Dennis A. Casciato and Mary C. Territo
INCREASED BLOOD CELL COUNTS
I. ERYTHROCYTOSIS (POLYCYTHEMIA). Erythrocytosis is defined as an elevation of the hematocrit and red blood cell (RBC) count above the upper limits of normal. Normal limits in adults are as follows:
A. Relative erythrocytosis is characterized by normal RBC mass and decreased plasma volume. Causes of relative erythrocytosis include dehydration, diuretics, burns, capillary leak, decreased oncotic pressure (“third spacing”), hypertension, and stress (“Gaisböck syndrome”). The majority of patients with Gaisböck syndrome have an RBC mass that is at the upper limits of normal and a plasma volume that is toward the lower limits.
B. Primary erythrocytosis is caused by intrinsic defects of erythroid progenitors.
1. Acquired primary erythrocytosis (polycythemia vera [PV]) is a clonal disorder. The majority of patients with PV have a somatic mutation in a gene on chromosome 9p (the JAK2 gene). Erythrocytosis develops independently of serum erythropoietin (EPO) concentration. Uncontrolled proliferation of marrow elements results in an increased RBC mass. PV, including diagnostic criteria, is discussed in Chapter 24, “Polycythemia Vera.”
2. Primary familial and congenital polycythemias result from germ line rather than somatic mutations.
a. Chuvash polycythemia is the most common congenital polycythemia in the world and the only known endemic polycythemia. The condition is named after the Chuvash population in the mid–Volga River region of Russia. The condition results from an abnormality in the oxygen-sensing pathway. Inheritance is as an autosomal recessive involving mutation of the von Hippel–Lindau (VHL) gene. Marked erythrocytosis occurs in the presence of normal to increased levels of EPO.
b. Primary erythrocytosis due to mutations of the EPO receptor (usually truncation) can be congenital or familial. Inheritance is as an autosomal dominant. An increased proliferation of erythrocytes, elevated RBC mass, hypersensitivity of erythroid progenitors to EPO, low serum EPO levels, and normal hemoglobin oxygen dissociation characterize this rare disorder.
C. Secondary erythrocytosis is associated with increased RBC mass due to extrinsic stimulation of progenitors by circulating substances such as EPO.
1. Appropriate erythrocytosis
a. Chronic hypoxemia is a potent stimulus for EPO production. Causes of hypoxemia include pulmonary diseases, right-to-left intracardiac shunts, low atmospheric0 pressure (high altitudes), alveolar hypoventilation (brain disease or pickwickian syndrome), and portal hypertension. Intermittent arterial desaturation and erythrocytosis may be caused by sleep apnea or by supine posture, particularly in obese patients with pulmonary disease.
b. Heavy smoking. Excessive and sustained exposure to carbon monoxide from cigarettes or cigars, which produces an increased affinity between the remaining oxygen and the hemoglobin molecule, is a common cause of erythrocytosis.
c. Congenital disorders include hemoglobinopathies with high oxygen affinity (abnormal oxyhemoglobin dissociation), overproduction of EPO, and familial deficiency of 2,3-biphosphoglycerate (rare).
d. Androgen therapy stimulates erythropoiesis.
e. Cobalt chloride induces tissue hypoxia and consequent EPO production.
f. Chuvash polycythemia has elements of both primary and secondary erythrocytosis.
2. Inappropriate erythrocytosis occurs with elevated EPO levels in the absence of generalized tissue hypoxia and is seen in a variety of diseases.
a. Renal diseases account for about 60% of all cases of inappropriate erythrocytosis, and renal adenocarcinomas account for half of those cases. Cysts, other tumors, hydronephrosis, and transplantation make up the remaining renal causes of erythrocytosis.
(1) Renal cell carcinomas synthesize EPO in association with erythrocytosis in 1% to 5% of cases.
(2) Renal transplantation is associated with erythrocytosis in 10% of patients. The erythrocytosis has been ascribed to transplanted artery stenosis, graft rejection, hypertension, hydronephrosis, diuretic use, and EPO overproduction from residual renal tissue, especially in polycystic disease.
b. Hepatocellular carcinoma and cerebellar hemangioblastoma each account for 10% to 20% of the cases of inappropriate erythrocytosis in the literature.
c. Other causes of inappropriate erythrocytosis are rare. Huge uterine leiomyomas and ovarian carcinoma can cause renal hypoxia or ectopic EPO production. Pheochromocytomas and aldosteronomas cause erythrocytosis through multiple mechanisms.
D. Evaluation of patients with erythrocytosis
1. Initial evaluation. The following studies are obtained in all patients with persistent erythrocytosis:
a. Perform a complete history and physical examination to search for known causes of elevated hematocrits. Search for treatments that are associated with absolute or relative erythrocytosis (androgen therapy, diuretics) and for splenomegaly, which would suggest PV. If intravascular volume depletion is suspected, replete the volume and then reassess.
b. Analyze the hemogram. The presence of granulocytosis, eosinophilia, basophilia, or thrombocytosis suggests PV.
c. Measure arterial oxygen saturation. The RBC mass is roughly proportional to the degree of arterial desaturation. Arterial oxygen saturation <90% and a PaO2 <60 to 65 mm Hg may result in erythrocytosis.
d. If the patient smokes tobacco, measure the carboxyhemoglobin concentration; values >5% are associated with erythrocytosis. Smoking may also cause granulocytosis.
e. Serum EPO level is decreased in PV and abnormalities of the EPO receptor. The concentration is normal or increased in the other disorders associated with erythrocytosis.
2. Special diagnostic studies
a. RBC mass determination previously was paramount for distinguishing absolute erythrocytosis from relative erythrocytosis. RBC mass is measured with 51Cr-labeled erythrocytes, and plasma volume is measured concomitantly with 125I-labeled albumin to assess for intravascular volume reduction. However, this useful test is becoming increasingly unavailable.
b. Abdominal radiography (ultrasonography or CT scanning) is indicated in all patients with absolute erythrocytosis that is not explained by either PV or hypoxemia because the frequency of renal causes is high.
c. JAK2 gene mutation should be sought if PV is suspected.
d. Oxyhemoglobin dissociation curve is indicated in patients with a family history of unexplained erythrocytosis.
e. Other diagnostic studies for inappropriate erythrocytosis are obtained only if the screening evaluation exposes abnormalities that could indicate pathology of a specific organ.
f. Bone marrow examination is not diagnostic of any disorder associated with erythrocytosis.
II. GRANULOCYTOSIS
A. Definitions
1. Granulocytosis. The upper limit of normal for neutrophils is 8,000/mL.
2. Leukemoid reactions. The term leukemoid reaction should be restricted to granulocytosis with circulating promyelocytes and myeloblasts.
3. Leukoerythroblastic reactions are characterized by immature granulocytes in association with nucleated erythrocytes in the peripheral blood. Platelet counts may be normal, increased, or decreased. Differential diagnosis includes the following:
a. Metastatic tumor in the marrow
b. Marrow fibrosis with extramedullary hematopoiesis
c. Marrow recovery after severe hematosuppression
d. Shock, hemorrhage
e. Brisk hemolysis, hereditary anemias
B. Causes of granulocytosis
1. Increased proliferation in the marrow is seen in myeloproliferative disorders (MPDs), in marrow rebound after suppression by drug or virus, and as a chronic response to infection, inflammation, or tumor. The mechanism of tumor-induced granulocytosis most often involves increased production of granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF, GM-CSF), interleukin (IL)-1, and IL-3.
2. Increased marrow proliferation and increased granulocyte survival are seen in chronic myelogenous leukemia (CML).
3. Shift from the marrow storage pool into the circulation is seen in response to stress, endotoxin, corticosteroids, and etiocholanolone.
4. Demargination (resulting in granulocytosis involving only mature neutrophils) is seen in stress, including emotional upset, epinephrine administration, exercise, infection, hypoxia, and intoxication.
5. Decreased egress into the tissues is seen after chronic treatment with corticosteroids.
C. Differentiation of leukemoid reactions from MPDs and CML involves complete clinical evaluation, especially for the history and presence of splenomegaly. The leukocyte differential count, neutrophil alkaline phosphatase score, and cytogenetics may be helpful (see Table 24.1). Bone marrow biopsies are frequently not discriminatory.
1. Neutrophil alkaline phosphatase scores are normal or increased in MPDs and reactive granulocytosis and decreased in CML.
2. Vitamin B12. Transcobalamins I and III are synthesized by granulocytes. The total-body granulocyte mass, when increased, is reflected by increased serum levels of vitamin B12 and unsaturated B12-binding capacity. These levels are usually elevated in patients with MPD and CML and normal in patients with erythrocytosis or granulocytosis of other causes. Transcobalamin I is increased in CML, and transcobalamin III is increased in PV.
III. THROMBOCYTOSIS
A. Thrombocytosis in cancer patients. Persistent thrombocytosis may indicate cancer. Thrombocytosis in neoplastic disease may be idiopathic or the result of bleeding or bone marrow metastases. Generally, thrombocytosis associated with solid tumors is mild, but values may exceed 1,000,000/µL.
B. Common causes of transient thrombocytosis
1. Acute hemorrhage or phlebotomy
2. Acute infection
3. Recovery from myelosuppression (viruses, ethanol, cytotoxic agents)
4. After surgery (persists for about 1 week)
5. Response to therapy for folic acid or vitamin B12 deficiency
6. Certain drugs (epinephrine, vinca alkaloids, and perhaps miconazole)
C. Causes of chronic thrombocytosis
1. Iron deficiency (the most common cause of thrombocytosis)
2. MPDs
3. Neoplasms (idiopathic or bone marrow metastases)
4. Chronic inflammatory diseases
5. Hyposplenism (postsplenectomy states, hemolytic anemias, regional enteritis, sprue, and splenic atrophy from repeated infarctions)
D. Differentiation of causes of chronic thrombocytosis. After history and physical examination, helpful screening tests for the evaluation of chronic thrombocytosis include the following:
1. Peripheral blood. Megathrombocytes and fragments of megakaryocytes are rarely seen in disorders other than the MPDs and CML. A normal mean platelet volume suggests reactive thrombocytosis. The granulocyte differential is helpful for recognizing MPDs and CML. The presence of hypochromia and microcytosis supports iron deficiency.
