient agitation, headache, and disorientation but that can sometimes progress explosively to hemiparesis, aphasia, seizures, focal deficits, coma, and death; and (5) renal disease, which is usually mild and produces moderate elevations of serum creatinine and urinary protein levels. It should be emphasized that many patients do not present with all these signs and symptoms. Patients with familial TTP/HUS typically exhibit a chronic relapsing course.
The adult form of HUS has features similar to those of TTP, although the pathophysiology may not be identical [see Pathogenesis, above]. Common features of TTP and HUS include microangiopathic hemolytic anemia, thrombocytopenia, and the presence of platelet fibrin thrombi in the small vessels. Renal involvement is uniformly severe in HUS, whereas CNS disease is less prominent than in TTP. There is a distinct form of HUS that occurs in children after gastrointestinal infection with Escherichia coli, usually serotype 0157:H7. These patients present with bloody diarrhea and hemorrhagic colitis. E. coli 0157:H7 or other strains elaborate verotoxins (also called Shiga toxins) that bind to specific receptors on the endothelial surface, causing cell damage and even cell death.63 Verotoxin-1 (VT-1) can induce the upregulation of various prothrombotic and proinflammatory adhesive molecules on endothelial cells.64 The microvascular endothelial cells are particularly susceptible because they have a high expression of VT-1 receptors, which may explain the propensity for thrombosis in the microcirculation. Antibiotic treatment of children with E. coli 0157:H7 infection increases rather than decreases the risk of HUS, presumably because it causes the release of verotoxins from injured bacteria in the intestine, making the toxins more available for absorption. Thus, routine treatment with antibiotics is not recommended.65
Whereas a severe deficiency of ADAMTS13 (< 5%) may be specific for TTP,66 patients with severe ADAMTS13 deficiency may have prolonged asymptomatic periods. It is becoming clear that loss of ADAMTS13 activity, with an associated increase in circulating ULvWF multimers, is necessary but insufficient to cause an acute clinical TTP episode. The current data support the hypothesis that severe ADAMTS13 deficiency, be it from familial or acquired cause, predisposes the patient to thrombosis, and a second vascular inflammatory stimulus, such as infection, surgery, or pregnancy, causes the endothelium to increase its release of the stored UlvWF multimers, which, in the setting of grossly impaired processing, gives rise to ULvWF platelet thrombi in the microcirculation and clinical thrombosis.
Both TTP and HUS must be differentiated from SLE and from Evans syndrome. Microangiopathic hemolysis, neutrophilic leukocytosis, and a negative direct Coombs test (direct antiglobulin test) strongly suggest TTP or HUS. Coagulation tests usually reveal no significant abnormalities (i.e., no evidence of DIC); serum LDH is usually elevated. A marrow biopsy is generally not required but may show the characteristic, but not pathognomonic, platelet-fibrin hyaline thrombi in small arteries and arterioles.
Prompt institution of plasma exchange with fresh frozen plasma is the treatment of choice for TTP/HUS. In a large randomized trial by the Canadian Apheresis Group, intensive plasma exchange was more effective than plasma infusion in terms of patient survival (78% versus 63%).67 In that study, 1.5 times the calculated plasma volume was removed and replaced with fresh frozen plasma during each of the first 3 days of therapy; subsequently, one single-volume exchange a day was performed for a minimum of 7 days. Some investigators obtained good results with a daily single-volume exchange instead of a 1.5-volume exchange.68 It is reasonable to start with a daily single-volume exchange if the patient is clinically relatively stable, with moderate thrombocytopenia and no significant neurologic impairment. However, if the clinical situation worsens, more intensive double-volume plasma exchange (5,000 to 6,000 ml/day, or approximately 80 ml/kg/day) is indicated. Because vWF multimers are present in cryoprecipitate, cryosupernatant (i.e., fresh frozen plasma from which cryoprecipitate has been removed) can be substituted as replacement fluid when a patient is not responding to routine plasma exchange. One uncontrolled study showed increased benefit from this preparation as compared with fresh frozen plasma.69 Once therapeutic benefit has been achieved (as measured by restoration of normal CNS function, by rising platelet counts, and by falling LDH levels), the intensity and frequency of plasma exchange can be reduced to single-volume exchanges, first three times weekly and then twice weekly.
