Patrick F. Fogarty and Cynthia E. Dunbar
PLATELET BIOLOGY
Platelets are anucleate blood cells that participate in primary hemostasis, the formation of a platelet plug at sites of vascular injury.
Platelets are produced from megakaryocytes, multinucleate hematopoietic cells located in the bone marrow. Cytokines such as thrombopoietin are necessary for normal platelet maturation and release.
Once released into the circulation, the average life span of a platelet is 7 to 10 days. Platelets are removed from circulation when they are activated and utilized at sites of vascular injury or as they become senescent.
At any given time, up to one-third of the platelet mass is stored in the spleen, providing a reserve of platelets that may be released during periods of physiologic stress.
The normal platelet concentration in the blood is 150,000 to 400,000/μL as measured in most hospital laboratories.
ETIOLOGY AND CLINICAL FEATURES OF THROMBOCYTOPENIA
Thrombocytopenia may occur due to
Decreased production of platelets
Increased consumption of platelets
Increased sequestration of platelets
Any combination of these mechanisms (Table 19.1)
Regardless of the cause of thrombocytopenia, “platelet-type” bleeding is typically mucocutaneous and is characterized by petechiae, ecchymoses, epistaxis, and gingival and conjunctival hemorrhages. Less commonly, severe thrombocytopenia may lead to gastrointestinal, genitourinary, or central nervous system bleeding.
Spontaneous bleeding or bruising normally does not occur until the platelet count has fallen below 10,000 to 20,000/μL. The rate of decline of the platelet count may also influence the likelihood of unprovoked bleeding, presumably due to compensatory processes in remaining platelets that may occur over time with persistent thrombocytopenia. Patients with dysfunctional platelets may bleed with higher platelet counts. Patients with thrombocytopenia and platelet counts greater than 20,000 to 30,000/μL without bleeding usually do not require immediate treatment to increase the platelet count. A platelet count of 80,000 to 100,000/μL is generally adequate for hemostasis during most invasive procedures, including surgery (Table 19.2).
Table 19.1 Causes of Thrombocytopenia
Disorders Characterized by Decreased Production of Platelets
Bone marrow failure syndromes
Congenital (amegakaryocytic thrombocytopenia, Fanconi anemia, dyskeratosis congenita, Schwachmann-Diamond syndrome, thrombocytopenia–absent radii syndrome,Wiskott-Aldrich syndrome) Acquired (aplastic anemia, amegakaryocytic thrombocytopenia)
Myelodysplasia
Marrow infiltration (neoplastic, infectious)
Chemotherapy-induced
Irradiation-induced
Cyclic thrombocytopenia (some cases)
Immune thrombocytopenia
Folate, B12, or iron (advanced cases) deficiency
Ethanolism
Disorders or Conditions Characterized by Increased Clearance of Platelets
Immune thrombocytopenia
Heparin-induced thrombocytopenia
Thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome
Disseminated intravascular coagulation (HELLP syndrome)
Posttransfusion purpura
Neonatal alloimmune thrombocytopenia
Von Willebrand disease, type IIB
Cyclic thrombocytopenia (most cases)
Mechanical destruction (aortic valvular dysfunction; extracorporeal bypass)
Disorders Characterized by Increased Sequestration of Platelets
Hypersplenism (see Table 19.5)
Other Conditions
Artifactual (pseudothrombocytopenia)
Drug-induced (see Table 19.6)
Gestational thrombocytopenia
HIV-associated thrombocytopenia
Infection- and sepsis-related thrombocytopenia
Hemophagocytosis
Qualitative platelet disorder-related (Bernard-Soulier disease, gray platelet syndrome, May-Hegglin anomaly)
HIV, human immunodeficiency virus.
DISORDERS CHARACTERIZED BY DECREASED PRODUCTION OF PLATELETS
Bone Marrow Failure
Congenital disorders, such as Fanconi anemia or dyskeratosis congenita, typically present early in life; these syndromes often cause depression of other blood cell lineages (i.e., white cells and red cells) in addition to the platelet count.
Other congenital disorders such as congenital amegakaryocytic thrombocytopenia and the thrombocytopenia with absent radius (TAR) syndrome are characterized by isolated thrombocytopenia.
Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder featuring thrombocytopenia, eczema, and immunodeficiency. Thrombocytopenia may improve with splenectomy, but allogeneic hematopoietic stem cell transplantation alone is potentially curative for the disorder.
Adult patients with acquired amegakaryocytic thrombocytopenia initially may appear to have immune thrombocytopenia (ITP) (see ensuing section), but the bone marrow reveals markedly reduced or absent megakaryocytes. The disorder may progress to aplastic anemia.
Patients with acquired aplastic anemia rarely present with isolated thrombocytopenia. Marked bone marrow hypocellularity with decreased megakaryocytes would suggest this diagnosis (see Chapter 6).
Myelodysplasia
Mild thrombocytopenia with macrocytosis, with or without anemia or neutropenia, in an older individual is a typical presentation of myelodysplasia (MDS). Isolated severe thrombocytopenia (less than 20,000/μL) without any other blood count abnormalities is not typical.