2. Serum iron, iron-binding capacity, and serum ferritin to evaluate for iron deficiency
3. Bone marrow aspirate examination demonstrates panmyelosis in MPDs and CML. Bone marrow biopsy may detect tumor involvement. Iron staining is unreliable in patients with cancer or chronic inflammatory diseases if the results show low or absent iron stores.
IV. EOSINOPHILIA
A. Definition. The upper limit of normal in absolute cell count is 550/µL.
B. Nonneoplastic causes of eosinophilia
1. Allergies and drug hypersensitivities
2. Skin diseases (many types)
3. Infection with fungus, protozoan, or metazoan; convalescence after a febrile illness
4. Eosinophilic gastroenteritis, inflammatory bowel disease
5. Eosinophilic pulmonary syndromes (e.g., Löffler syndrome)
6. Collagen vascular diseases, especially rheumatoid arthritis, polyarteritis nodosa, and Churg-Strauss syndrome
7. Contaminated tryptophan eosinophilia–myalgia syndrome
8. Chronic active hepatitis, pernicious anemia, immunodeficiency syndromes
9. Hyposplenism (see Section III.C.5)
10. Hypereosinophilic syndrome/chronic eosinophilic leukemia
C. Eosinophilia associated with neoplasia
1. Hodgkin lymphoma (up to 20% of cases)
2. MPDs and CML (common)
3. Acute lymphocytic leukemia and lymphoma (especially T-cell types)
4. Acute monocytic leukemia with inv(16)
5. Angiolymphoid hyperplasia with eosinophilia (Kimura disease)
6. Pancreatic acinar cell carcinoma (syndrome of polyarthritis, subcutaneous panniculitis, and peripheral eosinophilia)
7. Tumors undergoing central necrosis or metastasizing to serosa
8. Malignant histiocytosis
9. Eosinophilia related to treatment: RT to the abdomen, hypersensitivity to cytotoxic agents
V. BASOPHILIA
A. Definition. The upper limit of normal is 50/µL.
B. Causes of basophilia
1. Hypersensitivity reactions
2. MPDs
3. CML
4. Mastocytosis
5. Hyposplenism (see Section III.C.5)
6. Infections: tuberculosis, influenza, hookworm
7. Endocrine: diabetes mellitus, myxedema, menses onset
8. Miscellaneous: hemolytic anemia, ulcerative colitis, carcinoma
VI. MONOCYTOSIS
A. Definition. The upper limit of normal is 500 to 800/µL.
B. Causes of monocytosis
1. Hematologic neoplasms (leukemias, lymphomas, myeloma), myelodysplastic syndromes, immune hemolytic anemias, immune thrombocytopenia, and other hematologic disorders
2. Solid tumors with and without metastases
3. Inflammatory bowel disease, sprue, and alcoholic liver disease
4. Collagen vascular disease (including rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa, and temporal arteritis)
5. Sarcoidosis
6. Mycobacterial infections, subacute bacterial endocarditis, syphilis, and resolution from acute infection
7. Infections with varicella-zoster virus or cytomegalovirus (CMV)
8. Hyposplenism (see Section III.C.5)
9. Factitious monocytosis may occur when blood samples are taken from finger-tips affected by peripheral vascular disease.
VII. LYMPHOCYTOSIS. The differential diagnosis of lymphocytosis is discussed in Chapter 23, Section III.D in “Chronic Lymphocytic Leukemia.”
CYTOPENIA
Decreased formed elements in the circulating blood can result from decreased or ineffective production within the bone marrow, increased destruction of cells, or sequestration in the spleen. Patients with cancer often have a combination of these abnormalities. The type and duration of cytopenia depend on several factors (Table 34.1).
Table 34.1 Hematopoiesis, Cell Kinetics, and Bone Marrow Injury
aThe type, severity, and duration of cytopenia depends on the etiology of the injury, its dose and exposure time, and other factors.
bReticulocytopenia; anemia requires prolonged and repeated arrests of erythropoiesis.
I. PANCYTOPENIA BECAUSE OF BONE MARROW FAILURE
A. Metastases to the marrow
1. Occurrence. Carcinomas of the breast, prostate, and lung are the solid tumors most likely to be associated with extensive marrow metastases. Melanoma, neuroblastoma, and carcinomas of the kidney, adrenal gland, and thyroid also frequently have marrow metastases.
2. Findings. Tumor volume in the marrow does not correlate directly with the degree of hematosuppression. Marrow metastases are often found in patients without any hematologic abnormality. Patients may have bone pain, bone tenderness, radiographic evidence of cortical bone involvement, or elevated serum alkaline phosphatase levels.
a. Bone marrow paraneoplastic alterations can result in qualitative and quantitative abnormalities in hematopoiesis. In the absence of marrow metastases, changes can develop that are comparable to those seen in the primary myelodysplastic syndromes, including myelodysplasia in all cell lines, marked reactive changes, stromal modifications, and bone marrow remodeling.
b. Desmoplastic reactions to metastases can result in myelofibrosis.
c. Bone marrow biopsy is superior to aspiration (with examination of the clot specimen) for detection of metastases; both techniques are complementary. Cytologic preparations of bone marrow aspirates must be inspected at the edges of the smears for clumps of tumor cells. Immunohistochemical staining for epithelial markers may be helpful in identifying carcinomas.
d. Peripheral blood abnormalities. Nearly all patients with solid tumors and leukoerythroblastosis have demonstrable marrow metastases. Thrombocytopenia (in the absence of RT or chemotherapy) is the next best indicator. Leukocytosis, eosinophilia, monocytosis, and thrombocytosis each is associated with positive marrow biopsies in about 20% of cases.
B. Marrow fibrosis
1. Occurrence. Extensive primary marrow fibrosis is characteristic of myelofibrosis with agnogenic myeloid metaplasia and late-stage polycythemia vera. Marrow fibrosis may also be secondary to neoplastic infiltration with leukemia or metastatic carcinoma or as a distant effect of some tumors without demonstrable tumor cells in the marrow. Secondary fibrosis in the marrow may also be seen in reaction to the following:
a. Collagen vascular disorders (particularly systemic lupus erythematosus, in which the fibrosis can reverse after treatment with high-dose corticosteroids)
b. Toxic agents (benzene, radiation, cytotoxic agents)
c. Infectious agents (especially tuberculosis and syphilis)
d. Hematologic diseases (myelodysplasia, pernicious anemia, hemolytic anemia)
e. Miscellaneous disorders (osteopetrosis, mastocytosis, renal osteodystrophy, Gaucher disease, giant lymph node hyperplasia, angioimmunoblastic lymphadenopathy)
2. Findings. Splenomegaly and a leukoerythroblastic blood smear are characteristic of marrow fibrosis of any cause.
C. Marrow necrosis
1. Occurrence. When diagnosed antemortem, marrow necrosis nearly always is due to either sickle cell disease or a malignancy, particularly a hematologic neoplasm. Systemic embolization of fat and marrow frequently occurs. The median survival of patients with marrow necrosis from a malignancy is <1 month. Patients with severe weight loss may develop gelatinous transformation of the marrow with marrow hypoplasia and fat atrophy; this condition is reversible.
2. Findings. Patients have severe bone pain in the back, pelvis, or extremities (75%), fever (70%), cytopenias, and a leukoerythroblastic blood smear.
a. Serum levels of alkaline phosphatase and lactate dehydrogenase (LDH) are usually elevated.
b. Radiographs are normal.
c. Bone marrow aspiration demonstrates characteristic findings: Individual hematopoietic cells are not recognizable, and cells with indistinct margins and intensely basophilic nuclei are usually surrounded by amorphous acidophilic material.
D. Bone marrow failure secondary to treatment. Ionizing radiation and most chemotherapeutic agents cause suppression of bone marrow function. Although recovery is usual after chemotherapy, recovery after irradiation is inversely proportional to dose and volume treated and may never be complete. Indeed, after doses in excess of 3,000 cGy, the bone marrow may be replaced by fatty and fibrous tissue. The distribution of marrow in the human skeleton is shown in Figure 34.1.
Figure 34.1. Distribution of bone marrow in healthy 40-year-old persons. Marrow cellularity is relatively decreased and amounts of fat increased in elderly subjects. (Data from Ellis RE. The distribution of active bone marrow in the adult. Phys Med Biol 1961;5:255.)
The occurrence of therapy-related myelodysplasia and acute myelogenous leukemia (AML) is even more worrisome for the development of treatment strategies. To develop this complication, the patient must have been treated long enough and then live long enough to manifest this long-term toxicity.
1. Occurrence. Nearly half of the patients have a primary hematologic malignancy. The risk for AML is increased 10- to 50-fold in patients treated for multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, ovarian cancer, germ cell tumors, small cell lung cancer, and childhood acute lymphoblastic leukemia (ALL). For children with ALL who achieve complete remission, the risk for therapy-related AML is greater than the risk for developing relapsed ALL.
2. Leukemogenic agents. The risk of inducing AML is directly related to the total cumulative dose and probably to dose intensity. The risk may also depend on the schedule of administration; for example, the risk in children with ALL is greatest in those undergoing weekly or biweekly therapy with epipodophyllotoxins.
a. Alkylating agents are the drugs with the most clearly demonstrated leukemogenic potential. Melphalan and chlorambucil are most often associated with AML in this class of drugs.
b. Other drugs. Epipodophyllotoxins (etoposide, teniposide), nitrosoureas, and procarbazine are also leukemogenic. Cisplatin is not a classic alkylating agent and is possibly leukemogenic; however, it is nearly always given in combination with other drugs, some of which are leukemogenic. Hydroxyurea has been implicated as being possibly leukemogenic in the treatment of MPDs, but the risk has been found to be low.
c. RT is associated with a minimally increased risk for AML when given alone but with a synergistically increased risk when combined with leukemogenic drugs.
3. Chromosome abnormalities, particularly involving chromosomes 5q or 7q, are found in 70% of therapy-linked AML associated with alkylating agents. These same aberrations are seen in patients developing AML after exposure to leukemogenic solvents and pesticides. In contrast, certain balanced translocations involving 11q23 appear to be characteristic of myelodysplasia and AML occurring after treatment with cytostatic agents acting on DNA topoisomerase II, such as etoposide.
