Chapter 73: Thrombocytopenia

• Thrombocytopenia is defined as a platelet count below the lower limit of normal for the specific method used (eg, <150 10⁹/L).

• The types and causes of thrombocytopenia are listed in Table 73–1.

• A false diagnosis of thrombocytopenia can occur when laboratory conditions cause platelets to clump, resulting in artificially low platelet counts as determined by automated counters. This occurs in 0.1% to 0.2% of automated platelet counts. Occasionally, if a high proportion of platelets are unusually large, the automated count can be spuriously low.

• Blood films should always be carefully examined to confirm the presence of thrombocytopenia.

Etiology and Pathogenesis

• Falsely low platelet counts are caused by platelet clumping most often occurring in blood samples collected in EDTA anticoagulant. Blood collected in citrate will often confirm the spurious nature of the thrombocytopenia, although clumping may occur in any anticoagulant.

• Platelets may attach to each other to form clumps or may form clumps with leukocytes, usually neutrophils.

• Platelet clumping is usually caused by a low-titer IgG antibody reacting with an epitope exposed on platelet GP IIb/IIIa by in vitro conditions.

Laboratory Features

• A film made from blood anticoagulated with EDTA demonstrates more platelets than expected from the platelet count, but many are in large pools or clumps (see Figure 117–1 in Williams Hematology, 9th ed). A blood film made directly from a fingerstick sample accurately reflects the true count.

• Pseudothrombocytopenia is often accompanied by a falsely elevated white count because some platelet clumps are sufficiently large to be detected as leukocytes by an automated counter.

• Correct platelet counts can be obtained by placing fingerstick blood directly into diluting fluid at 37°C and performing counts by phase-contrast microscopy.

Clinical Features

• The platelet agglutinins causing spurious thrombocytopenia appear to have no other clinical significance.

• Platelet clumping is usually persistent.

(See also Chap. 26)

Etiology and Pathogenesis

• The spleen normally sequesters about one-third of the platelet mass. Reversible pooling of up to 90% of the platelet mass occurs in patients with splenomegaly. A good example of this phenomenon is seen in patients with Gaucher disease.

• Total platelet mass is normal, platelet production is usually normal but may be reduced, and platelet survival is often normal.

• Hypothermia can cause temporary thrombocytopenia in humans and animals, presumably because platelets are transiently sequestered in the spleen and other organs.

Clinical Features

• Thrombocytopenia caused by sequestration is often of no clinical importance. The degree of thrombocytopenia is moderate, the total body content of platelets is normal, and platelets can be mobilized from the spleen.

• In patients with liver disease and splenomegaly, bleeding is usually a result of blood coagulation disorders, and the thrombocytopenia is worsened by thrombopoietin (TPO) deficiency.

• Hepatic cirrhosis with portal hypertension and congestive splenomegaly is the most common disorder causing platelet sequestration, but any disease with an enlarged congested spleen can be associated with thrombocytopenia.

• The spleen is usually palpable, and the degree of thrombocytopenia is correlated with the size of the spleen.

• Patients with very large spleens and severe thrombocytopenia usually have decreased platelet production because of a marrow infiltrative process or severe liver disease, as well as sequestration.

• Only a few patients with hypothermia develop thrombocytopenia.

Laboratory Features

• Rarely is the platelet count less than 50 × 10⁹/L unless a second contributing factor is present. Marrow megakaryocytes are usually normal in number and morphology.

Treatment and Prognosis

• Because thrombocytopenia caused by sequestration is usually not a clinically significant problem, no treatment is indicated.

• Splenectomy for another reason usually results in return of the platelet count to normal or above normal (see Chap. 26). Platelet counts may also return to normal after portal-systemic shunting for cirrhosis.

• Therapy for thrombocytopenia of hypothermia is rewarming and documenting normalization of platelet count.

• Patients with massive blood loss requiring 15 or more units of red cells within 24 hours regularly develop thrombocytopenia with platelet counts as low as 25 × 10⁹/L.

• The severity of the thrombocytopenia is related to the number of transfusions, but counts may be higher than predicted because of release from the splenic pool, or lower because of microvascular consumption.

• Management depends on the severity of the thrombocytopenia and the clinical condition of the patient.

• These disorders generally have a clear inheritance pattern. Because prenatal infection or developmental abnormalities may be implicated, some are congenital but not hereditary.

• Thrombocytopenia may be the only abnormality, or it may be associated with well-defined abnormalities of platelet function, as in the Bernard-Soulier, Wiskott-Aldrich, and gray platelet syndromes (discussed in Chap. 75).

• Thrombocytopenia may be diagnosed at any age, including adulthood. In those cases discovered after infancy, a mistaken diagnosis of immune thrombocytopenia (ITP) may be made, particularly in children with moderate thrombocytopenia. Family studies can be helpful in such situations.

Fanconi Anemia

• Autosomal recessive severe aplastic anemia usually beginning at age 8 to 9 years (See Chap. 4).

• Cells from homozygotes have increased sensitivity to chromosomal breakage by DNA cross-linking agents.

• Diverse congenital abnormalities may occur, including short stature, skin pigmentation, hypoplasia of the thumb and radius, and anomalies of the genitourinary, cardiac, and central nervous systems.

• Patients are at risk for acute leukemia and other malignancies.

• The condition is generally fatal unless corrected by allogeneic hematopoietic marrow transplantation with a reduced intensity conditioning regimen.

Thrombocytopenia with Absent Radius Syndrome

• Inheritance pattern suggests autosomal recessive but may be more complex.

• Usually noted at birth because of absence of both radii. Both ulnas are often absent or abnormal, and the humeri, bones of the shoulder girdle and feet may also be abnormal.

• One-third of patients have congenital heart anomalies.

• Allergy to cow’s milk is common.

• Platelet counts are typically 15 to 30 × 10⁹/L, lower during infancy and during periods of stress (surgery, infection). Thrombocytopenia may not be severe and may be overlooked until adulthood.

• Megakaryocytes are diminished or absent.

• Leukemoid reactions and eosinophilia are common.

• Treatments with glucocorticoids, splenectomy, and intravenous immunoglobulin (IVIG) are generally ineffective. Splenectomy may be effective in rare patients presenting as adults.

• Death is usually due to hemorrhage and usually occur within the first year.