Bone marrow aspirate and blood smear may show megakaryocytic dysplasia (including small and mononuclear “micromegakaryocyte” forms) and maturation abnormalities of erythrocytic and granulocytic precursor cells. Concurrent cytogenetic abnormalities may be present (see Chapter 7).
For treatment of thrombocytopenia due to MDS, see Chapter 7. Note that thrombopoietin receptor agonists may be contraindicated in MDS due to a potential acceleration in transformation to acute leukemia.
Marrow Infiltration
Infiltration of the bone marrow by malignant cells may cause thrombocytopenia, but usually only after massive replacement of the marrow space by tumor cells or immature hematologic precursor cells has occurred. Examination of the bone marrow biopsy and aspirate is required.
The acute and chronic leukemias, myeloma, and lymphoma are the most common tumors resulting in cytopenias due to neoplastic marrow infiltration and direct suppression of normal hematopoiesis with some tumor types.
Certain infections (such as tuberculosis and ehrlichiosis) can result in formation of granulomas in the bone marrow that supplant the normal marrow architecture.
Effective treatment of the underlying condition should be expected to restore a low platelet count to the normal range, but platelet transfusions may be required initially if bleeding is present or invasive procedures are planned (Table 19.2).
Irradiation and Chemotherapy
Irradiation and/or myelotoxic chemotherapy induce thrombocytopenia via direct toxicity to megakaryocytes or more immature hematopoietic stem and progenitor cells. The degree and duration of thrombocytopenia depends on the intensity and the type of the myelotoxic regimen.
Chemotherapy-induced thrombocytopenia typically resolves more slowly than does neutropenia and/or anemia, especially following repetitive cycles of treatment.
Platelet transfusions may be given if required. Trials of novel platelet growth factors for thrombocytopenia due to specific chemotherapeutic regimens are ongoing.
Cyclic Thrombocytopenia
This exceedingly rare disorder is characterized by episodes of thrombocytopenia that occur cyclically, typically every 3 to 6 weeks. The thrombocytopenia is frequently severe and may be associated with significant bleeding. Treatment with oral contraceptives (female patients), androgens, immunosuppressive agents (such as azathioprine), or thrombopoietic growth factor has led to responses in some cases.
Nutritional Deficiencies
Folate deficiency (commonly associated with alcoholism) and vitamin B12 deficiency may cause decreased megakaryocytopoiesis and thrombocytopenia, usually in conjunction with anemia. In contrast, thrombocytosis is typical in cases of significant iron deficiency; in very severe iron deficiency, however, thrombocytopenia may also occur. In any of these situations replacement of the deficient vitamin or mineral corrects the thrombocytopenia.
DISORDERS CHARACTERIZED BY INCREASED CLEARANCE OF PLATELETS
Immune Thrombocytopenia
ITP is an acquired autoimmune disorder of increased platelet destruction and decreased platelet production, causing thrombocytopenia that may lead to bleeding.
Epidemiology. The annual incidence of ITP in adults has been estimated to be about 2 to 4 cases per 100,000 persons and increases with age. 1
Pathophysiology.2 Pathogenic antiplatelet antibodies can be identified in approximately 75% of patients with ITP and are directed against the platelet glycoprotein complexes IIb/IIIa and/or Ib/IX. The antibody-coated platelets are cleared by reticuloendothelial macrophages in the liver and/or spleen, decreasing the platelet life span from approximately 7 days to less than 2 days. Platelet production also is impaired in ITP, possibly because of antiplatelet antibody binding to bone marrow megakaryocytes. Primary adult-onset ITP is generally idiopathic and becomes chronic, whereas secondary ITP occurs in association with disorders of lymphoproliferation (lymphoma or chronic lymphocytic leukemia (CLL)) or immune dysregulation (systemic lupus erythematosus, human immunodeficiency virus (HIV) infection).3 In contrast, ITP in children often follows a viral infection and frequently resolves spontaneously without specific therapy.
Presentation. Typically, new-onset severe ITP (platelets <30,000/μL) manifests with petechial bruising and bleeding from mucous membranes, including conjunctival hemorrhages, gingival bleeding, and epistaxis. Milder disease (platelet count >50,000/μL) often presents as an asymptomatically low platelet count on routine blood work.
Diagnosis. ITP is a diagnosis of exclusion. New-onset, isolated thrombocytopenia with no other readily apparent cause (including medication-related) in an otherwise asymptomatic adult generally may be regarded as sufficient for the diagnosis of ITP and subsequent initiation of medical therapies (if appropriate based on the degree of thrombocytopenia; see below). 4
The presence of other cytopenias, age greater than 60 years, or failure of primary therapy (corticosteroids for a trial of 1 week) should prompt bone marrow examination. The presence of abnormal or decreased numbers of megakaryocytes or abnormal marrow cellularity should redirect the diagnostic evaluation away from ITP.
All patients should be screened for hepatitis B and hepatitis C virus (HBC/HCV) and HIV infection (see below) and undergo evaluation of the blood smear, direct antiglobulin test (DAT) (Coombs test), and blood type (for Rh status).