4. Natural history. AML usually develops 3 to 5 years after initiation of therapy but can arise after 10 years or longer; the syndrome rarely develops within 1 year. Therapy-induced AML is usually preceded by months to years of myelodysplasia. After AML develops, the course is rapid and usually refractory to treatment. Death usually occurs within 2 to 4 months of diagnosis. An important predictive factor for favorable response to intensive antileukemic therapy is the absence of a preceding myelodysplastic phase.
II. PANCYTOPENIA BECAUSE OF HYPERSPLENISM
A. Pathogenesis. Splenic enlargement from any cause (including carcinomatous metastases) may result in phagocytosis of the circulating blood cells and the development of cytopenias. Hypersplenism with severity sufficient to beg the question of splenectomy develops most often in lymphoproliferative disorders and myelofibrosis.
B. Diagnosis. The diagnosis of hypersplenism is based on clinical judgment. The only true diagnostic test for hypersplenism is improvement in the cytopenias after splenectomy.
C. Treatment
1. Indications for splenectomy for hypersplenism are all of the following:
a. The patient has palpable splenomegaly.
b. The cytopenia is severe (e.g., anemia requiring frequent transfusions; severe neutropenia associated with recurrent, serious bacterial infections; or thrombocytopenia with hemorrhagic manifestations).
c. Other causes of cytopenia have been ruled out (e.g., disseminated intravascular coagulation [DIC]).
d. A reasonable survival time after splenectomy is expected.
e. The patient’s general medical condition is satisfactory enough to make the operative mortality risk acceptable.
f. Surgeons experienced in performing splenectomy under adverse conditions are available.
2. Consequences of splenectomy
a. Postsplenectomy blood picture is characterized by Howell-Jolly bodies, neutrophilia, eosinophilia, basophilia, lymphocytosis, monocytosis, and thrombocytosis.
b. Postsplenectomy sepsis is a potentially fatal complication, especially in children younger than 6 years of age. The most common infecting organisms are Streptococcus pneumoniae and Haemophilus influenzae.The incidence of sepsis in patients with Hodgkin lymphoma who undergo splenectomy has been reported to be 1% to 3%. Immunization may be helpful. Febrile episodes must be treated immediately and aggressively.
III. PANCYTOPENIA DUE TO HISTIOCYTOSIS
A. Hemophagocytic histiocytosis is an acquired syndrome of exaggerated histiocytic proliferation and activation. The acquired form is frequently associated with systemic viral infection (particularly with Epstein-Barr virus [EBV]), although other microorganisms have also occasionally been implicated. These syndromes often develop on the background of another primary disease, such as autoimmunity, immunodeficiencies, or cancer (especially lymphomas). Abnormalities in genes involved in immune response pathways (i.e., PRF1, STX11, and MUNC13-4) are evident in children with the genetic form of the disease and are being identified in patients with the acquired forms of the disease with increased frequency, so that patients who do develop the disease may have an underlying genetic predilection.
1. Pathogenesis. This is a systemic hyperinflammatory syndrome in which excessive stimulation of T cells and proliferation of these cells lead to disruption of immune regulation, cytokine storm, and systemic macrophage activation. This can lead to major organ failure of the liver, kidneys, or lung. The severity of the syndrome varies from mild to lethal.
2. Clinical findings include fever, severe malaise, myalgias, and often hepatosplenomegaly (which is less prevalent in adults than in children). At least two cytopenias are seen in nearly all cases.
a. Bone marrow biopsy is often hypocellular with an increase in marrow macrophages. The macrophages are vacuolated and contain ingested RBCs and erythroblasts (and perhaps other hematopoietic elements).
b. Lymph node biopsy shows normal nodal architecture with hemophagocytic histiocytes. These cells can also be seen on liver biopsies and may be evident in other effected organs.
c. Blood studies
(1) Acute phase reactants and proinflammatory cytokines are elevated.
(2) Triglycerides, ferritin, and LDH are frequently elevated. Fibrinogen and sodium are frequently decreased.
(3) Parameters indicating DIC are frequently present.
3. Treatment
a. Patients with mild to moderately severe disease may recover in weeks if the infectious agent is treatable, or the disease may resolve naturally if the patient’s immune system is intact.
b. Patients receiving immunosuppressive therapy may require drug dosage reduction.
c. Patients with the severe syndrome (EBV-induced or others) may require 10 months or more of treatment with dexamethasone, etoposide, and cyclosporine A to suppress the cytokine release and reverse proliferation of T cells. Alemtuzumab or allogeneic stem-cell transplantation can be considered for aggressive disease. Etoposide alone, antithymocyte globulin, and γ-globulin have been used for less severe manifestations.
B. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman syndrome) is a polyclonal disorder manifested by massive lymphadenopathy (particularly cervical) and is usually self-limited. It usually occurs in the first two decades of life.
1. Pathogenesis. The etiology is unknown.
2. Clinical findings. Lymphadenopathy may be isolated or generalized. Extranodal involvement, especially in the head and neck region, is common. Virtually any organ may be involved. Fever is common and weight loss may occur. Blood studies are nonspecific and consistent with chronic inflammation.
a. Bone marrow biopsy is nondiagnostic.
b. Lymph node biopsy. Lymphophagocytosis and erythrophagocytosis by histiocytes in the lymph node sinus are characteristic. Marked fibrosis in the capsular areas and distention and engorgement of medullary and subcapsular sinusoids by phagocytic histiocytes are usually diagnostic. The polyclonal histopathologic appearance of extranodal biopsies is very similar to that of lymph nodes.
3. Treatment. Lymph node enlargement progresses for weeks to months, then gradually recedes so that most patients have no evidence of disease after 12 to 18 months. Surgical excision of problematic masses is often successful. Other forms of therapy have had no consistent effect.
C. Other disorders of macrophages that are relevant to the differential diagnosis of hemophagocytic histiocytosis include
1. Langerhans cell histiocytosis
2. Familial hemophagocytic lymphohistiocytosis
3. Malignant histiocytosis
IV. ANEMIA IN PATIENTS WITH CANCER
A. Anemia because of blood loss or iron deficiency
1. Pathogenesis includes ulcerating tumors, extensive surgery, benign gastrointestinal (GI) tract diseases, gastrectomy (unable to use heme iron but able to use ferrous salts), and hemosiderinuria from chronic intravascular hemolysis.
2. Diagnosis. Patients with known GI tract malignancies must not be presumed to be bleeding from an ulcerating tumor (see Chapter 30, Section I). Stools should be tested for occult blood.
a. Blood studies may demonstrate microcytosis and hypochromia (although this may be modified by the tendency toward macrocytosis induced by some chemotherapeutic agents). Important clues that may signify a recent hemorrhage are polychromasia (often prominent 5 to 10 days after acute hemorrhage) or thrombocytosis (as a reaction to bleeding). Hypoferremia and hypertransferrinemia are often obfuscated in cancer patients by the presence of concomitant anemia of chronic disease; serum ferritin levels are usually more helpful. Assays of soluble transferrin receptor (which is elevated in iron deficiency but not in anemia of chronic diseases) may be helpful.
b. Bone marrow examination demonstrating the absence of stainable iron is unreliable in patients with cancer. The presence of stainable iron eliminates iron deficiency.
c. Therapeutic trials. Ferrous sulfate, 325 mg PO given three times daily for 30 days, should elevate the hemoglobin concentration in patients with iron deficiency and otherwise intact hematopoiesis if ongoing bleeding is not present.
B. Anemia because of nutritional deficiencies results in megaloblastic anemia, macro-ovalocytosis, neutrophil hypersegmentation, and in severe cases, pancytopenia.
1. Folic acid deficiency is the most common cause of megaloblastic anemia in cancer patients. Decreased intake of folate is common with any advanced cancer. Increased requirements for folate develop with autoimmune hemolytic anemia, the postoperative state, prolonged IV therapy, and competition for use of folate by rapidly proliferating tumor cells. Folate deficiency may also develop after the use of folate antagonist drugs (e.g., methotrexate).
2. Vitamin B12 deficiency is usually seen in cancer patients who have undergone gastrectomy (the site of intrinsic factor production) or who have malabsorption secondary to lymphoma that involves the stomach or ileum (the site of vitamin B12 absorption).
C. Anemia of chronic diseases (ACD)
1. Pathogenesis. ACD is caused by immune activation in reaction to foreign antigens with the production of cytokines that directly inhibit both the action and production of EPO. ACD is more severe with widespread metastases but may be observed in patients with localized tumors.
The increased levels of tumor necrosis factor (TNF) and IL-1 seen in malignancies and inflammatory conditions result in anemia indirectly by means of interferons (IFNs). TNF stimulates marrow stromal cells to produce IFN-β, and IL-1 acts on T lymphocytes to produce IFN-γ. Both IFN-β and IFN-γ inhibit erythropoiesis directly. These cytokines can induce the production of hepcidin, which regulates the intestinal absorption and release from macrophages of iron.
Neopterin levels, which indicate the activation of macrophages by IFN-γ, are also increased in malignancies. The hemoglobin concentrations are inversely proportional to the blood concentrations of neopterin and IFN-γ. IFN-γ also inhibits granulocytopoiesis, but neutropenia is not a manifestation of ACD. IL-1 also stimulates the release of G-CSF and GM-CSF, which can overcome the inhibitory effects of IFN-γ.
2. Diagnosis
a. Hemogram. The erythrocytes in ACD are usually normocytic and normochromic. Some patients have microcytosis and hypochromia. The reticulocyte count is normal or slightly increased.
b. Serum iron studies. The diagnosis of ACD involves the demonstration of decreased levels of both serum iron and transferrin (total iron-binding capacity). Serum ferritin values are normal or increased. The levels of soluble transferrin receptor are normal.
c. Bone marrow studies demonstrate ineffective erythropoiesis that is manifested by decreased polychromasia of nonnucleated marrow RBCs, shortened RBC life spans, and decreased numbers of sideroblasts. Reticuloendothelial iron may be normal, increased, or decreased.
3. Treatment. ACD is rarely severe enough to necessitate RBC transfusions. However, recombinant human EPO can correct ACD in most situations in which it is encountered.
D. Anemia caused by parvovirus B19. Parvovirus B19 is the etiologic agent of transient acute aplastic crises in patients with underlying hemolytic anemias. This complication is also seen in patients receiving chemotherapy, particularly as treatment of leukemia. An acute infection is manifested by worsening anemia, exanthem, and polyarthralgia.