Although the importance of prompt plasma exchange has been established, the use of corticosteroids,70 aspirin, and dipyridamole has not been tested in prospective clinical trials. With the observation of autoantibody against ADAMTS13 as a significant cause of acquired idiopathic TTP, rituximab (375 mg/m2 I.V. once weekly for 4 weeks) has been tried and reported to be effective, although the overall experience is still limited.71,72,73 Because pheresis tends to lower the platelet count in a patient who is already thrombocytopenic, the problem of platelet transfusion arises. Some investigators have observed that platelet infusion may lead to exacerbation of TTP,74 whereas others use platelet transfusions as required.
In the previously described prospective study of patients with severe deficiency in ADAMTS13 activity (see above), plasma exchange proved to be a useful therapy; among the patients with idiopathic TTP and severe ADAMTS13 deficiency without detectable inhibitors, the majority responded to plasma exchange with complete remission and a rise in the ADAMTS13 level.58 However, in patients with mild ADAMTS13 deficiency and high inhibitor levels, plasma exchange was not effective in reducing the inhibitor titer or in increasing the ADAMTS13 activity. Nevertheless, some of these patients had a favorable clinical response, including resolution of thrombocytopenia and cessation of hemodialysis. Among the patients whose TTP was not idiopathic, response to plasma exchange was variable. Of note, mortality in patients with idiopathic TTP with severe ADAMTS13 deficiency has been shown to be 15% to 20%, whereas mortality in patients with nonidiopathic TTP has been much higher, at 55% to 60%.58,60 Many of the patients in the latter group have had serious underlying disease and comorbidities, such as hematopoietic stem cell transplantation, which likely has contributed to the high mortality.
Management of acute TTP should therefore depend on the clinical manifestations and course of the disease.75 In all cases, plasma exchange is first-line therapy. Patients who respond promptly and completely to plasma exchange—which most likely will be those patients with idiopathic TTP and very low or nondetectable levels of inhibitors—may not need any further treatment. For patients who show a suboptimal response—such as an initial rise in platelet counts or a recurrence in thrombocytopenia when the plasma exchange treatments are decreased—glucocorticoid is indicated. For patients who experience a more aggressive course (e.g., those with severe neurologic abnormalities or those who do not respond to the initial plasma exchange with or without steroid therapy), more intensive immunosuppressive therapies, such as rituximab, should be considered.
Microangiopathy may persist for weeks or months after all other evidence of disease has subsided. In a large follow-up study of TTP patients, about one third of patients who entered remission had a relapse over a 10-year period.76 The risk of recurrence is largely restricted to patients with severe ADAMTS13 deficiency—primarily, patients with idiopathic TTP. Relapse seldom occurs in patients who have TTP in association with hematopoietic stem cell transplantation or drugs. Conflicting data have been reported regarding patients who have had relapses after TTP associated with pregnancy.
Most experts treat adult HUS in a manner similar to that for TTP. However, the response to plasma exchange appears to be less favorable in HUS than in TTP, which may be consistent with the recent finding that the ADAMTS13 level is generally not diminished in HUS.
Thrombocytopenia Induced by Infection
Severe viral, bacterial, fungal, and parasitic infections can produce DIC and, consequently, thrombocytopenia [see 5:XIV Thrombotic Disorders]; however, mechanisms other than DIC may also cause infection-associated thrombocytopenia.
Viral infections such as dengue fever and congenital rubella can directly damage the megakaryocytes. Varicella can cause a form of thrombocytopenia that has the characteristics of an immune reaction: increased numbers of megakaryocytes, no evidence of DIC, and the presence of PA-IgG. Usually, no therapy is required. The acute thrombocytopenia in infectious mononucleosis is probably immune mediated, as shown by the increase in marrow megakaryocytes and the favorable response to corticosteroids.