• If patient can be sustained for the first 1 to 2 years of life, the platelet count usually recovers and survival is normal.

• Platelet counts vary during adulthood, but symptoms other than menorrhagia are unusual.

May-Hegglin Anomaly, Fechtner Syndrome, Sebastian Syndrome, and Epstein Syndrome

• May-Hegglin anomaly is characterized by autosomal dominant inheritance of giant platelets, and characteristic inclusion bodies in neutrophils, eosinophils, and monocytes. These resemble Döhle bodies seen with acute infections but have a different ultrastructure. Thrombocytopenia is common but may not be present and is rarely severe.

• Fechtner, Sebastian, and Epstein syndromes are quite similar to May-Hegglin anomaly but also manifest varying degrees of high-tone sensorineural deafness, nephritis, and cataracts.

• May-Hegglin anomaly, as well as Fechtner, Sebastian, and Epstein syndromes, are autosomal dominant macrothrombocytopenias with mutations in the MYH9 gene, located on chromosome 22q12-13. This gene encodes nonmuscle myosin heavy chain (NMMHC)-IIA, which is expressed in platelets, kidney, leukocytes, and the cochlea.

• Platelets are large but ultrastructurally normal. Megakaryocytes are normal in appearance and number. Platelet survival and bleeding times are normal or slightly abnormal.

• The thrombocytopenia of most patients is well tolerated, and so usually no treatment is necessary, even for surgery or delivery, but platelet transfusions are commonly given.

X-linked Thrombocytopenia with Dyserythropoiesis

• A family of X-linked disorders of thrombocytopenia associated with dyserythropoiesis and thalassemia has been described, causing a modest bleeding diathesis proportionate to the degree of thrombocytopenia. These patients also have porphyria.

• GATA-1 is an erythroid and megakaryocyte specific transcription factor that drives gene expression essential for each of these two cell lineages.

• In several families, mutations in the amino terminal-finger are associated with macrothrombocytopenia and variable abnormalities in the erythroid lineage, whereas in other families mutations in the amino-terminal finger that disrupt the interaction of GATA-1 with a cofactor (FOG-1) lead to macrothrombocytopenia with dyserythropoietic anemia or β-thalassemia.

• Treatment is supportive, with platelet or erythrocyte transfusions if necessary.

Familial Platelet Syndrome with Predisposition to Myeloid Neoplasms

• Familial platelet syndrome with predisposition to acute myelogenous leukemia is a rare autosomal dominant condition characterized by qualitative and quantitative platelet defects resulting in pathologic bleeding and predisposition to the development of AML.

• Genetic analysis of several pedigrees linked the causative defect to a mutation in the transcription factor Runx-1 (also previously known as AML1 and CBFA2). Runx-1 binds to transcriptional complexes and regulates many genes important in hematopoiesis.

• Allogeneic hematopoietic stem cell transplantation is the only known, curative treatment.

Congenital Amegakaryocytic Thrombocytopenia

• Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare autosomal recessive disease that in most cases presents with severe thrombocytopenia without physical abnormalities at birth.

• Bleeding complications usually are substantial because of the severe thrombocytopenia present in these children.

• The disorder progresses to aplastic anemia before age 3 to 5 years in most patients.

• CAMT results from mutations in the gene encoding the TPO receptor c-Mpl, rendering it deficient (type I CAMT) or of reduced function (type II CAMT), or rarely due to mutation in the TPO gene.

• Treatment with allogeneic stem cell transplantation is essential for survival.

Thrombocytopenia with Radial-Ulnar Synostosis

• Patients with amegakaryocytic thrombocytopenia with radial-ulnar synostosis present at birth with severe normocytic thrombocytopenia with absent marrow megakaryocytes, proximal radioulnar synostosis, and other skeletal anomalies such as clinodactyly and shallow acetabulae.

• Bleeding complications are proportional to the degree of thrombocytopenia.

• Subsequent development of hypoplastic anemia and pancytopenia occur in several patients, suggesting that the defect is not limited to megakaryocytic progenitors.

• Genetic analysis of patients with thrombocytopenia and radioulnar synostosis revealed a mutation in HoxA11, known to be expressed in hematopoietic stem cells.

Wiskott-Aldrich Syndrome

• Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder characterized by microthrombocytopenia, eczema, recurrent infections, T-cell deficiency, and increased risk of autoimmune and lymphoproliferative disorders (also see Chap. 50).

• The syndrome is caused by mutations of the WASP gene located on the short arm of the X chromosome (Xp11.22).

• The product of this gene, the WAS protein (WASP), is expressed in hematopoietic cells. WASP regulates actin polymerization and coordinates reorganization of the actin cytoskeleton and signal transduction pathways that occur during cell movement and cell–cell interaction.

• Supportive treatment during acute bleeding and disease complications consists of platelet transfusions, antibiotics, and systemic glucocorticoids when eczema is severe.

• Patients with mild phenotypes and severe thrombocytopenia may respond to splenectomy, but the risk of infection in these already immunocompromised patients may outweigh the benefit.

• If sufficiently severe, allogeneic hematopoietic stem cell transplantation is the only effective, curative treatment.

Paris-Trousseau Syndrome

• Paris-Trousseau syndrome and its variant Jacobsen syndrome are congenital dysmorphology syndromes in which affected individuals manifest trigonocephaly, facial dysmorphism, heart defects, and mental retardation.

• All affected patients have mild to moderate thrombocytopenia and dysfunctional platelets.

• The blood film shows a subpopulation of platelets containing giant α-granules. Marrow examination reveals two distinct subpopulations of megakaryocytes with expansion of immature megakaryocytic progenitors, dysmegakaryopoiesis, and many micromegakaryocytes.

• Pathologic bleeding usually is mild.

• Both disorders result from deletion of the long arm of chromosome 11 at 11q23, a region that includes the FLI1 gene, the product of which is a transcription factor involved in megakaryopoiesis.

• The dominant inheritance pattern of Paris-Trousseau syndrome despite the presence of one normal allele seems to result from monoallelic expression of FLI1 only during a brief window in megakaryocyte differentiation.

Autosomal Dominant Thrombocytopenia with Linkage to Chromosome 10

• This autosomal dominant thrombocytopenia displays variable degrees of thrombocytopenia, with bleeding proportionate to the degree of thrombocytopenia.