In immunocompromised hosts who are unable to produce neutralizing antibodies against the virus, an infection can persist and cause chronic bone marrow failure, usually manifested by anemia. The viral target is an erythroid progenitor cell. The bone marrow shows erythroid hypoplasia. Treatment with commercial hyperimmune γ-globulins may be helpful.
E. Pure red cell aplasia (PRCA) is the isolated severe hypoplasia of erythroid elements in the marrow.
1. Pathogenesis. Although previously reported to be associated with thymoma in more than half of the cases of PRCA, modern series show this association to be approximately 10%. Lymphoproliferative disorders and various carcinomas have also been associated with PRCA. Rare cases of thymoma have been associated with pure neutropenia.
2. Diagnosis. A normocytic, normochromic anemia and reticulocytopenia are present. Bone marrow biopsy demonstrates markedly decreased-to-absent erythroid precursors and normal megakaryocytes and myeloid elements. Chest radiographs demonstrate a mediastinal mass if associated with thymoma.
3. Treatment. Removal of a thymoma results in remission of PRCA in about 20% of these cases. Patients with and without thymoma have responded to therapy with cyclophosphamide, cyclosporine, or antithymocyte globulin.
F. Warm antibody (IgG) immune hemolysis
1. Pathogenesis. Autoimmune hemolysis because of IgG antibodies most commonly occurs in patients with lymphoproliferative neoplasms. More than half of the patients in some series have an associated malignancy, but only 2% of cases are associated with solid tumors. This complication has also been reported after treatment with various cytostatic drugs (e.g., fludarabine). The IgG-coated erythrocytes are removed from the circulation by the reticuloendothelial system, predominantly by the spleen (extravascular hemolysis).
2. Diagnosis. Patients with warm antibody autoimmune hemolysis usually have an insidious onset of severe anemia, mild jaundice, and splenomegaly. The blood smear shows polychromasia, a significant degree of spherocytosis, and, often, nucleated RBCs. Reticulocytes are typically increased but may be normal if any other cause of anemia is also present. The direct antiglobulin test (DAT, or Coombs test) is positive with anti-IgG or anticomplement antisera, usually with specificity for the Rh blood group system.
3. Treatment. Prednisone and successful treatment of the tumor are necessary. Patients with solid tumors associated with immune hemolysis respond to prednisone infrequently. Patients who have an unsatisfactory response or need chronic corticosteroid therapy require splenectomy if their general condition permits. Treatment with rituximab may be considered.
G. Cold antibody (IgM) immune hemolysis
1. Pathogenesis. Cold agglutinins are IgM molecules that attach to RBC membranes at cold temperatures and fix complement. At 37°C, the IgM molecules dissociate from the cell, but the complement remains fixed. Cold agglutinins are most common in lymphoma and are rare in other malignancies. Overt hemolysis (often intravascular) is unusual except in patients with very high titers (>1:10,000) of cold agglutinins.
2. Diagnosis. Patients with high titers of cold agglutinins may have acrocyanosis or Raynaud phenomenon. RBC agglutination may be observed on blood smears, but spherocytes are not prominent. The DAT is strongly positive when performed at 4°C but is positive only with anticomplement antisera at 37°C.
3. Treatment. Rituximab, 375 mg/m2 weekly for 4 weeks is often effective. Chlorambucil or cyclophosphamide may be helpful for patients with symptomatic chronic cold agglutinin disease.
H. Microangiopathic hemolytic anemia hemolysis (MAHA) with erythrocyte fragmentation has been described in patients with adenocarcinoma (particularly gastric cancer) and hemangioendothelioma. The pathophysiology of MAHA involves fibrin strands of DIC, pulmonary intraluminal tumor emboli, narrowing of pulmonary arterioles by intimal proliferations, or a side effect of chemotherapy. Most patients with MAHA, however, probably have DIC or chemotherapy-associated thrombotic thrombocytopenia (see Section V.C).
V. THROMBOCYTOPENIA BECAUSE OF INCREASED PLATELET DESTRUCTION. Decreased production is by far the most common cause of thrombocytopenia in patients with cancer. Splenic sequestration may cause thrombocytopenia, almost always in association with anemia. Increased destruction of platelets is usually associated with normal megakaryocytes in the bone marrow and decreased platelet life spans.
A. DIC is the most common cause of increased destruction of platelets in cancer patients (see “Coagulopathy,” Section II).
B. Idiopathic thrombocytopenic purpura (ITP) complicates lymphoproliferative diseases, especially malignant lymphoma and chronic lymphocytic leukemia, and is rarely associated with carcinoma. Thrombocytopenia in ITP is due to reticuloendothelial system destruction of IgG-coated platelets.
1. Diagnosis of ITP is made presumptively in the absence of evidence of DIC or of drug-induced thrombocytopenia with the finding of a nondiagnostic bone marrow containing normal or increased numbers of megakaryocytes.
2. Treatment. Control of the underlying disease is essential for satisfactory control of ITP.
a. Patients are treated with prednisone, 60 to 80 mg/d PO. Rituximab, single alkylating agents, or vinca alkaloids can successfully achieve remission in some patients. Splenectomy may be indicated in patients who fail these measures and have symptomatic thrombocytopenia or require relatively high doses of prednisone chronically.
b. Many cases of ITP are chronic; platelet counts are 50,000 to 80,000/µL. In the absence of symptoms, it is best to observe these patients without giving long-term immunosuppressive therapy.
C. Chemotherapy-induced thrombotic thrombocytopenic purpura (TTP) or hemolytic–uremic syndrome (HUS). TTP/HUS can develop during the treatment of patients with cancer, particularly when using mitomycin C for adenocarcinoma. More than 90% of cases have been associated with mitomycin C. About 10% of patients treated with mitomycin C develop TTP/HUS, especially when the cumulative dose is >60 mg. Manifestations are often precipitated or exacerbated by transfusion of blood products. Therapy with cisplatin, bleomycin, cyclosporine, or gemcitabine has also been associated with this complication. TTP has also occurred with clopidogrel (Plavix), ticlopidine (Ticlid), cyclosporine, and tacrolimus (used for transplant rejection prophylaxis).
Chemotherapy-induced TTP/HUS usually occurs 2 to 9 months after cessation of treatment, even when the cancer is in remission (about one-third of patients). Noncardiogenic pulmonary edema develops in 65% of patients with this syndrome, which is rapidly lethal if not successfully treated.
1. Diagnosis. TTP/HUS is characterized by the extensive deposition of hyalin-like material in arterioles and capillaries. Diagnostic hallmarks of TTP/HUS are microangiopathic hemolysis and severe thrombocytopenia; other features often include markedly elevated serum LDH levels, rapidly changing neurologic abnormalities, fever, and renal dysfunction. Coagulation abnormalities associated with DIC are absent.
2. Treatment. Transfusion of plasma and intensive plasmapheresis have been successful in achieving remissions in classic TTP/HUS. Treatment of chemotherapy-induced TTP/HUS with staphylococcal protein A extracorporeal immunoabsorption of circulating IgG immune complexes also achieves significant responses in half of the patients. Normalization of platelet counts and LDH values is seen 7 to 14 days after starting treatment.
VI. GRANULOCYTOPENIA. Granulocytopenia in cancer patients is usually the result of chemotherapy, radiotherapy, other drugs, severe infection, or myelophthisis. An immune or cytokine basis is involved in the granulocytopenia associated with T-γ-lymphoproliferative disease (syndrome of large granular T lymphocytes) and rare cases of thymoma. Experimental evidence also supports the existence of paraneoplastic suppression of granulopoiesis. These entities are discussed elsewhere in this book.
Granulocytopenia predisposes patients to infections. Infection in patients with severe neutropenia (<500 neutrophils/µL) can be a lethal complication and should be treated rapidly with antimicrobial agents (see Chapter 35Section II). Cultures should be obtained and broad spectrum antibiotics should be instituted at the first signs of fever or infection; these can be modified later if a specific organism is identified. Because fungal infections are also a risk with severe neutropenia, the addition of antifungal agents should be considered in patients who fail to respond to antibiotics if no other cause is identified.
VII. MONOCYTOPENIA. Monocytopenia as an isolated finding has no clinical significance. Monocytopenia is seen in all causes of aplastic anemia and is a constant finding in hairy cell leukemia, for which it can represent an important diagnostic clue.
VIII. BLOOD COMPONENT THERAPY
A. Transfusion of erythrocytes
1. Indications for transfusion of packed RBCs (PRBCs) are for increasing blood volume (with saline or colloid solutions when acute blood loss threatens the integrity of the cardiovascular system) and for increasing oxygen-carrying capacity (when anemia causes or threatens tissue hypoxia). Most patients tolerate chronic, moderately severe anemia well. No specific hemoglobin value mandates transfusion. PRBCs are given to increase the oxygen-carrying capacity of blood for actual or incipient congestive heart failure or to reverse cardiac or central nervous system ischemic symptoms. When the hemoglobin level that precipitated symptoms is determined, patients with chronic anemia are transfused prophylactically to exceed that level.
2. Transfusion reactions
a. Fever and chills. Most febrile reactions are caused by antibodies in the recipient directed against granulocytic antigens and specific human leukocyte antigens (HLAs) on leukocytes in the donor blood. Febrile reactions occur in up to 80% of patients who receive multiple transfusions. The reaction usually starts shortly into the transfusion, continues for 2 to 6 hours, and may persist for 12 hours.
b. Allergic reactions involving urticaria develop in 5% of transfused patients. Some of these reactions are due to antibodies in the recipient directed against immunoglobulin components and other proteins in the plasma of the donor. These reactions are usually mild and respond to antihistamines.