Helicobacter pylori testing, antiphospholipid antibodies, and antinuclear antibodies may be useful in selected patients.
Treatment. Individuals with mild or moderate thrombocytopenia (platelets >30,000/μL) who do not require a higher platelet count for surgery or active bleeding should not receive treatment. Rather, they may be observed at regular intervals for disease progression. Adults with platelet counts of <20,000 to 30,000/μL or those with significant bleeding generally should be treated.4
Initial treatment (Table 19.3) generally consists of a short course of corticosteroids (prednisone 1 mg/kg/day for 7–10 days with subsequent rapid tapering or “pulse” dexamethasone cycles of 40 mg daily for 4 days). A significant increase in the platelet count should be seen within 3 to 7 days. In the event of a platelet response, prednisone may be tapered rapidly to a dose of 20 mg/day; thereafter, tapering should proceed more slowly (by dose decrements of no more than 5 mg/adjustment, no more frequently than once every 2 to 3 weeks). Dexamethasone cycles may be given every other week for four cycles or monthly for up to 6 months.
For patients with serious active bleeding and/or very severe thrombocytopenia (<5,000–10,000/ μL), intravenous immune globulin (IVIg; 1 gm/kg/day for 2 days) or anti-D (WinRho®, 75 μg/kg/ dose; appropriate for non-splenectomized, Rh blood type-positive, non-anemic patients only) can be administered in addition to corticosteroids in order to decrease clearance of antibody-coated platelets. Responses are generally seen within 3 to 5 days of IVIg or anti-D administration.
Platelet transfusions may be administered if the presentation is complicated by serious (intracranial) bleeding. Transfused platelets are expected to be cleared very rapidly in the presence of antiplatelet antibodies, but they may improve hemostasis temporarily.
Immunize against encapsulated bacterial organisms (pneumococcus, Haemophilus influenzae, meningococcus) before prolonged immunosuppressive therapy in preparation for splenectomy if required at a later time point.
Second-Line Treatment (Table 19.3). Despite a high initial response rate (60%–75%), the majority of adults with ITP experience relapse and develop chronic thrombocytopenia once initial treatments are reduced or discontinued. Treatment is appropriate for patients with platelet counts <30,000/μL or clinically significant bleeding.4 The selection of specific therapies should take into account patient preference; some individuals prefer sequential medical therapies prior to undergoing splenectomy, but splenectomy may be preferable in cases of very severe thrombocytopenia associated with bleeding because of a typically rapid postoperative increase in the platelet count in most responding patients.
IVIg and anti-D (see above) typically must be readministered every 2 to 3 weeks in most instances.
The thrombopoietin receptor agonists eltrombopag (starting dose 50 mg orally daily; 25 mg daily in individuals of Asian descent) or romiplostim (starting dose 1 μg/kg SC weekly) produce platelet responses (≥50,000/μL) in approximately 70% of patients with chronic ITP, and they generally are well tolerated.5,6 Potential complications include reticulin deposition in the bone marrow, thrombocytosis, and thrombosis.
The monoclonal anti-B cell antibody rituximab (anti-cd20), given at a dose of 375 mg/m2 weekly for 4 weeks, induces initial and long-term responses in about 50% and 25%, respectively, of adults with severe, chronic ITP. 7
Splenectomy (preferably laparoscopic) yields an immediate response rate of 70% to 75% and durable response rates of 60% to 70%. All patients must receive immunization against encapsulated bacterial organisms (pneumococcus, H. influenzae, meningococcus) several weeks prior to splenectomy if possible. 4
Secondary ITP. A variety of autoimmune, infectious, inflammatory, or malignant conditions may underlie a presentation of ITP.3 Treatment of the underlying predisposing condition may be required in some cases, in addition to management of the thrombocytopenia using accepted interventions (Table 19.3)
Pregnancy-Associated ITP. Pregnant women with platelet counts <30,000/μL during the second or third trimester, or with platelet counts <10,000/μL, or bleeding in any trimester, should be treated. Intermittent infusions of IVIgor moderate-dose oral prednisone (commonly given on an every-otherday schedule) are standard. Splenectomy during the first or second trimester may be considered for women whose ITP has failed treatment with IVIg and corticosteroids and who have platelet counts <10,000/μL with associated bleeding. Platelets may be administered prophylactically prior to cesarean section in women who have platelet counts <10,000/μL or mucocutaneous bleeding near the time of delivery. A platelet count of >50,000/μL generally is regarded as adequate prior to cesarean section or vaginal delivery.