Patients who have severe gram-negative septicemia and platelet counts lower than 50,000/µl usually have evidence of DIC. However, many patients who have both gram-negative and gram-positive septicemia and platelet counts between 50,000 and 150,000/µl have no signs of DIC. The PA-IgG levels are often elevated, which may represent immune complexes deposited on the platelet surface rather than antiplatelet autoantibodies. The key to controlling the thrombocytopenia is establishing appropriate therapy for the infection. If DIC is present, it should be managed with careful control of hypotension and blood volume.
Thrombocytopenia is common in malaria, although DIC is rare. Platelet survival is short, and elevated PA-IgG has been found to be elevated. The IgG antibody appears to bind to malarial antigens adsorbed to the platelet surface.77
Thrombocytopenia during Pregnancy and Peripartum Period
Mild thrombocytopenia, with platelet counts generally in the range of 110,000 to 150,000/µl and seldom below 70,000/µl, occurs in 5% to 8% of pregnant women (gestational thrombocytopenia). It has no clinical significance, but it must be distinguished from ITP, pregnancy-associated TTP, and preeclampsia.
In addition to having hypertension, proteinuria, and evidence of pathologic changes in the kidneys, liver, CNS, and placenta, approximately 15% of patients with preeclampsia have moderate thrombocytopenia. Only a minority of patients with pre eclampsia and thrombocytopenia demonstrate laboratory evidence of DIC. The megakaryocyte number is increased, and platelet survival is somewhat shortened. Some patients with preeclampsia and thrombocytopenia also have microangiopathic hemolysis, which suggests that damaged vessels containing fibrin strands are destroying red blood cells and platelets. Intense vasospasm that causes endothelial damage and leads to platelet activation, adherence, and destruction may also play a role. The clinical picture may be indistinguishable from TTP, in which case it should be managed as TTP. Otherwise, management consists of prenatal care for preeclampsia and efforts to detect thrombocytopenia as early as possible.
The HELLP syndrome refers to a disorder that occurs during pregnancy and is characterized by hemolysis, elevated levels of liver enzymes, and a low platelet count. It probably represents an extremely severe form of preeclampsia. At some point between the 23rd and 39th week of pregnancy, affected patients present with thrombocytopenia marked by a platelet count of less than 100,000/µl, microangiopathic hemolysis, abnormal liver function test results, and, occasionally, hypertension.78 The results of the standard coagulation tests for DIC are normal, although there may be some elevation in the level of fibrin degradation products. Patients with the HELLP syndrome are often severely ill, with circulatory, respiratory, and renal failure; postpartum hemorrhage; intrahepatic hemorrhage; and seizures.
The differential diagnosis includes acute fatty liver of pregnancy and TTP/HUS. In acute liver of pregnancy, patients have a prolonged PT and aPTT and low fibrinogen levels; hypertension and proteinuria are usually absent. In TTP/HUS, the liver enzymes are normal or only mildly elevated.
HELLP is treated by terminating the pregnancy, usually by delivery, and by providing meticulous supportive care. In a large series of patients with HELLP, the nadir of thrombocytopenia occurred 1 to 2 days after delivery.79 It may also develop for the first time within 24 to 48 hours post partum.80 Treatment of HELLP remains controversial, but corticosteroids appear to be beneficial.81 Persistent thrombocytopenia with microangiopathy or the presence of organ failure suggests postpartum TTP/HUS; in such patients, plasma exchange therapy should be considered.
Platelet Washout and Vascular Bed Abnormalities
Patients who have brisk bleeding during surgery and who require massive transfusions (e.g., 10 units of packed red cells and multiple units of fresh frozen plasma) frequently develop nonimmune thrombocytopenia. If the platelet level falls below 100,000/µl and the patient is undergoing surgery or another hemostatic challenge, platelets should be administered. Platelets may also be removed by an abnormal vascular bed. In giant hemangiomas, there is sluggish blood flow through improperly endothelialized channels. These surfaces may produce low-grade DIC.
Another major mechanism of thrombocytopenia is platelet sequestration. Platelet counts of 40,000 to 80,000/µl are common in patients with marked splenomegaly. Clinically significant hemorrhage rarely occurs unless a coexistent hemorrhagic disorder is present. Management is directed toward the primary disease. Splenectomy is rarely necessary.