These kinds of reactions or anaphylaxis are particularly likely to occur in patients with congenital IgA deficiency who have formed anti-IgA antibody (1 per 800 people). Reactions can be prevented by using washed or frozen RBCs because these components are prepared by procedures that remove donor plasma.
c. Major acute intravascular hemolytic transfusion reactions are most likely to occur as a result of human error during blood preparation or administration. Fever and chills usually develop within the first 30 minutes into the transfusion and are often accompanied by back pain, sensations of chest compression, tachycardia, hypotension, tachypnea, nausea, vomiting, oliguria, hemoglobinuria, and DIC. The risk for a fatal hemolytic transfusion reaction is about 1:100,000. Plasma is examined for confirmatory findings and compared with the pretransfusion specimen: increased free plasma hemoglobin (pink plasma) and methemalbumin (brown plasma). Detailed evaluation of antibodies evaluated in the cross-matching process follows.
d. Delayed hemolytic transfusion reactions occur 5 to 14 days after transfusion, particularly in association with alloantibodies to antigens of the Kidd, Duffy, Kell, or Rh blood group systems. Hemolysis is extravascular and is manifested by jaundice and the absence of an improvement of hemoglobin levels after transfusion. In these cases, patients have become alloimmunized by a previous transfusion or pregnancy, but the antibody concentration was too low to be detected at the time of transfusion; an anamnestic antibody response was generated by the subsequent transfusion.
e. Posttransfusion purpura is manifested by severe thrombocytopenia developing 5 to 8 days after transfusion and occurs in the 2% of patients who lack the platelet antigen PlA1.
f. Bacterial contamination occurs rarely in packed RBC units (usually with cryopathic gram-negative bacteria) but is more likely with platelet packs that are stored (at room temperature) for >4 days.
g. Viral contamination. Predonation screening interviews and postdonation serologic testing have significantly reduced the incidence of some transfusion-transmitted viral infections (hepatitis B, hepatitis C, and human immunodeficiency virus [HIV]). The risks (per unit for blood units that are negative in laboratory testing) of transmitting viruses through transfusion are as follows:
Hepatitis B virus, 1:150,000
Hepatitis C virus, 1:1,200,000 to 1,900,000
HIV, 1:1,400,000 to 2,100,000
Human T-cell lymphotropic virus types 1 and 2, 1:640,000
h. Graft versus host disease (GVHD; see Chapter 37) can occur after blood cell transfusion in patients who have undergone a conditioning regimen for bone marrow transplantation (BMT). Transfusional GVHD can occur following blood transfusion in patients who are heavily immunosuppressed following chemotherapy or who have congenital immunodeficiencies. GVHD can also occur in patients who are less immunocompromised if the blood donor is homozygous for one of the HLA haplotypes of the recipient, and particularly if the donor is a first-degree relative. Transfusional GVHD is preventable by irradiation of blood products prior to transfusion (see Section VIII.A.3.f).
i. Other complications include those associated with massive transfusion (blood volume overload, hypocalcemia, hyperkalemia, hypothermia), iron overload with chronic transfusions, and alloimmunization.
3. Uses for erythrocyte preparations
a. Fresh whole blood. None
b. PRBCs. The mainstay of erythrocyte transfusion therapy
c. Saline-washed PRBCs are indicated in patients who have IgA deficiency (particularly those with high anti-IgA titers), prior urticarial reactions with transfusions, the need to avoid transfusion of complement, or the rare patient who is hypersensitive to plasma.
d. Leukocyte-reduced PRBCs are used for patients requiring chronic transfusion therapy and those with prior febrile nonhemolytic transfusion reactions and also for immunocompromised patients in whom reducing the risk for transfusion-transmitted CMV is sought (particularly when seronegative units for CMV are not available). Leukocytes can be removed by centrifugation, washing, or filtration (the latter technique is most frequently used). These products yield <5 × 108 leukocytes per unit of blood.
e. Frozen RBCs are a source for rare blood types, a backup supply for the common blood types, a substitute for saline-washed or leukocyte-filtered PRBCs when those methods fail to prevent febrile or allergic transfusion reactions, and an additional method of autologous donation. The extensive washing required to remove the cryopreservatives in frozen RBCs renders the suspension totally free of all leukocytes, platelets, and plasma constituents. The major limitations are the cost and the time required to prepare and store cells.
f. Gamma-irradiated PRBCs are given to prevent viable T lymphocytes from causing transfusion-induced GVHD in the recipient. A dose of 1,500 cGy is usually administered.
g. Directed or designated donors from among family members or friends, contrary to expectation, are no safer for viral transmission than volunteer blood donors (probably because of the sometimes unreliability of the history taken from these candidates in the screening process prior to donation). Furthermore, if not irradiated, these units are associated with an increased risk for transfusional GVHD when provided by first-degree relatives to immunocompromised patients.
B. Transfusion of granulocytes. Granulocytes collected by apheresis are rarely helpful in treating patients with granulocytopenia. The paramount factor in determining the outcome of sepsis is the recovery of marrow function. Transfusion of granulocytes can occasionally be helpful as a temporary adjunct to antimicrobials in severely neutropenic patients with active infections. Prophylactic transfusions for general patients with neutropenia are useless. Transfusion of leukocytes can result in transfusional GVHD and transmission of CMV. If granulocyte transfusion is used, the transfused cells should be irradiated, and donors who are seronegative for CMV should be used for seronegative recipients.
Granulocyte harvesting from the donor is promoted by the use of G-CSF. The donor and recipient must be compatible for Rh and ABO erythrocyte antigens. Daily granulocyte transfusions may be occasionally helpful only if all of the following criteria are met:
1. Recovery of bone marrow function is a reasonable expectation but is not expected to occur for 1 week.
2. The absolute granulocyte count is <200/µL.
3. A serious bacterial or fungal infection is proved by culture.
4. The infection is not responding to the appropriate antibiotics.
C. Transfusion of platelets
1. Factors influencing the decision to transfuse platelets
a. Platelet count. Spontaneous hemorrhage rarely occurs with platelet counts above 20,000/µL. Platelet counts of <10,000/µL are associated with an increased risk for spontaneous hemorrhage, especially when the thrombocytopenia results from decreased production rather than from increased platelet destruction. Progressively worsening thrombocytopenia is more likely to be associated with active hemorrhage than with stable or increasing platelet counts.
b. Platelet age. Young platelets (i.e., produced after peripheral destruction) are larger and better able to provide hemostasis than old platelets. Usually, patients with immune or postinfectious severe thrombocytopenia have no serious hemorrhagic sequelae.
c. Active bleeding, uncontrollable by local measures, or bleeding into vital or inaccessible organs, is an absolute indication for platelet transfusion in patients with thrombocytopenia of nearly any severity.
d. Fever, infection, and corticosteroid therapy increase the risk for serious hemorrhage in patients with very low platelet counts.
e. Drugs and diseases adversely affecting platelet function may necessitate platelet transfusions in times of hemorrhage or surgery despite adequate platelet counts (see Section VIII.C.6).
f. Immune thrombocytopenia usually makes platelet transfusions useless.
g. Patients with thrombocytopenia that is refractory to platelet transfusion may be alloimmunized, but they also may have DIC, TTP/HUS, or ITP.
2. Problems associated with platelet transfusion. The majority of platelets are now produced by plateletpheresis, wherein the platelet concentrate contains <5 × 106 white blood cells (WBCs); these products can be considered “leukocyte-depleted.”
a. Alloimmunization. Compatibility between donor and recipient for both ABO and HLAs is important for achieving a successful platelet count increment after transfusion. Alloimmunization requires the presence of class I and class II HLAs. Platelets alone do not result in the development of antibodies because they carry only class I HLAs and platelet-specific antigens; the class II antigens necessary for the development of alloimmunization are provided by transfused monocytes, lymphocytes, and dendritic cells. Rh antigens play only a minor role in alloimmunization after platelet transfusions.
b. Reactions to platelet transfusion. Infectious contamination occurs rarely but more commonly than with PRBCs because platelets are stored at room temperature for 5 days. Hemolysis of the small numbers of contaminating donor RBCs in donor platelet concentrates is of minor consequence. Febrile reactions, however, occur often in ABO-compatible platelet transfusions because
(1) Recipient antibodies to WBCs attack donor WBCs contained in transfused platelet packs. This reaction is prevented by effective leukodepletion of platelet packs.
(2) Cytokines released by leukocytes during storage, particularly TNF-α and IL-1β (which are exceptional pyrogens), are passively transfused. This reaction is prevented by performing leukodepletion before storage of the platelet packs.
(3) Recipient antibodies to cells and proteins in the donor unit form immune complexes that trigger the release of cytokines. This reaction involving incompatible platelets is unaffected by leukodepletion and justifies further testing for HLA antibodies or platelet-specific antibodies, if available.
c. Leukodepletion filters remove donor leukocytes by barrier retention of the filters’ microfibers, by adherence to the filter material, and by platelet–leukocyte–mediated interactions.
3. Selection of which platelet preparation to transfuse depends on expected future transfusions and the presence of alloimmunization.
a. Random (ABO-compatible) units. One random unit is the platelet concentrate from 1 unit of whole blood. These platelet units can be pooled and may be used in patients with transient thrombocytopenia that is not expected to recur and when platelets are needed immediately.
b. Single-donor platelets (plateletpheresis packs) are obtained by density centrifugation using an apheresis machine. One plateletpheresis pack is equivalent to about 6 to 8 random platelet units and may be obtained from one donor two or three times weekly. Single-donor platelet packs are the preferred blood product in conditions that require recurrent platelet transfusions because alloimmunization is delayed. Chemotherapy tends to reduce the risk of alloimmunization to platelets.
c. Platelets cross-matched for ABO compatibility are available for potential use in alloimmunized patients.
d. HLA-compatible platelets. HLA-matched platelets (HLA class I only) are required in alloimmunized patients but are not always available. The likelihood of an identical HLA match is 1 in 4 among siblings and 1 in 1,000 in the general population.
e. Platelets from family members should be avoided in patients who are possible candidates for BMT. The marrow donor may be used as the source of HLA-identical platelets, however, after the transplantation conditioning program has begun.
4. Prophylactic transfusions
a. Acute leukemia. Prophylactic transfusion of these patients with platelets is recommended to maintain the count above 10,000/µL if they are afebrile and above 20,000/µL if they are febrile.
b. In aplastic anemia, prophylactic transfusions are avoided if possible.
c. Pregnancy. Platelet packs are administered to patients with a platelet count of <100,000/µL just before delivery. After delivery, platelet counts should be maintained above 50,000/µL for 1 week. The possibility of DIC should be evaluated in patients with continued or massive postpartum bleeding associated with thrombocytopenia. Pregnant patients with thrombocytopenia induced by myelosuppressive therapy or leukemia are given platelet transfusions empirically.
5. Effectiveness of platelet transfusions is determined by measuring platelet counts just before, 1 hour after, and 24 hours after transfusions. If the patient does not respond with an increase of about 25,000 in the platelet count after 1 hour, the transfusion should be considered a failure. The result at 24 hours can be further affected by concurrent hematologic complications.