Heparin-Induced Thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is an antibody-mediated disorder that results in platelet activation and clearance. Although the disorder produces thrombocytopenia, patients with HIT paradoxically are at high risk for thrombosis. If HIT is suspected, all forms of heparin should be discontinued immediately, and, if appropriate, alternative anticoagulation administered.8
Epidemiology. HIT occurs in approximately 3% and <1% of patients who are exposed to unfractionated heparin or low molecular-weight heparin, respectively. As many as half of these individuals will develop thrombosis. 8
Pathophysiology. The pathogenesis of HIT begins with binding of the heparin molecule to platelet factor 4 (PF4), a platelet alpha granule chemokine. The heparin-PF4 complex stimulates formation of an IgG antibody (HIT antibody) that binds both to the heparin-PF4 complex (via its Fab portion) and to platelet Fc receptors (via its Fc portion). Binding of the HIT antibody to platelets activates them, resulting in release of procoagulant microparticles, platelet clearance, and subsequent thrombocytopenia. PF4 also binds to polysaccharides (heparan sulfate) on the endothelial surface; recognition of these PF4-polysaccharide complexes by HIT antibodies may lead to endothelial damage, expression of tissue factor, and a prothrombotic state.
Presentation. The typical presentation of HIT involves a hospitalized patient who develops thrombocytopenia within 5 to 10 days of receiving heparin.
A decline of 50% or more from the baseline value in a heparin-treated patient may signify HIT. Platelet counts generally do not fall below 20,000/μL.
Spontaneous bleeding (including petechiae) is not typical.
Venous (upper or lower limb, dural sinus) or arterial (lower limb, CVA, MI, other locations) thromboses may accompany detection of thrombocytopenia and occur in up to 50% of untreated cases. In a minority of patients with HIT, thrombosis is the presenting clinical sign. The risk of HIT-related thrombosis persists for at least 30 days after the discontinuation of heparin if anticoagulation is not administered.
Other presentations of HIT are possible:
Rapid-onset HIT occurs within 1 to 3 days of re-exposure to heparin in patients who have received heparin usually within the prior 30 days and have preexisting HIT antibodies. An acute systemic reaction characterized by fever, chills, hypotension, and/or cardiovascular compromise immediately after re-exposure to heparin is typical.
Delayed-onset HIT describes new thrombocytopenia and venous or arterial thrombosis that occurs up to 14 days after completion of an uneventful course of heparin therapy. Laboratory markers of disseminated intravascular coagulation (DIC) may be positive. Thrombocytopenia and thrombosis typically worsen if heparin is administered.
Diagnosis. Strictly, the diagnosis of HIT requires both an appropriate clinical context and confirmatory laboratory testing (e.g., demonstration of HIT antibodies). Due to the limited immediate availability of HIT-specific laboratory assays, however, any patient in whom the clinical probability for the disorder is intermediate or high should be managed HIT, even if the results of diagnostic tests are pending or immediately unavailable.
Clinical probability. Factors that make a diagnosis of HIT more likely are reviewed above. A variety of clinical prediction models, such as the 4Ts,9 that have been developed to assist in determination of pretest probability have not undergone external validation and may overestimate diagnoses.8 Review of the hospital chart (including nursing notes) may be necessary to document the extent and duration of exposure to heparin, especially if its use was transient (heparin flushes) or covert (heparin-impregnated catheters).
Laboratory diagnosis. All patients with suspected HIT ideally should undergo testing with two types of assays, immunologic and functional. The enzyme-linked immunosorbent assay (ELISA) for PF4-heparin-associated antibody (immunologic test) has a sensitivity of >90% but a limited specificity. Platelet activation assays (functional test) measure activation of donor platelets in the presence of the patient’s serum and a high and low concentration of heparin. These assays are much more specific for HIT than the immunologic test, but are less widely available and have a slow turnaround time (days). A positive result on both tests or the immunologic assay alone indicates high and intermediate, respectively, probability for HIT.
Treatment. All forms of heparin, including low-molecular weight preparations, must be discontinued immediately. In patients in whom laboratory testing for HIT eventually proves negative or in whom an alternative explanation for thrombocytopenia has been found, heparin may be subsequently restarted.
Doppler ultrasound of the lower extremities should be performed to rule out subclinical deep vein thrombosis.
Because (1) HIT patients rarely bleed and (2) transfused platelets may worsen the already increased thrombotic risk by providing substrate for HIT antibodies, platelet transfusions are rarely indicated.
Warfarin is contraindicated as initial treatment of clinically proven or suspected HIT, due to its propensity to exacerbate hypercoagulability by reduction of plasma levels of proteins C and S (see Chapter 23).
Because of the high rate of serious thrombosis among HIT patients, an alternative anticoagulant such as a direct thrombin inhibitor (DTI; Table 19.4; see also Chapter 23) is required in all cases of suspected (intermediate or high clinical probability) or proven HIT.
The alternative anticoagulant should be continued at least until significant recovery of the platelet count has occurred or for approximately 5 days, whichever is longer.
Longer-term anticoagulation. Due to the extended risk of thrombosis up to 1 month following a diagnosis of HIT, patients without concurrent thrombosis require at least 30 days of anticoagulation. Warfarin therapy is appropriate in most patients, and the DTI should be continued until therapeutic anticoagulation with warfarin has been achieved. (Because Argatroban raises the INR, a special approach is required for transitioning from this DTI to warfarin; see Chapter 23.) Patients with HIT and thrombosis should receive anticoagulation with warfarin for duration of 3 to 6 months at an INR of 2.0 to 3.0.