• Unlike familial platelet syndrome with predisposition to myeloid neoplasms, there is no risk of progression of the disease.

• Patients with this disorder have a genetic defect localized to 10p11-12 on the short arm of chromosome 10. In one large kindred with the disorder, a missense mutation was identified within the gene FLJ14813a, which encodes a putative tyrosine kinase of unknown function.

• Megakaryocyte precursors from affected individuals produce low numbers of polyploid cells in vitro, with delayed nuclear and cytoplasmic differentiation when analyzed by electron microscopy.

Kasabach-Merritt Syndrome

• Kasabach-Merritt syndrome is thrombocytopenia associated with giant cavernous angiomas. These lesions can infiltrate aggressively and require intensive treatment.

• The mechanism is platelet consumption in the tumor caused by intravascular coagulation.

• The hemangiomas are usually present at birth and neonatal thrombocytopenia may be present. The syndrome may develop in adults.

• Hemangiomas are usually solitary and superficial but may involve any internal organ.

• A bruit may be heard over the hemangioma, and cardiac failure may develop as a consequence of arteriovenous shunting.

• Thrombocytopenia may be severe, with marked red cell fragmentation. Laboratory abnormalities consistent with disseminated intravascular coagulation (DIC) are often present.

• Treatment may be necessary because of bleeding or growth of the tumor. Surgery can eliminate accessible lesions, and radiation therapy may be effective.

• In some cases, hemostatic abnormalities have been corrected by local thrombosis induced by antifibrinolytic agents, and thrombocytopenia has been corrected by treatment with antiplatelet agents.

• A heterogeneous group of disorders, including those caused by marrow aplasia (see Chap. 3), infiltration with neoplasms (Chap. 12), treatment with chemotherapeutic agents (see Chap. 38), and radiotherapy.

Megakaryocytic Aplasia

• Pure megakaryocytic aplasia or hypoplasia with no associated abnormalities is a rare disorder.

• Amegakaryocytic thrombocytopenia associated with other abnormalities such as dyserythropoiesis is more often seen and is likely a prodrome for myelodysplastic syndrome or aplastic anemia.

• Pure megakaryocytic aplasia appears to be a result of autoimmune suppression of megakaryocytes.

• The natural history is unclear and treatment with immunosuppression is empiric.

Infection

• Thrombocytopenia has been reported with diverse viral infections, usually the result of cytomegalovirus, Epstein-Barr virus, and hantavirus, in children receiving live-attenuated measles vaccine, and with many other infectious agents, such as Mycoplasma, Plasmodium, Mycobacterium, and Ehrlichia. The thrombocytopenia appears usually to be a result of decreased platelet production, but in some cases, immune-mediated platelet destruction may occur.

Thrombocytopenia Associated with Human Immunodeficiency Virus Infection

• Thrombocytopenia has been reported to occur in up to approximately 40% of adults with human immunodeficiency virus (HIV) infection but is usually of modest severity. It is usually not clinically relevant when the patient is successfully treated with highly active antiretroviral therapy, or HAART.

Etiology and Pathogenesis

• The principal cause is ineffective platelet production due to HIV infection of the stromal cells that facilitate hematopoiesis, such as macrophages and microvascular epithelial cells, and direct infection of megakaryocytes.

• Platelet survival is also decreased, possibly because of immune platelet injury.

• The occurrence of thrombocytopenia correlates with plasma viral load and CD4 cell depletion.

• Granulomatous infection or infiltration of the marrow with lymphoma may also contribute to the thrombocytopenia.

Clinical and Laboratory Features

• Platelet counts are rarely below 50 × 10⁹/L, and thrombocytopenia frequently resolves spontaneously.

• The marrow contains normal or increased numbers of megakaryocytes and may be infiltrated with lymphoma or granulomas.

Treatment, Course, and Prognosis

• Antiretroviral drug regimens are the principal treatment for thrombocytopenia.

• Severe and symptomatic thrombocytopenia should be treated with prednisone (1 mg/kg per day) or with short courses of dexamethasone.

• IVIG given weekly at a dose of 0.4 g/kg for up to 5 weeks may be effective. Anti-D reagent has also been used.

• Splenectomy may be the most effective therapy, and does not appear to influence the course of the HIV infection adversely.

Nutritional Deficiencies and Alcohol-Induced Thrombocytopenia

Alcohol

• In alcoholics, thrombocytopenia is usually the result of cirrhosis with congestive splenomegaly, or of folic acid deficiency.

• Acute thrombocytopenia may also occur, because of direct suppression of platelet production by alcohol.

• After withdrawal of alcohol, platelet counts return to normal in 5 to 21 days and may rise above normal levels.

Nutritional Deficiencies

• Mild thrombocytopenia occurs in about 20% of patients with megaloblastic anemia caused by vitamin B₁₂ deficiency. The frequency may be higher with folic acid deficiency because of the frequent association with alcoholism.

• Thrombocytopenia is caused primarily by ineffective platelet production.

• Iron deficiency typically causes thrombocytosis, but severe thrombocytopenia may occur, especially in children.

Thrombotic Thrombocytopenic Purpura

• Thrombotic thrombocytopenic purpura (TTP) is a clinical syndrome of consumptive thrombocytopenia that left untreated results in a 95% mortality rate (see also Chap 90).

Etiology and Pathogenesis

• A well-documented mechanism for formation of platelet thrombi is disseminated platelet aggregation caused by increased plasma levels of ultra-high-molecular-weight multimers of von Willebrand factor (VWF). These appear to accumulate because of deficiency of a plasma VWF-cleaving metalloprotease (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 [ADAMTS13]).

• The deficiency may be inherited or more commonly acquired due to rapid clearance or inhibition of the enzyme by an autoantibody.

Clinical Features

• Sixty to 70% of patients with TTP are female.

• Full clinical expression of the disease is the “classic” pentad: thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, renal involvement, and fever.

• Because current treatment depends on prompt plasma exchange, the diagnosis now requires only thrombocytopenia and microangiopathic hemolytic anemia without another clinically apparent cause. However, more than 50% of patients also have neurologic signs and renal abnormalities.