Platelet Function Disorders
The clue to the existence of a platelet function defect is the finding of clinical hemorrhage in the presence of a prolonged bleeding time and a platelet count higher than 100,000/µl. Petechiae are rare. Platelet morphology and tests of platelet function may be abnormal [see Table 4].
HEREDITARY ABNORMALITIES OF PLATELET FUNCTION
Platelet Membrane Disorders
Bernard-Soulier syndrome is a rare autosomal recessive disease that is characterized by giant platelets, a prolonged bleeding time, moderate thrombocytopenia, and risk of fatal hemorrhage. The defect, which is an absence of the platelet GPIb-IX-V complex (the major vWF binding site of the platelet), causes impaired platelet adhesion to wound surfaces. Ristocetin-induced platelet agglutination is abnormal and is not corrected by the addition of normal plasma containing vWF. Acute hemorrhage is treated by platelet transfusions.
Glanzmann thrombasthenia is a rare autosomal recessive disorder in which platelet morphology and the platelet count are normal but the bleeding time is prolonged. Because the critically important GPIIb-IIIa complex that forms the platelet binding site for fibrinogen is absent, the platelets do not undergo aggregation after stimulation by ADP, thrombin, or collagen. Ristocetin-induced agglutination, however, is normal. Treatment consists of platelet transfusions when necessary.
Platelet Granule Disorders
Patients with the gray platelet syndrome, a rare disorder, have mucosal bleeding, ecchymoses, and petechiae. Moderate thrombocytopenia is present, and the bleeding time is prolonged. The platelets are larger than normal and appear agranular because of the absence of α-granules. Because the α-granule contents are severely reduced, platelet adhesion and platelet-supported coagulation are deficient. Platelet aggregation with collagen is abnormal. Bleeding episodes should be treated by infusion of normal platelets.
Another rare disorder, the dense granule deficiency syndrome, is characterized by mucosal bleeding associated with a normal platelet count, normal platelet morphology, and variable prolongation of the bleeding time. Platelet aggregation with ADP and collagen are abnormal. The decrease in the dense granular contents of ADP impairs ADP-mediated events. Hemorrhage is treated by platelet transfusion.
1-Desamino-8-D-arginine vasopressin (DDAVP, or desmopressin) is an alternative therapy for patients with primary platelet disorders that require surgery.
ACQUIRED ABNORMALITIES OF PLATELET FUNCTION
Myeloproliferative Diseases and Associated Platelet Abnormalities
Platelet function abnormalities occur in the myeloproliferative diseases: chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and acute leukemia. The platelet count in chronic myeloproliferative disorders is often very high, but the bleeding time may be prolonged, and clinical bleeding may appear as mucosal hemorrhage and hematomas. The abnormality resembles an acquired storage-pool defect. Megakaryocytes often are abnormal with separated nuclei; the peripheral blood platelets are large and may be degranulated. Management of acute hemorrhage consists of transfusion of normal platelets to bring the level of normal platelets up to 50,000/µl. Aspirin and other NSAIDs should be avoided.
Uremia and Associated Platelet Abnormalities
A prolonged bleeding time associated with clinical bleeding despite a normal platelet count has been well documented in uremia. Uremic platelet dysfunction is presumably caused, in part, by several dialyzable uremic toxins, including phenolic acids and guanidinosuccinic acid.82 DDAVP (0.3 µg/kg in 50 ml of saline over a 30-minute period) is effective in controlling uremic bleeding for about 4 to 6 hours. DDAVP infusion produces an increase in plasma vWF activity, particularly among the larger multimers of vWF, which may enhance platelet adhesion.
The hematocrit should be maintained above 30% in bleeding uremic patients because the bleeding time is prolonged when the hematocrit falls below 26%.83 Bleeding may also be controlled by the use of conjugated estrogens. Conjugated estrogen (Premarin) given orally (50 mg/day) or intravenously (0.6 mg/kg/day) for 4 to 5 days shortens the bleeding time by approximately 50% for about 2 weeks.84 The advantage of conjugated estrogens over DDAVP is the longer duration of their beneficial effect on platelet function, but they have a more delayed onset of action. The two drugs can be used concomitantly.