Thrombolysis/thromboembolectomy. Low-dose or very low-dose thrombolytic agents may be indicated in acute limb ischemia or life-threatening pulmonary embolism caused by HIT-associated thrombi. Surgical removal of large-vessel arterial thrombi may be required if the limb is threatened and other treatments have failed. Patients managed by either medical or surgical means require concomitant use of an alternative anticoagulant, regardless of the degree of thrombocytopenia.
Retreatment with heparin. HIT antibodies probably do not persist beyond 100 days from the initial episode of HIT,8 in which case very transient use of heparin for cardiac or vascular surgery at least 100 days beyond an initial episode may be considered safe, if immunologic (ELISA) and functional (SRA) tests are both negative. If the immunologic test is positive but the functional test is negative, either the surgery can be delayed until the functional test becomes negative or a DTI can be used.
Thrombotic Microangiopathies
The thrombotic microangiopathies (TMAs) comprise thrombotic thrombocytopenic purpura (TTP) and the related disorder, the hemolytic-uremic syndrome (HUS), and feature microangiopathic hemolytic anemia (MAHA) due to the formation of platelet-rich thrombi in the arterial and capillary microvasculature and thrombocytopenia. Acquired (or “spontaneous” or “classical”) and congenital forms of TTP are recognized, and endemic (or “typical”) and atypical forms of HUS may occur (Table 19.5). In addition, some forms of TMA have been recognized in association with surgery, pregnancy, exposure to certain medical drugs, and bone marrow transplantation. Importantly, early aggressive intervention with plasma exchange is crucial in cases of classical TTP due to its extremely high mortality rate.
Epidemiology. The incidence of classical TTP is approximately 3 to 4 cases/100,000 persons; there is a slight female predominance. Most cases of endemic or “typical” HUS occur in young children and are related to infection with enteropathogenic bacteria. TMA occurs at an increased rate during pregnancy and in the peri-partum period.
Pathophysiology. The TMAs are thought to arise from factors that directly or indirectly cause platelet aggregation and/or endothelial cell damage, leading to the formation of microvascular thrombi and ischemia in involved organs. These factors include toxins, cytokines, drugs, or deficiencies in the function of the von Willebrand factor cleaving protease (VWFCP or ADAMTS-13). Red cells are sheared as they negotiate thrombotic obstructions and fibrin strands in the microvasculature, leading to hemolytic anemia. Consumption of platelets results in thrombocytopenia and bleeding.
In classical TTP, an acquired deficiency of VWFCP results from production of an autoantibody against the VWFCP10 leading to an accumulation of ultra large VWF (ULVWF) in the plasma. The VWFCP, or ADAMTS-13, is a metalloproteinase whose normal function is to cleave newly synthesized, ULVWF multimers released in the plasma into multimers of smaller size. ULVWF multimers bind to platelets more avidly than smaller VWF molecules and may incite platelet aggregation.
Patients with congenital TTP have decreased activity of the VWFCP due to an inherited deficiency.
In many cases of endemic HUS, Shiga toxin from Escherichia coli (especially type 0157:H7) is thought to promote platelet aggregation by damaging endothelial cells or by other mechanisms.
Patients with atypical HUS may have genetic defects in proteins that regulate complement activity, such as factor H. 11
Pregnancy-associated TTP-HUS may stem from decreased levels of the VWFCP that naturally occur in the second and third trimesters; in some cases an antibody to VWFCP is present. 12
Drugs such as cyclosporine, quinine, ticlopidine, clopidogrel, mitomycin C, and bleomycin may cause TMA by endothelial cell injury and/or pro-aggregatory effects on platelets. Antibodies inhibiting the VWFCP have been described in patients who received some of these medications.TMA in the setting of cancer, hematopoietic stem cell transplantation, or HIV infection has not been linked to abnormalities of VWFCP, but effects on endothelial cells or platelets may be responsible.
Presentation. All patients with TMA have MAHA. Varying degrees of neurologic impairment (more typical of classical TTP) or symptoms related to renal failure (predominant in HUS) may also be present (Table 19.4). MAHA, thrombocytopenia, fever, renal insufficiency, and neurologic system abnormalities (the classic pentad of TMA) occur in only about 25% of patients with TTP. Most patients with typical HUS have a recent or current diarrheal illness.
In adults, TTP and HUS are often difficult to distinguish due to the overlap of symptoms, but if renal dysfunction predominates, the syndrome usually is classified as HUS.
Manifestations of renal insufficiency may include elevated creatinine, azotemia, proteinuria, hematuria, and/or oliguria.
Neurologic impairment (from microthrombi in the cerebral vasculature) occurs in about 75% and 30% of patients with TTP and HUS, respectively, and includes headache, somnolence, confusion, seizures, and (less commonly) paresis and coma.
Diagnosis. The presence of new-onset MAHA and thrombocytopenia (and/or renal failure) in the absence of any other plausible explanation will suffice for the diagnosis.
MAHA is essential to the diagnosis of TTP-HUS and is defined by anemia with positive markers of intravascular hemolysis (elevated LDH, elevated indirect bilirubin, decreased haptoglobin, and reticulocytosis) and negative DAT (Coombs test). The blood smear shows >3 schistocytes per high-power microscopic field, although fewer schistocytes may be present if the disorder is caught early.