• The most common presenting symptoms are neurologic abnormalities (headache, confusion, seizure, dysphagia, paresis), hemorrhage (epistaxis, hematuria, gastrointestinal bleeding, menorrhagia), fatigue, and abdominal pain.

Laboratory Findings

• Thrombocytopenia is essential for the diagnosis and is usually found at presentation or develops rapidly thereafter.

• Anemia and red cell fragmentation may also be absent at presentation but develop rapidly during the course of the disease.

• Consistent with severe hemolysis, serum lactic acid dehydrogenase (LDH) values are often markedly elevated and serum indirect bilirubin levels are also increased.

• Most patients have microscopic hematuria and proteinuria; some have acute, oliguric renal failure.

• Tissue biopsy is usually not required for diagnosis but may be necessary in difficult cases. The characteristic lesions are arteriolar and capillary thrombi composed primarily of platelets but also containing VWF and fibrin. Morphologically identical lesions are found in preeclampsia, malignant hypertension, acute scleroderma, and renal allograft rejection.

• Based on increased understanding of pathophysiology, several tests of ADAMTS13 activity are available. Severe acquired ADAMTS13 deficiency appears to be specific for TTP, although the sensitivity of the association is debated and the frequency of severe ADAMTS13 deficiency in TTP depends on how patients are ascertained. If adult patients with thrombotic microangiopathy are selected with no plausible secondary cause, no diarrheal prodrome, and no features suggestive of hemolytic uremic syndrome (HUS; eg, oliguria, severe hypertension, need for dialysis, serum creatinine > 3.5 mg/dL), then at least 80% have undetectable ADAMTS13 activity and the majority will have easily detected autoantibodies that inhibit the protease.

Differential Diagnosis

• Sepsis and DIC may cause an acute illness with fever, chills, and multiple organ dysfunction. The distinction should be clear from coagulation studies, which in TTP are not usually severely abnormal.

• Bacterial endocarditis can present with anemia, thrombocytopenia, fever, neurologic symptoms, and renal abnormalities.

• Evans syndrome, a combination of autoimmune hemolytic anemia and ITP, may be confused with TTP. The direct red cell antiglobulin (Coombs) test is usually positive in Evans syndrome.

• Other considerations include systemic lupus erythematosus, catastrophic antiphospholipid syndrome, scleroderma, megaloblastic anemia, or myelodysplastic thrombocytopenia.

Treatment

• Plasma exchange is the most important treatment modality.

• Rapid initial therapy with plasma exchange is essential. If facilities are not immediately available for apheresis, plasma infusions should be administered until the patient can be transferred to a facility that provides plasma exchange therapy.

• Plasma exchange is effective because of removal of the autoantibody and of large VWF multimers, and because of replacement of the ADAMTS13.

• Daily exchange of one plasma volume (40 mL/kg) is performed until the patient responds, as defined by correction of neurologic abnormalities, return to a normal platelet count, and normal or nearly normal serum LDH levels.

• Initial response typically occurs in the first week, and recovery is nearly complete in 3 weeks, but response may not occur for more than 1 month.

• If prompt response is not achieved, plasma exchange of 40 mL/kg should be done twice daily.

• After neurologic findings have resolved and the platelet count is normal, plasma exchange should be continued at increasing time intervals for another 1 to 2 weeks to avoid relapse, although solid evidence that such tapering of therapy reduces relapses is lacking.

• Renal function recovers more slowly than the neurologic and hematologic abnormalities. It is unknown if continued plasma exchange will affect recovery of renal function.

• With plasma exchange, mortality has been reduced from greater than 90% to less than 20%.

• With the realization that TTP represents an autoimmune disorder, treatment with glucocorticoids or other immunosuppressive regiments, such as rituximab, are appropriate and reduce relapse rates.

• Therapy with antiplatelet agents has not been generally effective and carries a significant risk of hemorrhage.

• In patients who have had a stroke or transient cerebral ischemic events, aspirin therapy is appropriate when severe thrombocytopenia has resolved.

• Anecdotal reports of success have appeared for numerous agents, including IVIG, vincristine, azathioprine, cyclophosphamide, cyclosporine, and extracorporal immunoadsorption.

• Platelet transfusion has been reported to exacerbate TTP and has been suggested as a cause of death in some reports.

• However, cautious administration of platelet transfusions may be indicated in some patients with major bleeding associated with marked thrombocytopenia.

Course and Prognosis

• Most of the now rare deaths occur early in the course of the disease.

• Approximately 30% to 50% of patients have relapsing disease.

• Patients who relapse long after the initial episode predictably recover with retreatment.

• It is not known whether or not those with chronic thrombocytopenia are more likely to relapse.

• The frequency of long-term sequelae after recovery from acute TTP is not known. Some patients may continue to have mild thrombocytopenia or abnormal renal function. Permanent neurologic complications are uncommon.

Epidemic HUS in Children Caused by Shiga-Toxin–Producing Escherichia coli

• This type of HUS follows acute enteric infection with E coli (most often infection with E coli serotype 0157:H7) or Shigella dysenteriae serotypes, which produce the Shiga toxin.

• Progression of E coli 0157:H7 infection to HUS occurs in 2% to 7% of sporadic cases and in up to 30% of cases in some epidemics.

• Boys and girls are equally affected, and most cases occur between April and September.

• Most outbreaks are caused by undercooked beef, but other sources have been implicated including lettuce. Person-to-person transmission may also occur.

Clinical and Laboratory Features

• The major presenting symptom is diarrhea, which is bloody in most patients. The diarrhea may be sufficiently severe to require colectomy.

• Most patients are oliguric on admission, but average duration of symptoms before diagnosis of HUS is 6 days.

• Fever and hypertension are common. Pancreatitis and seizures may occur.

• Laboratory features are thrombocytopenia, microangiopathic hemolytic anemia, and the findings of acute renal failure.

Treatment, Course, and Prognosis

• Treatment is supportive. Approximately 50% of patients require dialysis.

• Plasma exchange appears to have minimal or no benefit.

• Mortality of epidemic childhood HUS is 3% to 10%, but HUS in the elderly may have mortality up to approximately 90%.

• Patients frequently have permanently impaired renal function after recovery.

• Relapses do not appear to occur.

TTP-HUS Associated with Infections Other than Shiga-Toxin–Producing E coli

• A syndrome resembling TTP and HUS has been reported to occur sporadically after infection caused by rickettsia, viruses, or bacteria other than those producing Shiga toxin.