Table 4 Classification of Platelet Function Disorders
Patients with end-stage renal disease have complex hemostatic disorders. Despite decreased platelet function (caused by uremic toxins present in the circulating blood), thrombosis of vascular access shunt commonly occurs in patients with end-stage renal failure who are on hemodialysis. Hemostatic parameters suggestive of a hypercoagulable state, such as increased plasma fibrinogen and factor VIII levels, have been described.82
Effects of Macroglobulinemia and Other Dysproteinemias on Platelet Function
The presence of high concentrations of viscous proteins produces complicated effects on the entire hemostatic mechanism. The proteins appear to coat platelets and interfere with adhesion and perhaps with aggregation. Management is directed at the primary disease, but if hyperviscosity and bleeding are significant, prompt plasmapheresis may be required to lower the level of abnormal protein and to correct the bleeding disorder.
Drug-Induced Platelet Disorders
Aspirin and other nonsteroidal anti-inflammatory drugs
In normal persons, ingestion of 0.6 g of aspirin prolongs the template bleeding time by 2 to 3 minutes. The platelets are irreversibly affected. Thromboxane A2 (TXA2) is a potent inducer of platelet release and aggregation [see 5:XII Hemostasis and Its Regulation]. Aspirin acetylates and irreversibly inhibits cyclooxygenase-1 (COX-1) and blocks the subsequent generation of thromboxane. Some apparently normal persons display marked sensitivity to the action of aspirin, so that their bleeding times are very much prolonged and they have clinically significant bleeding, particularly during or after surgery or trauma. These patients may have a mild form of von Willebrand disease or storage-pool disease, and their mild bleeding diathesis becomes exacerbated by aspirin's antiplatelet effect.
Uremic patients are especially sensitive to bleeding induced by aspirin. A small dose of aspirin does not prolong the bleeding time of normal persons, but in uremic patients, it produces a significant prolongation, often as much as 15 minutes. The combination of alcohol and aspirin is also dangerous because of aspirin's ability to prolong the bleeding time.
Aspirin-induced bleeding is diagnosed by determining the existence of an acquired platelet function defect (a platelet count above 100,000/µl, abnormal platelet aggregation test results, and no prior bleeding history) and finding evidence of aspirin ingestion. Because approximately 300 compounds on the market contain aspirin, a negative history should be supplemented either by determining a serum salicylate level or by detecting an abnormal collagen aggregation pattern that reverts to normal in 7 days (the typical pattern of aspirin ingestion).
If bleeding is significant, it can be managed by platelet transfusion. Because inhibition of platelet COX-1 by aspirin is irreversible, the hemostatic compromise may last for 4 to 5 days after the aspirin has been discontinued. If the patient needs analgesia, acetaminophen or codeine can be used because neither affects platelet function.
In addition to producing thrombocytopenia by suppressing platelet production, alcohol consumption can cause platelet function defects.85 In vitro studies have shown that alcohol impairs platelet aggregation and TXA2 release. Platelet function returns to normal after 2 to 3 weeks of abstinence.
Carbenicillin and ticarcillin can inhibit platelet aggregation and contribute to a bleeding disorder, as can massive doses of penicillin. Massive doses of penicillin impair collagen-induced and ristocetin-induced platelet aggregation. Moxalactam, a third-generation cephalosporin, also causes a platelet function disorder. The clinical situation is most important when an acquired platelet function defect develops in a pancytopenic patient being treated for septicemia. Changing the antibiotics usually corrects this problem.
A wide variety of other agents can modify platelet function [see Table 5].86
Thrombocytosis and Thrombocythemia
A platelet count higher than 500,000/µl is referred to as reactive thrombocytosis. In reactive thrombocytosis, tests of platelet function (including platelet aggregation studies) are generally normal, and patients do not experience an increased incidence of hemorrhage or thromboembolism even when the platelet count exceeds 1 million/µl.