6. Other measures
a. Diseases affecting platelet function. Patients with uremia require dialysis, cryoprecipitate, or desmopressin acetate (DDAVP) with ε-aminocaproic acid (EACA; Amicar) to improve platelet function. In patients with platelet dysfunction secondary to paraproteins, it is necessary to control the underlying disease or to perform plasmapheresis.
b. DDAVP may be useful in patients with aspirin-induced platelet dysfunction at a dose of 0.3 µg/kg given over 20 minutes.
c. Alloimmunized patients who are refractory to transfused platelets. High-dose intravenous γ-globulin (400 mg/kg/d for 5 days) occasionally permits better platelet increments in patients who are refractory to platelet transfusion. Cross-matched or HLA-matched platelets may be helpful. Plasmapheresis may be tried empirically in difficult situations but is rarely helpful.
d. Menorrhagia in patients with thrombocytopenia should be treated with medroxyprogesterone, 20 mg PO daily, to induce amenorrhea. Alternatively, leuprolide, 3.75 mg IM monthly, can be used if the platelet count is high enough to permit IM administration. Treatment is continued until the platelet count exceeds 60,000/µL.
D. Transfusion of plasma proteins
1. Preparations
a. Fresh frozen plasma (FFP) contains all coagulation factors and is useful in replacement of all acquired clotting factor deficiencies (e.g., DIC, massive transfusion, liver disease). The indications for FFP are as follows:
(1) Replacement of isolated coagulation factor deficiencies
(2) Reversal of documented coagulation factor deficiencies after massive blood transfusions
(3) Reversal of warfarin effect in patients requiring immediate surgery or having active bleeding
(4) Treatment of antithrombin (AT) deficiency or TTP
b. Cryoprecipitate contains von Willebrand factor, fibrinogen (factor I), factor VIII, and factor XIII. Cryoprecipitate is useful in treating acquired deficiencies of fibrinogen and factor VIII (e.g., DIC) when volume overload from plasma treatment is to be avoided and in severe von Willebrand disease.
c. Plasma protein fractionation has resulted in the following commercially available products, which are obtained by pooling plasma from thousands of donors and then fractionating into components:
(1) Fibrinogen. This form is never indicated because of the 100% risk for hepatitis.
(2) Prothrombin complexes (factors II, VII, IX, X, protein C, and protein S) are used in congenital factor deficiencies and in occasional cases of coumarin overdose with life-threatening hemorrhage. The risk for hepatitis with this blood product is 60%. This product carries the risk of inducing venous thrombosis and/or DIC, but the risk appears to have been reduced with modern preparations.
(3) Albumin and purified protein fraction have the same concentration of albumin and the same cost. They are useful for blood volume expansion, but their use in chronic hypoalbuminemia of malabsorption, nephrosis, or cirrhosis or as a nutritional supplement is futile.
(4) Gamma globulin is useful for passive immunization.
d. Hyperimmune IV γ-globulin must be infused at a rate slower than 1 mL/min to avoid complications. This very expensive product is of definite therapeutic importance in only a few clinical circumstances:
(1) Congenital humoral immunodeficiency states
(2) Acquired humoral immunodeficiency states (e.g., chronic lymphocytic leukemia, lymphoma, myeloma) when complicated by recurrent bacterial infections that do not respond to prophylactic antibiotics
(3) Platelet alloimmunization in conjunction with platelet transfusion
(4) ITP when severe or life-threatening hemorrhage occurs, when severe thrombocytopenia refractory to steroids occurs during pregnancy, or when splenectomy is performed and hemostasis is a problem
2. Hazards
a. Allergy. All plasma preparations are associated with a small incidence of serum sickness reactions. Fever, urticaria, or erythema may also occur in reaction to residual leukocyte antigens.
b. Volume overload is an important consideration when administering FFP. Citrate toxicity may occur with very rapid transfusion rates (100 mL/min).
c. Infection with hepatitis B, hepatitis C, delta agent hepatitis, HIV, CMV, and EBV is a potential risk for all plasma products.
(1) Very high risk: fibrinogen, prothrombin complex, repeated use of cryoprecipitate
(2) Intermediate risk: single-donor units screened for hepatitis B surface antigen of plasma
(3) Very low risk: γ-globulin, albumin, purified protein fraction (nil for HIV)
COAGULOPATHY
I. THROMBOSIS IN PATIENTS WITH CANCER. The presence of cancer, particularly when disseminated, is recognized to be a “hypercoagulable” or “thrombophilic” state. Multiple or migratory venous thromboembolism (VTE) in cancer patients has been repeatedly documented since Trousseau’s description in 1865. Fibrin–platelet vegetations, usually undetectable by echocardiography, may form on mitral or aortic valves and result in noninfectious (“marantic”) endocarditis with paradoxical emboli to peripheral organs; fewer than one-third of affected afebrile patients have heart murmurs. An accelerated course of intermittent claudication and of ischemic heart disease has also been described in cancer patients and probably represents additional variants of Trousseau syndrome.
A. Incidence. The overall incidence of thrombotic episodes in cancer patients is 10% to 15%, especially during postoperative periods. The postoperative risk of VTE in cancer patients is about double that in patients without cancer (37% vs. 20%), and the risk of fatal pulmonary embolism is about fourfold higher in cancer patients.
About 5% to 10% of patients with idiopathic VTE ultimately are proved to have a malignancy, particularly during the first 6 months after diagnosis. Pulmonary emboli have been found at necropsy in about half of the patients with disseminated cancer and have antedated the diagnosis of cancer in 1% to 15% of patients. The malignancies most commonly associated with thrombosis are MPDs and carcinomas of the GI tract, lung, or ovary. Only 7% of patients with pancreatic cancer develop classic Trousseau syndrome.
B. Mechanisms for hypercoagulability
1. Cancer is associated with the following thrombophilic factors:
a. The tumor’s disruption of blood vessels exposes collagen and endothelial basement membrane, which may trigger clotting. Tumor neovascularization activates both factor XII and platelet reactions.
b. Cancers can directly produce various procoagulants. The best characterized is tissue factor–like procoagulant (TF). TF forms a complex with factor VIIa to activate factors IX and X, initiating the activation cascade of clotting protease complexes.
(1) TF is normally expressed only on fibroblasts of the vascular adventitia and other stromal cells. TF is produced by many solid tumor cells and leukemic blasts.
(2) TF also appears to be an important promoter of tumor growth and of angiogenesis. TF expression directly correlates with the malignant phenotype of various tumors. TF upregulates expression of vascular endothelial growth factor (VEGF) by tumor cells. VEGF in turn upregulates TF. The induction of angiogenesis by TF also involves its interaction with the protease-activated receptors (PARs).
c. Inflammatory cytokines (CKs), particularly TNF and IL-1, can be released by tumor cells and immune regulatory cells under pathologic conditions. These CKs can induce TF expression on tumor-associated macrophages and endothelial cells. The endothelial cells become procoagulant under the influence of these CKs.
(1) The CKs also upregulate adhesion molecules, platelet-activating factor, and plasminogen activator inhibitor type-1 (PAI-1).
(2) The CKs downregulate the expression of thrombomodulin and endothelial cell protein C receptor.
d. Thus, a hypercoagulable state is established in cancer patients through activation of the clotting cascade, activation of platelets, enhancement of endothelial cell adhesion, suppression of fibrinolysis, and inhibition of the anticoagulant protein C pathway.
2. Comorbid factors, such as advanced age, previous history of VTE immobility, obesity, hospitalization, surgery, catheterization, major medical conditions (such as infection), concomitant chemotherapy, and hereditary thrombophilia, play contributory roles for blood hypercoagulability to become manifest clinically. Venous stasis as a result of bed rest or extrinsic vessel compression from tumor masses also contributes.
3. Cancer therapies associated with enhanced risk for thrombosis are high-dose chemotherapy with BMT, bevacizumab (Avastin), 5-fluorouracil, thalidomide and its derivatives, and high doses of estrogen. Several other cytotoxic agents (asparaginase, bleomycin, carmustine, cisplatin, thalidomide and lenolidomide, mitomycin C, vinca alkaloids) have been reported to cause VTE, but the true incidence and mechanisms are not clear.
a. Tamoxifen increases the risk for venous thrombosis slightly (1.5-fold to 2-fold) when given alone and significantly increases the risk for venous and arterial thrombosis when given concomitantly with chemotherapy, particularly in premenopausal women. The aryl aromatase inhibitors used in the treatment of postmenopausal women with breast cancer also increase the risk for thrombosis.
b. The presence of the prothrombin G20210A gene mutation or of activated protein C resistance as a result of the inheritance of factor V Leiden may increase the risk further for hormonal therapies. However, these mutations have been shown not to be contributing factors for the development of VTE in patients receiving cytotoxic chemotherapy.
C. Management of cancer-associated thrombosis. Standard-dose intravenous unfractionated heparin (UH), low-dose UH (LDUH), adjusted-dose SC UH (while monitoring the partial thromboplastin time), and weight-adjusted low-molecular-weight heparin (LMWH) are traditional options for initiating therapy of VTE, depending on the clinical and social circumstances. However, LMWH is the preferred anticoagulant for both the initial and long-term treatment of cancer-associated thrombosis in major consensus guidelines.
LMWH is superior to warfarin and more convenient than UFH. LMWH can be used to treat venous thrombosis outside the hospital setting without the need for monitoring clotting tests; the switch to oral warfarin, if that drug is chosen, is made after 8 to 12 days. For secondary prophylaxis of VTE in cancer patients, studies indicate more favorable efficacy for LMWH with treatment extended for 3 to 6 months compared to warfarin. The new antithrombins and anti–factor Xa oral agents (dabigatran, rivaroxaban, apixaban) are attractive options but have not been properly studied in cancer patients.
D. Management of recurrent thrombosis in cancer patients is difficult because it is often resistant to therapy and because patients often have worrisome sites for potential hemorrhage.
1. Anticoagulant therapy. The use of LMWH is supported by observational data in this setting.
a. If recurrent thrombosis develops while on warfarin therapy, switch to LMWH. Increasing the warfarin dosage limit excessively increases the risk for hemorrhage.
b. If recurrent thrombosis develops while on LMWH therapy, increase the dose by 20% to 25%. If clinical improvement does not occur within a week, measure the peak anti-Xa level (the target would be 1.6 to 2.0 U/mL for once daily dosing or 0.8 to 1.0 U/mL for twice daily dosing).