• None of these infections is as clearly associated with TTP-HUS as is infection with E coli 0157:H7.

• It appears some infections may cause bona fide HUS; others may exacerbate existing TTP.

• Patients infected with HIV may develop a syndrome similar to TTP and HUS, but differ in having a gradual onset and a less predictable response to plasma exchange. Some patients survive for weeks or months without plasma exchange. These patients often have associated medical problems that could account for some of the findings interpreted as caused by TTP or HUS.

Drug-Induced TTP

• A syndrome resembling ADAMTS13-deficient TTP may be due to drug-dependent antibodies to platelets and other cells.

Quinine

• Quinine is a frequent offender. Patients may have quinine-dependent antiplatelet antibodies. Some patients also have antineutrophil antibodies and develop severe neutropenia.

• Abdominal pain and nausea are common presenting symptoms.

• Plasma exchange is ineffective. Most patients also require hemodialysis, but they usually recover normal renal function.

• Reexposure to quinine, even in small amounts, can cause immediate recurrence.

Ticlopidine

• Acute, severe TTP-HUS has been reported to occur in some patients treated with short courses of ticlopidine.

Cancer Chemotherapy

• Nearly all chemotherapy patients who develop TTP have been treated with mitomycin C, most often for gastric cancer. Cisplatin, bleomycin, and pentostatin have also been reported to cause TTP.

• Induction of TTP by mitomycin C may be dose related, but less than 10% of patients receiving high doses develop the disease.

• Renal pathology is identical to that of other patients with TTP.

• The efficacy of plasma exchange is uncertain.

• Most patients die of their cancer or of renal failure.

Cyclosporine A

• A syndrome of severe renal failure, microangiopathic hemolytic anemia, and thrombocytopenia has been reported in patients receiving cyclosporine after allogeneic marrow transplantation, but the etiologic role of cyclosporine is uncertain.

• Tacrolimus has also been reported to cause TTP.

Other Drugs

• TTP has been associated with administration of metronidazole, cocaine, simvastatin, and ecstasy.

TTP Associated with Marrow Transplantation

• Most patients have had allogeneic transplants, but the disorder has also occurred with transplantation of autologous marrow or peripheral blood stem cells.

• The diagnosis of TTP may be difficult to establish because of the severe, multiorgan dysfunction accompanying allogeneic hematopoietic stem cell transplantation.

• All features of TTP in these patients could be caused by graft-versus-host disease, radiation toxicity, and systemic infection.

• Most patients do not respond to plasma exchange, and even in responsive patients plasma exchange may not affect outcome.

TTP Associated with Cancer

• TTP may develop rarely in patients with metastatic carcinoma of various types, but more than half of such patients have had gastric cancer.

• Laboratory evidence of DIC is found in a minority of these patients.

• Therapy, course, and prognosis depend on the response of the tumor to chemotherapy. Plasma exchange appears not to be effective.

TTP Associated with Autoimmune Disorders

• Systemic lupus erythematosus, acute scleroderma, and the catastrophic antiphospholipid syndrome may present with clinical and pathologic findings difficult or impossible to distinguish from TTP.

• Treatment with plasma exchange has been reported to be effective in the severe autoimmune disorders as well as in TTP.

TTP Associated with Pregnancy

• TTP occurs in about 1 in 25,000 pregnancies.

• The clinical and pathologic features of TTP are similar to those of preeclampsia, particularly the HELLP syndrome (microangiopathic hemolytic anemia, elevated liver enzymes, low platelet count), suggesting a relationship between these disorders and complicating differential diagnosis.

• TTP has recurred in successive pregnancies in some patients and during pregnancy in women who have recovered from previous episodes of TTP unrelated to pregnancy. Pregnancy is therefore considered a risk for recurrence of TTP.

• With severe disease and a viable fetus, delivery should be induced. This will resolve preeclampsia but may or may not resolve platelet consumption. Some patients have delivered healthy term infants after developing TTP during the pregnancy.

Gestational Thrombocytopenia

• Gestational thrombocytopenia, as defined by the following five criteria, occurs in approximately 5% of pregnancies: mild, asymptomatic thrombocytopenia; no past history of thrombocytopenia (except during a prior pregnancy); occurrence during late gestation; absence of fetal thrombocytopenia; and spontaneous resolution after delivery.

• Platelet counts are usually greater than 70 × 10⁹/L and most are between 130 and 150 × 10⁹/L. Lower platelet count or onset early in gestation suggest the diagnosis of immune thrombocytopenia (see “Immune Thrombocytopenia,” below).

• Usual obstetric care is appropriate for both mother and infant.

Preeclampsia

• Preeclampsia is defined by the presence of hypertension, proteinuria, and edema occurring during pregnancy and resolving after delivery. Eclampsia is preeclampsia plus neurologic abnormalities occurring peripartum.

• Thrombocytopenia develops in approximately 15% of women with preeclampsia, but platelet counts below 50 × 10⁹/L occur in less than 5%.

• Some patients with severe preeclampsia may develop the HELLP syndrome, which may mimic TTP.

• Delivery of the fetus is the most effective approach to these disorders. Recovery usually begins promptly but may be delayed for several days.

• Plasma exchange is indicated for patients with severe thrombocytopenia and microangiopathic hemolytic anemia if the fetus cannot be delivered or prompt recovery does not occur after delivery. Earlier initiation of plasma exchange is indicated for severe clinical problems, such as acute, anuric renal failure or neurologic abnormalities.

• Immune thrombocytopenia (ITP) is an acquired disease of children and adults that is defined as isolated thrombocytopenia with no clinically apparent associated condition or other causes of thrombocytopenia. No specific criteria establish the diagnosis of ITP; the diagnosis relies on exclusion of other causes of thrombocytopenia.

• Adult ITP typically has an insidious onset and rarely resolves spontaneously.

• Childhood ITP characteristically is acute in onset and resolves spontaneously within 6 months.

Adult ITP

Etiology and Pathogenesis

• The mechanism of thrombocytopenia appears to be shortened intravascular survival of platelets as a consequence of splenic sequestration and destruction caused by antiplatelet antibodies.