Elevated platelet counts (often, 1 million to 3 million/µl or more) also occur in chronic myeloid leukemia, agnogenic myeloid metaplasia with myelofibrosis, polycythemia vera, and essential thrombocythemia. In the diagnosis of essential thrombocythemia, the platelet count is higher than 600,000/µl and other causes of thrombocytosis (e.g., another myeloproliferative disorder or reactive thrombocytosis) have been excluded. A gain-of-function mutation in tyrosine Janus kinase-2 (JAK2) has been found in many patients with myeloproliferative disorders; it is found in about 80% of patients with polycythemia vera and in about 25% to 50% of patients with essential thrombocythemia.87,88,89 In myeloproliferative disorders, test results of platelet function are frequently abnormal [see Platelet Function Disorders, above]. Some patients with myeloproliferative disorders seem to show an enhanced propensity for hemorrhage and thromboembolism. Neither platelet number nor measurements of platelet function predict the degree of thrombosis or hemorrhage.
Table 5 Selected Platelet-Modifying Agents98
Clinically, the hemorrhagic signs include mucosal, particularly gastrointestinal, bleeding; hematomas; and ecchymoses. There may be splenic vein thrombosis, portal or mesenteric vein thrombosis, and recurrent deep vein thrombosis with or without pulmonary embolism. Arterial thrombosis is less common.
Patients with essential thrombocythemia and polycythemia vera may have debilitating erythromelalgia (burning and itching of the fingers and toes) that can progress to ischemic acrocyanosis.90 This symptom complex appears to be caused by occlusion and inflammation of arterioles by platelet aggregates. Aspirin or indomethacin produces relief within hours. Aspirin given at a dosage of 325 mg daily can produce lasting benefit.
Hemorrhage and thrombosis are uncommon events even with platelet counts of 1 million/µl. In a patient with essential thrombocythemia who has clinically significant hemorrhage or thrombosis, good control of the platelet count can be achieved with oral hydroxyurea (15 mg/kg/day), with adjustments in the dosage as needed to lower the platelet count. Hydroxyurea therapy requires careful monitoring of the blood count; thus far, hydroxyurea therapy does not appear to increase the risk of a second malignant disorder. Newer therapies for thrombocythemia include the use of anagrelide, a powerful platelet-lowering agent.91 A recent prospective, randomized trial comparing hydroxyurea with anagrelide showed that although the two agents were equally efficacious in long-term control of the platelet count, anagrelide was associated with an increased risk of arterial thrombosis (mostly transient ischemic attacks) and serious hemorrhage.92 Thus, hydroxyurea (0.5 to 2.0 g daily to maintain the platelet count at less than 400,000/µl) plus low-dose aspirin (81 mg daily) should be the first-line therapy for patients with essential thrombocythemia who are considered at high risk for vascular events.
Vascular purpuras are a heterogeneous group of disorders [see Table 6] that are characterized by cutaneous hemorrhage and are occasionally associated with mucosal bleeding. The leakage occurs from terminal arterioles, capillaries, and postcapillary venules. The results of tests of platelet number and function and tests of procoagulant function are normal.
HEREDITARY HEMORRHAGIC TELANGIECTASIA
Hereditary hemorrhagic telangiectasia (HHT) is transmitted as an autosomal dominant disease and has an estimated incidence of one in 5,000 to 8,000 persons.93 Recent linkage analyses have identified at least three HHT loci, including the genes for endoglin and activinlike receptor kinase. Both proteins are expressed on vascular endothelial cells and may function as receptors for transforming growth factor-β (TGF-β). TGF-β plays a complex role in coordinating responses between endothelial cells and the extracellular matrix. A mutation in the gene for either endoglin or activinlike receptor kinase results in a 50% reduction in the normal quantity of protein on endothelial cells (haploinsufficiency) and leads to the development of abnormal blood vessels and arteriovenous malformations (AVMs).94
HHT generally does not present at birth but manifests itself with age. Recurrent epistaxis is typically the earliest sign of disease, commonly occurring in childhood. Pulmonary AVMs, occurring in about 30% of HHT patients, become apparent after puberty and may present as dyspnea, chest pain, and hemoptysis. Physical examination may reveal chest bruits and digital clubbing. Mucocutaneous telangiectasias, which occur in the majority of patients and at characteristic sites (e.g., lips, oral cavity, fingers, and nose), typically become noticeable by the third decade of life and increase in size and number as the patient ages. The diagnosis of HHT should be based on four criteria: (1) spontaneous and recurrent epistaxis, (2) multiple mucocutaneous telangiectasias, (3) evidence of visceral telangiectasias and AVMs (e.g., gastrointestinal tract, pulmonary, hepatic, or cerebral AVMs), and (4) a positive family history of HHT.