2. Contraindications to anticoagulant therapy include the following:
a. Pre-existing clotting defect or bleeding source
b. Inaccessible ulceration (e.g., GI tract)
c. Recent hemorrhage or surgery in the eye or central nervous system
d. Severe hypertension or bacterial endocarditis
e. Regional or lumbar anesthesia; tube drainage
f. Pregnancy (if anticoagulation is mandatory, UH or LMWH is used because it crosses the placenta less readily than warfarin)
3. Vena caval interruption, usually with a Greenfield filter, is performed if anticoagulants are contraindicated. The filter is effective for preventing pulmonary embolism but increases the risk for recurrent VTE. Vena cava filters should be avoided for the treatment of thrombosis because of their invasiveness, cost, and the lack of proven efficacy.
4. Graduated compression stockings should be used, if practical, particularly in postoperative patients.
5. Removal of the tumor may control thrombotic episodes but is often impossible.
6. Special considerations for anticoagulation in cancer patients. The objective in treating VTE (prevention of death due to and other complications of pulmonary embolism) is not necessarily applicable in the preterminal patient with cancer. The goal of anticoagulation in these patients is more likely to prevent pain in the extremities or chest. Therapy with warfarin in cancer patients is often chaotic and associated with unpredictable changes in dose response because of the presence of poor nutrition, impaired liver function, infection, and concomitant medications (especially antibiotics). Furthermore, temporary cessation of anticoagulation may be necessary because of thrombocytopenia induced by chemotherapy.
E. Prophylaxis against venous thrombosis in cancer patients
1. Cancer surgery is associated with a 35% risk of venous thrombosis without prophylaxis. The use of LMWH decreases the rate to 13%. The addition of mechanical prophylaxis to the anticoagulant program reduces the risk to 5%. Fondaparinux has also been shown to be effective in this setting. There appears to be no major difference between the anticoagulation agents, but higher doses appear to be more effective than lower doses (e.g., 1.5 mg/kg rather than 1.0 mg/kg daily for enoxaparin).
Consensus guidelines recommend extending prophylaxis for at least 1 month after surgery in patients with cancer, particularly in patients with several risk factors for VTE. The benefit for longer prophylaxis has been demonstrated, but the optimal duration of treatment is unknown. Published rates of major bleeding complications are low, particularly in those patients without significant risk factors for bleeding.
a. Issues with anesthesia. Patients receiving thienopyridine platelet inhibitors (clopidogrel, ticlopidine) should discontinue those drugs 2 weeks prior to surgery. The timing of spinal anesthesia should coincide with the trough blood levels of heparin.
b. Heparin-induced thrombocytopenia occurs in 1% to 5% of patients treated with LDUH and in <1% of patients receiving LMWH under these circumstances.
2. Hospitalization. Consensus recommendations support thromboprophylaxis in patients with cancer when they are admitted to the hospital. Some investigators suggest that cancer patients require higher doses of LMWH, but it has not been shown that the potential benefit justifies the increased risk for bleeding that would be associated with the higher doses.
3. Central venous catheters. Low doses of warfarin or LMWH seem to have no effect on reducing catheter-related thrombotic complications. Increased risk for thrombosis is seen in those patients with a poorly positioned catheter tip, insertion of the catheter in left-sided veins, age >60 years, or metastatic disease.
4. Chemotherapy. The risk of VTE in cancer patients undergoing chemotherapy is particularly high. LMWH reduces clinically important VTE, but the optimal dose, duration, and specific patient populations are poorly defined.
F. Diagnostic tests in patients with idiopathic (unprovoked) VTE
1. The clinical diagnosis of venous thrombosis is made by physical examination and venous ultrasonography or venography. Venography and the fibrinogen uptake test have higher rates of detection than ultrasonography. The presence of venous thrombosis, a heart murmur, and arterial embolism suggests an underlying mucin-producing carcinoma.
2. An occult malignancy should be sought in patients who present with any of the following:
a. Idiopathic deep vein thrombosis or pulmonary emboli
b. Idiopathic deep vein thrombosis combined with arterial thrombosis
c. Idiopathic thrombosis that is recurrent or at multiple sites
d. Thrombosis that is resistant to anticoagulation therapy
e. Associated paraneoplastic syndromes and thrombosis
3. A reasonable screening evaluation for occult cancer in patients with thrombotic disease includes a thorough history and physical examination (including rectal or pelvic examination), CBC, LFTs, LDH, prostate-specific antigen in men older than 50 years, urinalysis, stool for occult blood, and chest radiograph. An abdominopelvic CT scan and carcinoembryonic antigen assay may be considered for patients who are suspected to have cancer.
Routine screening for cancer in patients with unprovoked VTE using extensive studies evaluating systems not suggested by basic screening is not justified. Detecting cancers in this way has not been shown to provide a survival advantage.
4. Laboratory tests of coagulation can be obtained during the first idiopathic thromboembolic event in an otherwise healthy person to seek a possible biologic defect predisposing to thrombosis. Such assays would include the following:
a. Assays for lupus anticoagulant and serologic tests for antiphospholipid antibodies
b. Functional assays for protein C and antithrombin 3 (AT)
c. Functional assays for protein S (immunologic assays of total and free protein S)
d. Clotting assay for resistance to activated protein C (genetic test for factor V Leiden if clotting assay is positive)
e. Screening for dysfibrinogenemia (thrombin time, immunologic and functional assays of fibrinogen)
f. Total plasma homocysteine
g. Genetic test for prothrombin gene mutation (prothrombin 20210A)
h. Various laboratory findings that are not predictive of thromboembolic disease in cancer patients include increased levels of platelets, markers of platelet activation, markers of thrombin generation, fibrinogen, and factors V, VIII, IX, and XI; decreased plasma levels of AT; and suppression of fibrinolytic activity.
II. DIC is provoked by numerous disorders. If series of cases with disproportionate numbers of obstetrics and trauma cases are excluded, the vast majority of cases result from infectious diseases or cancer. DIC is a frequent complication for patients with metastatic cancer, either as a consequence of the metastases themselves or complicating infections. Local or diffuse thrombosis or hemorrhage can occur in all combinations. The incidence depends on the definition of DIC and assays used. Severe DIC is common in only two malignancies: metastatic carcinoma of the prostate and acute hypergranular promyelocytic leukemia (type M3).
A. Factors in pathogenesis of DIC. With all inciting conditions, procoagulants are produced or introduced into the blood and overcome the anticoagulant mechanisms, leading to the generation of thrombin and DIC. The endothelium of the capillary bed in conjunction with mononuclear inflammatory cells is the mainstay of host defense against organ and tissue injury. Compromising the endothelium with injury or infection can trigger the sequential “systemic inflammatory response syndrome,” which can lead to microvascular thrombosis and ensuing multiorgan dysfunction. The following is an overview of the extraordinarily complex interactions that result in the clinical syndrome of DIC.
1. Tissue factor and the cascade of cytokines leading to thrombosis are discussed in Section I.B. Once TF is expressed on the membrane of monocytes and endothelial cells, thrombin is generated, and fibrin and platelets are deposited.
2. Thrombin generation amplifies both clotting and inflammation by activating
a. Factors VIII, V, and XI, yielding further thrombin generation
b. Platelets, giving rise to platelet aggregation and activation
c. Proinflammatory factors via PARs
d. Factor XIII, which makes fibrin insoluble by covalent cross-linking
e. Thrombin-activatable fibrinolysis inhibitor, making clots resistant to fibrinolysis
f. Inflammatory effects of leukocytes
3. Activation of complement (C′5 and C′5 to C′9) by injury or inflammation accelerates the rate of coagulation reactions. C′4b binding protein can become a procoagulant and proinflammatory by binding protein S, thereby decreasing free protein S levels and slowing the quenching of inflammation via the endothelial protein C receptor pathway.
4. Upregulation of inflammation is induced by the coagulation proteases (e.g., thrombin, Xa, VIIa-TF) via PARs, which are located on endothelial cells, platelets, and leukocytes.
5. Activated protein C, which has an anti-inflammatory effect, decelerates thrombin generation by inactivating factors Va and VIIIa in the presence of protein S. Protein C is activated by thrombin–thrombomodulin complexes on endothelial cells. Thrombomodulin is most ubiquitous in the capillary beds of the microcirculation where the disruptions and inflammations are occurring.
6. AT is an important circulating serine protease inhibitor that neutralizes thrombin, factor Xa, and the other coagulation serine proteases. AT is consumed in DIC.
7. Fibrinolysis often becomes impaired in DIC, resulting in persistent microthrombosis. In patients with DIC and multiorgan failure, tissue plasminogen activator antigen and PAI-1 are often elevated, and α-antiplasmin is reduced.
8. Superoxides and hydroxyl radicals generated during sepsis and other organ injury states are proinflammatory agents that induce endothelial apoptosis, which would exacerbate capillary leak.
9. Elastase released by damaged endothelium interacting with activated neutrophils promotes DIC by inhibiting thrombomodulin function, causing detachment of endothelial cells and inhibiting fibrinolysis.
B. Diagnosis. The widespread generation of thrombin in DIC induces the deposition of fibrin, which results in the consumption of platelets, fibrinogen, factors V and VIII, protein C, AT, and components of the fibrinolytic system. The severity of DIC manifestations depends on the underlying diagnosis, the acuteness of the DIC, the integrity of the reticuloendothelial system, and the intensity of secondary fibrinolysis. Some patients hemorrhage profusely and have marked abnormalities of all of the tests for DIC. On the other hand, DIC may be subclinical and manifested only by a positive paracoagulation test and mild thrombocytopenia.
1. Clinical features
a. Type of bleeding. Patients with severe DIC bleed from multiple sites simultaneously. Petechiae, ecchymoses, mucosal bleeding, and oozing from venipunctures, lines, and catheters are common. Patients with chronic DIC (the usual DIC seen with malignancies) may have minimal bleeding.
b. End-organ damage. Microangiopathic hemolysis, hypotension, oliguria, and renal failure are frequent complications of serious DIC. Renal cortical ischemia induced by microthrombosis of afferent glomerular arterioles and acute tubular necrosis due to hypotension are the major causes of renal dysfunction in DIC. Both the diseases underlying DIC and DIC itself can cause shock. Microvascular thrombi and thromboembolism can result in dysfunction of any organ (e.g., acral necrosis, neurologic manifestations, and pulmonary dysfunction).