• Antiplatelet antibodies also appear to bind to megakaryocytes and interfere with thrombopoiesis, leading to normal or decreased rates of platelet production even with increased or normal numbers of megakaryocytes in some patients.

• Most patients with ITP have demonstrable antibodies to platelet membrane glycoproteins GP IIb/GP IIIa and/or GP Ib/IX, but their specific pathogenetic role is not clear because they are also demonstrable in other conditions.

• In some patients, impaired platelet function is demonstrable, but its clinical significance is unknown.

• In some patients, it is likely that T-cell–mediated immune dysfunction is responsible for thrombocytopenia, and such patients are less likely to respond to now standard immunosuppressive treatments (rituximab, immune globulin).

Clinical Features

• Adult ITP appears to be more common in young women than in young men, but among older patients, the sex incidence may be equal.

• Most adults present with a long history of purpura, but many patients are now asymptomatic at diagnosis because of the widespread inclusion of platelet enumeration in routine blood counts.

• Petechiae are not palpable, and they occur most often in dependent regions. Hemorrhagic bullae may appear on mucosal surfaces with severe thrombocytopenia.

• Purpura, menorrhagia, epistaxis, and gingival bleeding are common. Gastrointestinal bleeding and hematuria are less so. Intracerebral hemorrhage occurs in approximately 1% of patients but is the most common cause of death.

• Overt bleeding is rare unless thrombocytopenia is severe (< 10 × 10⁹/L), and even at this level most patients do not experience major hemorrhage.

• A palpable spleen strongly suggests that ITP is not the cause of thrombocytopenia.

Laboratory Features

• Thrombocytopenia is the essential abnormality. The blood films should be reviewed to rule out pseudothrombocytopenia (see above). The platelets are usually of normal size but may be enlarged.

• White blood cell count is usually normal, and the hemoglobin level is also normal unless significant hemorrhage has occurred.

• Coagulation studies are normal.

• The bleeding time does not provide useful information.

• Marrow megakaryocytes may be increased in number, with a shift to younger, less polypoid forms, but assessment of megakaryocyte morphology and number is not quantitative. In a patient with isolated thrombocytopenia and no symptoms or signs pointing to other causes a marrow examination is not necessary.

Differential Diagnosis

• The diagnosis is one of exclusion. Other conditions that can mimic ITP are acute infections, myelodysplasia, chronic DIC, drug-induced thrombocytopenia, and chronic liver disease with platelet sequestration.

• The distinction from congenital thrombocytopenia is especially important to avoid inappropriate treatment.

Treatment: Initial Management

• Patients who are incidentally discovered to have asymptomatic mild or moderate ITP can safely be followed with no treatment.

• Patients with platelet counts of more than 50 × 10⁹/L usually do not have spontaneous, clinically important bleeding, and may undergo invasive procedures.

Emergency Treatment of Acute Bleeding Caused by Severe Thrombocytopenia

• Immediate platelet transfusion is indicated for patients with hemorrhagic emergencies. Despite having a presumably short platelet survival time, some patients have substantial posttransfusion increments in their platelet counts.

• IVIG may be given as a single infusion of 0.4 to 1.0 g/kg followed immediately by a platelet transfusion. IVIG, 1 g/kg per day for 2 days, increases the platelet count in most patients within 3 days.

• High doses of glucocorticoids, such as 1 g of methylprednisolone daily for 3 days, may cause a rapid increase in the platelet count.

• ε-Aminocaproic acid can be effective in controlling acute bleeding after failure of platelet transfusion and prednisone.

Glucocorticoids

• Glucocorticoid therapy likely decreases sequestration and destruction of antibody-sensitized platelets and may enhance platelet production.

• Prednisone, given in a dose of 1 mg/kg per day orally, is indicated for patients with symptomatic thrombocytopenia, and probably for all patients with platelet counts below 30 to 50 × 10⁹/L who may be at increased risk for hemorrhagic complications.

• Sixty percent of patients will increase their platelet count to greater than 50 × 10⁹/L, and approximately 25% will achieve a complete recovery. Most relapse when the prednisone dose is tapered or discontinued.

• The duration of prednisone therapy prior to consideration of splenectomy depends on the severity of the bleeding, the dose of prednisone required to maintain a response, and the risks of surgery.

• Long-term therapy with glucocorticoids can lead to many important side effects, including immunosuppression and osteoporosis.

• Courses of high-dose dexamethasone (40 mg/d for 4 days) is being used increasingly frequently in an attempt to induce a more sustained remission than the rather poor results obtained with standard prednisone therapy. Randomized clinical trials are necessary to prove that this therapy is superior to standard doses of prednisone, or whether the addition of other immunosuppressive agents (eg, rituximab) is of real value.

Intravenous Immunoglobulin

• IVIG is used in adults when a transient rise in platelet count is desired or when glucocorticoids are contraindicated.

• Initial dose is 2 g/kg given over 2 to 5 days. Comparable responses may occur with half this dose, or with 0.8 g/kg given once.

• Typical response is an increase in platelet count 2 or 3 days after the infusions begin, with return to pretreatment levels within several weeks.

• Fever, headache, nausea, and vomiting occur in approximately 25% of recipients, and aseptic meningitis occurs in 10%. Acute renal failure may occur, and hemolysis because of alloantibodies is also a side effect. Such doses of IVIG are a large volume load for patients with borderline cardiac function.

Anti-Rh(D) Immune Globulin

• Approximately 70% of patients receiving infusions of anti-Rh(D) antiserum at a dose of 50 μg/kg will respond with an increase in platelet count greater than 20 × 10⁹/L, and half will have an increase greater than 50 × 10⁹/L.

• In most patients, the response lasts longer than 3 weeks.

• Anti-Rh(D) is ineffective in Rh(D)-negative patients or following splenectomy.

• Side effects include alloimmune hemolysis, which is usually no more severe than that encountered with IVIG, but several deaths have been reported due to massive hemolysis. Anti-Rh(D) is less expensive than a standard course of IVIG.

• Headache, nausea, chills, and fever are much less frequent than with therapeutic doses of IVIG.

Splenectomy

• Sustained remission occurs in about two-thirds of patients who undergo splenectomy.

• The risks of operative bleeding complications with splenectomy are low even with severe thrombocytopenia, but it is prudent to have platelet preparations available in case of excessive intraoperative bleeding.