Depending on the type of TMA, thrombocytopenia may be variable.
Clinical features such as an antecedent bloody diarrheal illness and/or renal insufficiency (more typically associated with HUS), or neurologic abnormalities with or without fever (more typically associated with TTP), or recent or current pregnancy, or treatment with associated drugs, or cancer, or recent hematopoietic stem cell transplantation are diagnostically corroborative.
Stool culture for E. coli 0157:H7 or assays for antibody against Shiga or Shiga-like toxins, or against specific bacterial lipopolysaccharide may be positive in patients with endemic HUS.
Assays for VWFCP activity typically are abnormal in congenital and classical TTP; activity is less than 5% in classical TTP.
The prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen are within the normal range in TMA.
Treatment. Without plasma exchange, the mortality rate of classical TTP exceeds 90%. Plasma exchange must be instituted expeditiously. An important exception is children or adults with endemic (E. colidiarrhea–associated) HUS, who generally recover with supportive care within 3 weeks, without plasma exchange.
Plasma exchange should begin once appropriate vascular access has been obtained. It should be performed once daily until the LDH has normalized and the platelet count has returned to the preexisting baseline (if known) for at least 2 or 3 days. Failure to respond to once-daily therapy requires twice-daily treatments; once the LDH and platelet count indicate response, once-daily treatments can be resumed until these parameters have normalized for 2 or 3 days. Whether treatments then may be discontinued or continued for a number of weeks in a tapering fashion is controversial, but many clinicians prefer to gradually increase the interval between treatments instead of abrupt termination of therapy.
Platelet transfusions generally are contraindicated in the treatment of TMAs due to possible propagation or new formation of platelet-rich microthrombi. If CT- or MRI-documented intracranial bleeding or other life-threatening bleeding is present, however, platelets may be transfused slowly, ideally after plasma exchange is initiated.
Packed red cells may be transfused commensurate with the pace of the MAHA and degree of bleeding.
In the event that plasma exchange is unavoidably delayed, infusion of fresh frozen plasma (FFP) may be helpful as a temporizing measure. Plasma infusion as a sole treatment of TMA, however, generally is regarded as substandard due to (1) the possible role of plasma exchange in removing offending drugs, cytokines, bacterial proteins, ULVWF multimers, or antibodies to the VWFCP and (2) the volume overload frequently incurred when the required large volumes of FFP are infused. An exception is familial relapsing TMA, wherein a congenital deficiency in the VWFCP can be corrected merely by infusion of smaller volumes of plasma.
Refractory and relapsing TMA. If remission is not achieved with aggressive plasma exchange, second-line treatments should be considered. These include the addition of steroids or IVIG to plasma exchange, vincristine, cyclophosphamide, cyclosporine (in select cases of sporadic TTP), and splenectomy. The monoclonal antibody rituximab has also achieved responses in a limited number of refractory cases.13 Up to a third of patients with classical TMA relapse after discontinuation of plasma exchange. In these cases, plasma exchange should be reinitiated according to the guidelines above, and, if ineffective, immunosuppressive treatments should be considered. Selected patients with atypical HUS may respond to infusion of the monoclonal antibody anti-C5 inhibitor eculizumab. 14
Hemodialysis. More than half of all patients with HUS (and a minority with TTP) require hemodialysis. Approximately half of these patients will attain durable restoration of renal function while 25% develop chronic renal failure. The remainder experience variable degrees of permanent renal insufficiency.
Disseminated Intravascular Coagulation
Thrombocytopenia in DIC occurs as a result of uncontrolled activation of coagulation in the circulation. Platelets participate in these reactions, leading to their consumption. If bleeding is present, platelet transfusions may be administered to reach a platelet count target of 20,000 to 30,000/μL (most cases) or >50,000/μL (if there is intracranial or life-threatening hemorrhage). Thrombocytopenia and the other clinical and laboratory manifestations of DIC are expected to resolve with effective treatment of the underlying, inciting disorder. (For a full discussion of DIC, see Chapter 21.)
Posttransfusion Purpura
Posttransfusion purpura (PTP) is characterized by the unexplained, sudden appearance of thrombocytopenia in an otherwise asymptomatic individual who recently has received a blood transfusion (red cells, platelets, or plasma) within 1 week prior to development of thrombocytopenia. The precipitating events are unknown, but more than 90% of individuals with PTP display antibodies against the human platelet antigen PlA1.
Most patients with PTP are postmenopausal females who are either multiparous or who have received prior transfusions; they commonly present with severe thrombocytopenia and bleeding.
If untreated, thrombocytopenia typically persists for up to 2 to 3 weeks, concurrent with a mortality rate of 10% from bleeding; hence, IVIg (1 gm/kg/day for 2 days) should be administered as soon as the diagnosis is suspected. Most patients will respond, but in the case of relapse, IVIg may be administered as a second course. Plasma exchange, adjunctive corticosteroids, and splenectomy are alternative treatments for refractory cases. Because transfused platelets are thought to be as susceptible to binding by antigen-antibody complexes as the patient’s own platelets, platelet transfusion is generally not performed unless severe bleeding is present; in this case, HLA antigen-matched platelets are preferred. Future transfusions should be administered judiciously, with washed or PlA1-negative blood products.