2. Laboratory tests. No single test is diagnostic for DIC.
a. Blood smear. The numbers of circulating platelets are decreased, and fragmented erythrocytes or microspherocytes may be seen.
b. Platelet count. Thrombocytopenia occurs nearly always, but DIC alone rarely causes platelet counts of <50,000/µL. Concomitant causes of thrombocytopenia should be sought for severe thrombocytopenia in the presence of DIC.
c. Clotting tests. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) may be slightly shortened, normal, or prolonged. Thrombin time (TT) prolongation occurs with severe hypofibrinogenemia (<50 mg/dL) or clinically significant elevation of fibrin degradation products; the TT can also be prolonged with heparin therapy, dysfibrinogenemia, or malignant paraproteinemia.
d. Fibrinogen level is usually decreased. Fibrinogen concentrations >50 mg/dL (normal range is 200 to 400 mg/dL) should not result in abnormalities of the TT. It is important to remember that fibrinogen is a phase reactant protein and is normally elevated in pregnancy and inflammatory states; thus, a normal result may actually be abnormal.
e. Paracoagulation tests for fibrin monomers (protamine sulfate or d-dimers) are positive in >95% of patients with DIC.
3. DIC versus primary fibrinolysis. Although primary fibrinolysis is rare and DIC is common, differentiation between these disorders is important to plan treatment. These disorders are compared in Table 34.2. The platelet count, paracoagulation test, and euglobulin lysis separate the disorders.
Table 34.2 Comparison of Acute Disseminated Intravascular Coagulation (DIC) and Primary Fibrinolysis
aDiscriminatory assays
C. Management. Few patients with DIC are helped if the underlying problem is not corrected. Treatment is not necessary for laboratory manifestations alone. The following sequence is recommended:
1. Treat the underlying disease. This may be futile for patients with disseminated cancer alone, but the possible advantages of antimicrobial therapy, further surgery, RT, or chemotherapy should be considered. Hypotension, tissue perfusion, acidosis, hypoxemia, and the triggering event (e.g., sepsis) must be addressed vigorously.
2. Administration of blood components. Platelet packs are given in the presence of thrombocytopenia and serious bleeding. DIC microangiopathy can induce organ failure long before the bleeding risk from DIC becomes relevant; thus, the threshold platelet count to prompt transfusion is dependent on the patient and the diseases that are evident.
FFP or cryoprecipitate (for fibrinogen and factor VIII) usually improve factor deficiencies unless the clotting process is severe. Replacement therapy may need to be repeated every 8 hours, with adjustment of doses according to platelet count, PT, aPTT, fibrinogen level, and volume status. Cryoprecipitate is useful in patients with borderline cardiac reserve who cannot tolerate large volumes of FFP.
3. The use of heparin remains controversial. At best, heparin has improved the levels of hemostatic factors in treated patients but has not reduced mortality. However, heparin can seriously aggravate bleeding. Heparin appears to have most benefit in patients with chronic DIC and can be considered if DIC is causing end-organ damage.
4. Fibrinolysis is inhibited only if necessary, that is, if the patient has documented primary fibrinolysis or DIC with life-threatening bleeding and evidence of extensive secondary fibrinolysis (i.e., shortened euglobulin lysis time). Use of these agents in patients with active DIC has been complicated by severe thrombosis. Fibrinolysis may be inhibited by EACA (Amicar) or tranexamic acid; renal failure is a relative contraindication for EACA use. A loading dose of 5 g is followed by 0.5 to 1 g/h IV or 2 g every 2 hours PO. If the episode of DIC has abated, EACA may be given alone. If the status of DIC is uncertain or ongoing, heparin should be given with EACA.
5. Antiplatelet drugs (aspirin and dipyridamole) may be useful in patients with chronic DIC who are not bleeding.
6. Other measures. Activated protein C infusion can reduce mortality in septicemia, particularly if DIC is demonstrable. Infusion of AT also has been tested but has not been shown to be beneficial.
7. Patient surveillance. The platelet count, fibrinogen level, and clinical evaluation are the most useful factors to follow. Following paracoagulation tests is not useful for monitoring therapy because their clearance can be delayed. The reptilase time (performed like the TT) is sensitive to the presence of fibrin degradation products; unlike the TT, the reptilase test is not affected by heparin.
III. PRIMARY FIBRINOLYSIS. Primary fibrinolysis occurs essentially only in metastatic prostatic carcinoma, advanced cirrhosis of the liver, heat stroke, or amniotic fluid embolism.
A. Malignancies may promote fibrinolysis by releasing plasminogen activators, such as urokinase or other proteolytic enzymes. Extensive metastatic liver disease may result in decreased clearance of plasminogen and its activators. Prostatic carcinoma and, to a lesser extent, benign prostatic conditions are capable of triggering both thrombosis and fibrinolysis. Other cancers that have been reported to activate fibrinolysis are sarcoma and carcinomas of the breast, thyroid, colon, and stomach.
B. Diagnosis of primary fibrinolysis: see Section II.B.3.
C. Management of primary fibrinolysis: see Section II.C.4.
IV. OTHER HEMOSTATIC DEFECTS ASSOCIATED WITH CANCER
A. Platelet function abnormalities are common in malignancies.
1. Mechanisms
a. Coating of platelet surfaces by fibrin degradation products with DIC
b. Coating of platelets by paraproteins with myeloma
c. Concomitant azotemia
d. Inherent platelet dysfunction associated with myelodysplastic disorders or MPDs
e. Patients may be taking drugs with antiplatelet activity, such as aspirin, other nonsteroidal anti-inflammatory drugs, clopidogrel, or ticlopidine.
2. Diagnosis
a. Signs of platelet dysfunction include easy bruisability, gingival bleeding with toothbrushing, and other minor mucosal bleeding.
b. Laboratory studies. A variety of in vitro platelet function tests have uncertain clinical validity. Thrombocytopenia, DIC, and azotemia should be ruled out by appropriate tests.
3. Treatment. Patients with bleeding and platelet dysfunction require treatment of the underlying disorder and may require platelet transfusions. DDAVP, 0.3 µg/kg IV over 20 minutes, may also be helpful temporarily.
B. Paraproteinemia. Hemostatic abnormalities associated with plasma cell myeloma were discussed in Chapter 22, Section IX.A.1.a.(1).
C. Liver metastases, when extensive, can result in the inability to synthesize clotting factors. Treatment with vitamin K is ineffective. Bleeding may be controlled by the administration of FFP, which also may be impractical.
D. Dysfibrinogenemia. Dysfibrinogens are abnormal fibrinogen molecules, which may be inherited or acquired in association with hepatocellular carcinoma or liver metastases. The PT, aPTT, and TT are all markedly abnormal. Fibrinogen concentrations are low when measured by clotting methods but are normal when measured by immunologic or physical precipitation methods. Hemorrhage is not common with dysfibrinogenemia but may occur. Thrombosis is a more common complication.
E. Acquired circulating inhibitors of coagulation occur in a wide variety of tumors (e.g., a heparin-like inhibitor has been described in mastocytosis). It is doubtful that these inhibitors are responsible for hemorrhage in the absence of other causes, such as uremia or thrombocytopenia.
F. Specific factor deficiencies
1. Factor XIII deficiency or dysfunction is common in patients with cancer but usually does not cause clinical problems. The PT, aPTT, and TT are normal, but the assay for factor XIII is abnormal. Hemorrhagic episodes are treated with FFP, 5 mL/kg weekly.
2. Factor X deficiency may occasionally be an isolated coagulation abnormality in patients with amyloidosis, which can also be associated with systemic fibrinolysis. Hemorrhagic episodes are treated with FFP or prothrombin complexes.
3. Factor XII and Fletcher factor (prekallikrein) deficiencies have been described in patients with cancer but have little clinical significance.
4. Acquired von Willebrand disease has been reported in cancer patients, particularly in the MPDs in association with marked thrombocytosis. (See Chapter 24, Section II.C.2 in “Comparable Aspects.”)
G. Hemostatic abnormalities associated with cytotoxic agents
1. Hypofibrinogenemia or dysfibrinogenemia is an almost universal complication of treatment with L-asparaginase.
2. Vitamin K antagonism occurs with actinomycin D therapy.
3. DIC is a common complication of administration of mithramycin.
4. Primary fibrinolysis has been reported to be activated by the anthracyclines.
5. Platelet dysfunction (of questionable significance) has been reported with cytarabine, daunorubicin, melphalan, vincristine, mitomycin C, L-asparaginase, and high-dose chemotherapy in preparation for BMT.
6. Budd-Chiari syndrome is associated with dacarbazine therapy.
Suggested Reading
Thrombosis and Cancer
Bergqvist D. Risk of venous thromboembolism in patients undergoing cancer surgery and options for thromboprophylaxis. J Surg Oncol 2007;95:167.
Carrier M, et al. Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost 2009;7:760.
Falciani M, Imberti D, Prisco D. Prophylaxis and treatment of venous thromboembolism in patients with cancer: an update. Intern Emerg Med 2006;1:273.
Kearon C, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133:454S.
Lee AYY. Thrombosis in cancer: an update on prevention, treatment and survival benefits of anticoagulants. Hematology Am Soc Hematol Educ Program 2010;2010:144.
Leonardi MJ, McGory ML, Ko CY. A systematic review of deep venous thrombosis prophylaxis in cancer patients: Implications for improving quality. Ann Surg Oncol 2007;14:929.
Sallah S, et al. Disseminated intravascular coagulation in solid tumors: clinical and pathologic study. Thromb Haemost 2001;86:828.
Trousseau A. Phlegmasia alba dolens. Clin Med Hotel Dieu Paris 1865;3:94.
Other Topics
Castello A, Coci A, Magrini U. Paraneoplastic marrow alterations in patients with cancer. Haematologica 1992;77:392.
Filipovich, AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am Soc Hematol Educ Program 2009:127–31.
Jannssens AM, Offner FC, Van Hove WZ. Bone marrow necrosis. Cancer 2000;88:1769.
Kuderer NM, et al. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol 2007;25:3158.
Kuter DJ. New thrombopoietic growth factors. Blood 2007;109:4607.
Thompson CA, Steensma DP. Pure red cell aplasia associated with thymoma: clinical insights from a 50-year single-institution experience. Br J Haematol 2006;135:405