• Intravenous IVIG can induce a transient remission of thrombocytopenia and may be used to prepare for the operation.

• Most responses to splenectomy occur within several days. Responses after 10 days are unusual. The rapidity and extent of the response appear to correlate with durability of response.

• Splenectomy is associated with a small but significantly increased risk of severe infectious complications. All patients should be immunized with polyvalent pneumococcal, Haemophilus influenzae type b and meningococcal vaccines at least 2 weeks before surgery.

• One-half of patients who relapse after an initial response to splenectomy will do so within 6 months.

Removal of Accessory Spleens

• Accessory spleens are found at splenectomy in 15% to 20% of patients, and they may be present in as many as 10% of those refractory to splenectomy or who relapse after splenectomy.

• Remission after removal of an accessory spleen is unpredictable.

Thrombopoietin Receptor Agonists

• Two small molecule mimics of TPO have been approved by the US Food and Drug Administration for the treatment of refractory chronic ITP: romiplostim (N-plate), a “peptibody” composed of four copies of a TPO receptor binding peptide on an Ig scaffold, and eltrombopag (Promacta), a small organic molecule that is orally bioavailable. Several other thrombopoietin receptor agonists (TRAs) are currently undergoing clinical trials.

• Both drugs are potent stimulators of thrombopoiesis and rapidly (3–5 days) lead to major, dose-dependent increases (into the normal range) in platelet levels in the majority of patients.

• While on TRA therapy, hemorrhagic complications of thrombocytopenia occur less commonly and are less severe, and the use of coexistent ITP therapeutics and salvage agents is significantly reduced.

• Although studied carefully during clinical trials, with the exception of patients with liver cirrhosis, neither agent has been associated with a statistically significant increase in thrombotic complications, and in only a small number of patients have marrow reticulin fibrosis been noted. Eltrombopag has been associated with a low (approximately 4%) incidence of a modest rise in hepatic transaminases.

• Neither of the approved agents was initially thought to be disease modifying (ie, the platelet count remains normal only so long as the drug is used). However, recent publications indicate that a fraction of patients might have long-lasting remissions of ITP following a 6-month or longer course of a TRA. It should be noted that abrupt discontinuation of TRAs can lead to rebound thrombocytopenia more severe than the patient’s baseline thrombocytopenia seen before institution of the drug.

Treatment: Chronic Refractory ITP

• Most other treatments available for patients with ITP who have relapsed after splenectomy have given inconsistent results and are often associated with significant risk. Refractory ITP presents an unusually complex clinical problem.

• Observation may be appropriate for asymptomatic patients, even those with platelet counts of less than 30 × 10⁹/L.

• The goal of treatment is to achieve a platelet count that ensures hemostasis, not necessarily a normal platelet count.

Treatment of ITP During Pregnancy and Delivery

• It is extremely important to attempt to differentiate ITP from gestational thrombocytopenia.

• Early in pregnancy, treatment of maternal ITP should be the same as if the patient were not pregnant, using glucocorticoids in those patients whose symptoms require intervention.

• Splenectomy should be deferred if possible because ITP may improve after delivery. Therapy with IVIG may help delay splenectomy.

• In infants born to mothers with ITP, there is a 10% risk of a platelet count less than 50 × 10⁹/L and a 4% risk of a platelet count less than 20 × 10⁹/L.

• The severity of neonatal thrombocytopenia correlates with the severity of maternal thrombocytopenia. Treatment of the mother with glucocorticoids or with IVIG close to term has no effect on the platelet count of the infant.

• No satisfactory method is available to obtain accurate fetal platelet counts.

• Current practice is to recommend cesarean section only for obstetric indications.

• It is critical to monitor the newborn’s platelet count during the first several days of life because severe thrombocytopenia may develop after delivery.

Childhood ITP

Clinical Features

• Peak incidence is from ages 2 to 4 years and is the same in both sexes until age 10 years, when female predominance appears.

• Bruises and petechiae are nearly universal presenting symptoms, usually of less than 1 to 2 weeks duration.

• Epistaxis, gingival bleeding, and gastrointestinal bleeding are uncommon.

• The frequency of a palpable spleen is the same as in unaffected children (approximately 10%).

Laboratory Features

• Most children present with platelet counts less than 20 × 10⁹/L.

• Marrow examination is usually performed to rule out acute lymphocytic leukemia.

Course and Prognosis

• About 85% of patients selected for no specific treatment (eg, glucocorticoids or splenectomy) have a complete response within 6 months.

• Good prognostic features are abrupt onset, brief duration, and mild symptoms.

• Most responders develop no new purpura after the first week, and the platelet count is usually normal in 2 to 8 weeks.

• Purpura for more than 2 to 4 weeks before diagnosis is the most important predictor of chronic thrombocytopenia. Other factors are female sex, age greater than 10 years, and higher platelet count at presentation.

• Few children with ITP have critical complications, and even fewer die. Only 1% or less have intracerebral hemorrhage.

Treatment

• The need for treatment is controversial. No specific treatment is recommended by some for patients with bruising as the only symptom, regardless of the severity of the thrombocytopenia, but most patients receive treatment, more often with IVIG than with glucocorticoids.

• IVIG given 0.8 g/kg in a single dose or 2.0 g/kg in divided doses is expected to improve the platelet count significantly more rapidly than no treatment.

• Treatment has not been shown to decrease the risk of bleeding or death.

• Because of the risks of severe infection, splenectomy should be deferred for 6 to 12 months after diagnosis, and then recommended only for children with severe thrombocytopenia and significant bleeding symptoms.

• Splenectomy in children is associated with an increased risk of severe infection. In addition to all routine immunizations, polyvalent pneumococcal, H influenzae type b, and meningococcal vaccines should be given more than 2 weeks prior to splenectomy. Penicillin prophylaxis is routinely given to splenectomized children up to the age of 5 years.

• Efficacy of measures for therapy of chronic ITP in childhood is uncertain. Because the mortality is low and spontaneous remissions occur even after many years, potentially harmful treatments should be used only when there is a substantial risk of death or morbidity from hemorrhage.

• This rare disorder occurs predominantly in young women, usually related to the menstrual cycle, but it also occurs in men and postmenopausal women. In some patients, there are parallel cycles of leukopenia.