Coagulation test results are generally normal. The pulmonary AVMs may be associated with hypoxemia and secondary polycythemia. The diagnosis can be confirmed by pulmonary angiography. If the shunts are large and clinically significant, they can be treated by balloon embolotherapy.95 Paradoxical embolus with stroke can occur in patients with HHT who have pulmonary arteriovenous shunts and malformations. It has been advocated that asymptomatic HHT patients be screened for AVMs and be treated prophylactically with embolotherapy if AVMs are found.96 Management of recurrent epistaxis should be conservative and often involves devising methods for obtaining nasal tamponade. Cauterization should be avoided because damage to nasal mucosa may result in vascular regrowth. Gastrointestinal bleeding is managed by the use of iron preparations when possible.
Table 6 Vascular Purpuras
ACQUIRED DISORDERS OF BLOOD VESSELS THAT CAUSE BLEEDING
Vitamin C is required for the normal metabolism of collagen, folate, and perhaps iron. The patient with scurvy suffers primarily from impaired collagen synthesis. The lack of proper collagen support for the microvasculature leads to perifollicular hemorrhages, bleeding gums, and even deep tissue hematomas. Presumably, similar collagen defects lead to the so-called corkscrew hair and hyperkeratosis associated with this disorder.97 The characteristic clinical picture in a malnourished person suggests the diagnosis. Plasma or buffy coat levels of ascorbic acid are low, and other vitamin deficiencies are usually present. Effective therapy consists of 1 g of ascorbic acid daily in divided doses.
Glucocorticoid excess, whether from endogenous or exogenous causes, produces cutaneous hemorrhages, probably because of glucocorticoid-induced catabolism of protein in vascular supportive tissues.
Amyloidosis can present as subcutaneous ecchymoses that have a predilection for the neck and upper chest. Biopsy of the site shows the amyloid, which by its infiltration may weaken the vessel walls or interfere with surface activation of platelets, procoagulants, or both. In patients with primary systemic amyloidosis, especially when accompanied by a huge amyloid spleen, the amyloid can in some instances adsorb enough factor X to cause profound factor X deficiency and clinical bleeding. Infusions of fresh frozen plasma are usually ineffective. Recombinant factor VIIa is effective, but it is extremely expensive and provides only temporary benefit. Splenectomy may provide long-term benefit and should be considered in a patient with recurrent serious clinical bleeding.
The purpuric lesions in patients with immunoglubulin disorders (e.g., cryoglobulinemia, Waldenström macroglobulinemia, Henoch-Schönlein purpura, and multiple myeloma) may be raised (palpable purpura). On biopsy, these lesions may show mast cell degranulation and, when stained appropriately, immune complex deposition. Presumably, the immune complexes provide the chemotactic stimulation that leads to the congregation of neutrophils. Damage to the microvasculature is caused by the complement attack complex and by the release of the contents of the neutrophil granules. This inflammatory component produces the palpable purpura.
Damage to the Microvasculature Due to Emboli
DIC and TTP can cause localized vaso-occlusions leading to microvascular damage and leakage of red blood cells. Similar damage can be caused by emboli that arise from infected heart valves. Fat embolism may complicate fractures of the long bones and pelvis. The syndrome consists of fever; confusion; and petechiae, purpura, or both over the neck, chest, face, and axillae. Cholesterol embolism can also cause petechiae, usually over the lower extremities. It typically occurs in a patient with severe atherosclerosis who has recently undergone an invasive procedure involving the abdominal aorta or renal arteries. Biopsy of the purpura shows cholesterol crystals when an appropriate stain is used.
Figure 1 Seward Hung.
Editors: Dale, David C.; Federman, Daniel D.