Neonatal Alloimmune Thrombocytopenia
Neonatal alloimmune thrombocytopenia (NAIT) is a cause of severe thrombocytopenia in neonates. It occurs when fetal platelet antigens cross the placenta and trigger formation of maternal alloantibodies that can then enter the fetal circulation, bind platelets, and induce thrombocytopenia. Antibodies commonly have specificity for human platelet antigen [HPA]-1a, also known as PlA1. The presence of certain maternal platelet phenotypes (such as the homozygous HPA-1b state) appears to influence the risk of the disorder, especially if the fetus inherits a different, paternal platelet phenotype.
The thrombocytopenia is typically severe and a high prevalence of intracranial hemorrhage (ICH) during or following delivery is observed, resulting in neonatal death in 5% of cases of NAIT. Thrombocytopenia typically resolves by 2 to 3 weeks of age.
IVIg, with or without corticosteroids, is recommended for any neonate with platelet counts <20,000 to 25,000/μL. Random donor or (ideally) irradiated maternally antigen-matched platelets are often administered in cases of ICH. Subsequent pregnancies are regarded as high risk for recurrent NAIT.
Von Willebrand Disease,Type 2B
This type of von Willebrand disease (VWD) is characterized by an abnormal von Willebrand factor (VWF) that has increased affinity for its platelet receptor, glycoprotein Ib. Due to the bridging action of VWF, platelets aggregate in vivo and are cleared, typically resulting in a mild thrombocytopenia. VWD is discussed in detail in Chapter 21.
Extracorporeal Circulation-Related Thrombocytopenia
Passage of the blood for prolonged periods outside the body in an artificial circuit (such as used for cardiac bypass surgery) typically results in platelet activation and clearance. Thrombocytopenia generally is not severe. Other common causes of thrombocytopenia in the postsurgical patient (such as HIT, DIC, and sepsis-related and drug-induced thrombocytopenia) concomitantly must be considered.
DISORDERS CHARACTERIZED BY INCREASED SEQUESTRATION OF PLATELETS
Hypersplenism results in sequestration of blood cells (including platelets) in an enlarged or abnormal spleen. Mild to moderate thrombocytopenia is most commonly observed, but if the bulk of the platelet mass is contained within a massively enlarged spleen, thrombocytopenia can be severe.
Splenomegaly with hypersplenism is almost always an acquired condition, and there are many possible underlying disorders (Table 19.6).
If adequate production of platelets can be documented and significant splenomegaly with thrombocytopenia is present, splenectomy may be considered in some cases. Splenic embolization and splenic irradiation are alternatives to removal of the spleen that generally do not result in maximal platelet responses. They may be considered, however, in patients with significant hypersplenism and disorders such as CLL or lymphoma who cannot tolerate surgery.
OTHER CAUSES OF THROMBOCYTOPENIA
Pseudothrombocytopenia
For reasons that are unclear, the calcium chelation induced by the anticoagulant ethylenediaminetetraacetic acid (EDTA) (present in blood-collecting tubes) causes changes on the platelet membranes of certain patients that expose cryptic antigens to which preformed, otherwise non-pathogenic agglutinating antibodies may bind; the result is artifactual platelet clumping. Typically, automated cell counters (such as those that are present in most hospital laboratories) will report a falsely low platelet count; examination of the blood smear reveals platelet clumps. Normalization of the platelet count upon automated determination from a blood specimen collected in citrate anticoagulant and /or disappearance of platelet clumps on a blood smear obtained from a finger stick source yields a correct assessment of platelet number and confirms the presence of this benign phenomenon.
Table 19.6 Selected Causes of Splenomegaly
Lymphoproliferation
Lymphoma
Chronic lymphocytic leukemia
Collagen vascular disease (Felty syndrome, systemic lupus)
Autoimmune lymphoproliferative disorder
Myeloproliferation
Myeloid leukemia
Polycythemia vera
Essential thrombocythemia
Inborn Errors of Metabolism
Gaucher disease
Niemann-Pick disease
Congestion
Cirrhosis
Heart failure
Hemolysis
Hereditary spherocytosis
Paroxysmal nocturnal hemoglobinuria
Thalassemia
Infection
Viral (CMV, EBV, hepatitis)
Parasitic (malaria, babesiosis)
Immunodeficiency
Common variable immunodeficiency
Drug-Induced Thrombocytopenia
By definition, drug-induced thrombocytopenia develops after initiation of a given drug, resolves when the offending medication is discontinued and may recur if the agent is reintroduced.15 The mechanisms by which many drugs may lead to a low platelet count, however, have not been elucidated.
Chemotherapeutic agents are clearly linked to decreased platelet production.
Quinine purpura is a type of drug-induced immune thrombocytopenia (DITP), in which there is antibody-mediated destruction of platelets after exposure to a given drug. Quinine is thought to induce a conformational change in the platelet membrane allowing exposure of an otherwise cryptic antigen; circulating antibodies then bind the antigen, but only in the presence of the drug. Patients with DITP present with severe thrombocytopenia (<20,000/μL) and mucocutaneous bleeding, including purpura and ecchymoses. Thrombocytopenia should resolve within days to weeks of discontinuing the agent. In cases of severe bleeding, IVIg and platelet transfusions appear to be more effective than steroids in inducing responses.
Other medications commonly associated with thrombocytopenia are listed in Table 19.7.
Gestational Thrombocytopenia
The blood volume increases by as much as 40% to 45% over baseline during pregnancy, causing a progressive hemodilution. Cytopenias result, though production of blood cells is normal or increased. Approximately 10% and less than 1% of pregnant women experience platelet counts <100,000/μL and <50,000/μL by the third trimester, respectively; the incidence of ITP is thought to be even lower. Severe thrombocytopenia in pregnancy (<50,000/μL) should prompt investigation to rule out a preexisting condition, preeclampsia, or a pregnancy-related TMA; if negative, the etiology may be presumed to be ITP and treated accordingly (see Immune Thrombocytopenia on page 272).
Table 19.7 Drugs Associated with Thrombocytopenia
Antimicrobials
Amphotericin
Ampicillin
Isoniazid
Rifampin
Methicillin
Piperacillin
Sulfisoxazole
Trimethoprim-sulfamethoxazole
Linezolid
Vancomycin
Antiplatelet Agents
Anagrelide
Abciximab
Eptifibatide
Ticlopidine
Tirofiban
Analgesics/Anti-Inflammatory Agents
Acetominophen
Diclofenac
Ibuprofen
Sulindac
H2 Blockers
Cimetidine
Ranitidine
Cardiovascular Agents
Amiodarone
Captopril
Digoxin
Hydrochlorothiazide
Procainamide
Quinidine
Neuropsychiatric Agents
Carbamazepine
Chlorpromazine
Diazepam
Haloperidol
Lithium
Methyldopa
Phenytoin
Other
Gold
Heparin
Mycophenolate mofetil
Interferon-α
Quinine
Most chemotherapeutic drugs
Data from DeLoughery T. Hemorrhagic and thrombotic disorders in the intensive care setting. In: Kitchens C, Alving BM, Kessler C, eds. Consultative Hemostasis and Thrombosis. Philadelphia, PA: W.B. Saunders Company; 2002:493-513; George, JN, Raskob, GE, Shah, SR, et al. Drug-induced thrombocytopenia: a systematic review of published case reports. Ann Intern Med. 1998;129:886.
Human Immunodeficiency Virus-Related Thrombocytopenia
Thrombocytopenia in HIV infection may result both from immune-mediated phenomena leading to increased clearance of platelets and ineffective platelet production, possibly due to direct infection of megakaryocytes with HIV. Improvement or resolution of thrombocytopenia after initiation of antiretroviral therapy in newly diagnosed patients is commonly observed. If the thrombocytopenia proves refractory, therapies commonly used in the treatment of ITP (IVIg, anti-D, steroids, splenectomy, others) are employed, but the potentially immunosuppressive effects of some of these approaches need to be taken into consideration.
Infection- and Sepsis-Related Thrombocytopenia
Thrombocytopenia in the setting of infection or sepsis is common. DIC is often implicated in critically ill patients, but other causes, such as megakaryocyte-specific effects or increased clearance due to fever or splenic enlargement, may be responsible.
Transient thrombocytopenia is commonly observed in the setting of many viral infections; certain bacterial infections, such as ehrlichiosis, Rickettsial disease, and dengue characteristically produce thrombocytopenia. A corroborative travel history and directed microbiologic testing are usually necessary to make the diagnosis.
If the platelet count does not return to baseline with effective antimicrobial treatment or after resolution of the infection, an alternative etiology should be sought.
Hemophagocytosis
Hemophagocytosis is a process in which bone marrow macrophages (histiocytes) engulf cellular components of the marrow. The phenomenon is considered to be nonspecific if it is found only sporadically within an aspirate smear, but the observation of abundant histiocytes with intracytoplasmic white cells, red cells, or platelets in the setting of peripheral cytopenias indicates a pathogenic process.
In adults, sepsis or EBV-related infection or malignancy can drive T cells to produce cytokines that mediate hemophagocytosis, leading to thrombocytopenia. In these cases, the treatment is principally immunosuppressive, but the disorder often is aggressive and unresponsive to treatment.
Familial hemophagocytic lymphohistiocytosis is a rare, autosomal recessively inherited disorder featuring hemophagocytosis, fever, organomegaly, and hypertriglyceridemia or hypofibrinogenemia; it presents at a young age. The only curative treatment is allogeneic hematopoietic stem cell transplantation.
Qualitative Disorders
Several heritable platelet anomalies of structure or function (including the May-Hegglin anomaly and the Bernard-Soulier syndrome) are typically associated with a mild thrombocytopenia. These are discussed in more detail in Chapter 21.
References