• The pathogenesis may be autoimmune platelet destruction, increased platelet phagocytosis because of cyclic increments in macrophage colony-stimulating factor or cyclic decreases in platelet production.

• Although spontaneous remissions may occur, cyclic thrombocytopenia is chronic in most patients and may be a prodrome for marrow failure.

• Numerous therapies for cyclic thrombocytopenia have been attempted, with inconsistent success at best.

(See also Chap. 90)

Etiology

• Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder caused by antibodies that recognize a neoepitope in platelet factor 4 exposed when it binds heparin. The result is activation of platelets, monocytes, and the coagulation cascade and, ultimately, thrombosis.

Clinical Features

• It should be noted that the platelet count of many, if not most patients drop by approximately 10% following the institution of heparin therapy. This may begin soon after heparin is started and may resolve even while heparin is continued. This form of thrombocytopenia is most frequent with full-dose therapy. It is not antibody-mediated and may be a result of platelet aggregation by heparin.

• Patients may present with a wide range of platelet counts, including levels close to or above normal, as long as the count has dropped by 50% from baseline.

• Unless recently exposed to heparin (< 100 days), the platelet count begins to fall 4 to 5 days after heparin therapy is instituted.

• The disease can occur with any heparin preparation: unfractionated heparin, low-molecular-weight heparins, and heparin-like compounds such as pentosan and danaparoid. All doses and routes of administration may also lead to HIT. Higher-molecular-weight fractions of heparin may interact more readily with platelets and thereby cause thrombocytopenia more frequently.

• HIT affects up to 5% of patients exposed to regular heparin and to lesser numbers of patients exposed to other forms of heparin.

• Thrombocytopenia may recur on readministration of heparin.

• Regardless of the degree of thrombocytopenia, the disease is the most hypercoagulable condition known.

• Venous thromboembolism is more commonly seen than is arterial thrombosis, although the latter is usually more striking. Thrombosis usually appears the first week after diagnosis and has high morbidity and mortality.

Laboratory Features

• Two assay prototypes for confirming the diagnosis are available. One measures the Ig antibodies to the heparin/PF4 complex (antigen assay), and the other measures heparin-dependent antibodies that activate platelets (activation assay) in plasma or sera.

• Commercially available antigen assays measure either binding to PF4-heparin or PF4-polyvinylsulfate by enzyme-linked immunosorbent assay.

• Activation assays are not commercially established because specific platelet donors are needed each time, and donor platelets can vary greatly in their sensitivity to activation by HIT sera. One of the earliest and best-established activation assays, serotonin release assay, involves ¹⁴C-serotonin release from platelets induced by HIT antibodies and heparin.

• In patients with a high clinical risk, heparin should be stopped and alternative treatment started even before laboratory results are available. A positive antigen test and particularly a progressive increase in the number of platelets over the following days are confirmatory.

• A negative antigen test does not rule out the diagnosis and should be repeated after 24 hours while the patient is undergoing alternative anticoagulant therapy. If the repeat assay is negative and platelet count does not increase, alternative diagnoses should be considered.

Prevention, Diagnosis, and Treatment

• The platelet counts of patients on heparin therapy should be obtained frequently.

• For patients requiring long-term anticoagulation, the best means of avoiding thrombocytopenia associated with thrombosis is to initiate therapy with a vitamin K antagonist or direct anticoagulant agent simultaneously with heparin so that therapeutic anticoagulation will be achieved before HIT is likely to occur.

• A clinical suspicion of HIT should be made if the platelet count falls below 100 × 10⁹/L, or decreases by more than 50% from baseline and the decrease is unexplained by any other cause, or if a thromboembolic episode develops that is unexplained by other causes.

• Heparin therapy should be stopped once a strong clinical suspicion of HIT arises, and especially once a diagnosis is made.

• Several drugs available for anticoagulation in patients with HIT are now available, including argatroban, desirudin, bivalirudin, danaparoid, and fondiparinaux, which directly inhibit thrombin or fXa.

• Lepirudin prolongs the activated partial thromboplastin time (aPTT), so this test can be used to monitor effective dosing. Lepirudin induces antilepirudin antibodies in approximately half of patients who receive the drug. These antibodies rarely alter biologic activity but tend to prolong the drug’s half-life, necessitating careful monitoring by aPTT. The availability of lepirudin is uncertain.

• Argatroban is synthesized from arginine and is rapidly metabolized in the liver. It affects both the aPTT and prothrombin time.

• Use of these direct thrombin or fXa inhibitors in HIT is efficacious; the incidence of thrombotic complication is reduced, perhaps by half, and the time to platelet count recovery is shortened. However, bleeding complications can occur.

• Lepirudin or argatroban should be given until patients recover from thrombocytopenia before adding and then switching to a prolonged course of an oral anticoagulant.

Etiology and Pathogenesis

• In these patients, thrombocytopenia is assumed to be a consequence of immune platelet destruction by drug-dependent antibodies. The target of antibody attack is usually composed of a drug-platelet surface protein complex.

• A vast number of drugs have been implicated as causing thrombocytopenia. Drugs for which modestly rigorous criteria for a causal effect are presented in Chap. 117, Table 117–7 of Williams Hematology, 9th ed.

Clinical and Laboratory Features

• Drug-induced thrombocytopenia typically produces profoundly low platelet counts.

• The time from initiating drug therapy to the development of thrombocytopenia averages 14 days, but may be as long as 3 years. With rechallenge, thrombocytopenia may appear within minutes, but almost always appears within 3 days.

• Patients may have nausea and vomiting, rash, fever, and abnormal liver function tests. Leukopenia may also develop.

Diagnosis

• A careful history is crucial. In addition to prescription medications, the patients should be asked about over-the-counter drugs, alternative therapies, soft drinks, mixers, and aperitifs that may contain quinine.

• Laboratory tests to detect drug-dependent antiplatelet antibodies remain largely investigational.

• The diagnosis can only be made by rechallenge with the drug after recovery from thrombocytopenia, but rechallenge can be dangerous because of the possibility of developing severe thrombocytopenia, even with very small doses of a drug.

• For patients who require therapy with multiple drugs, it may be appropriate to reintroduce each drug individually and to observe the patient for several days before adding another drug.

Treatment

• Withdrawal of the offending drug is essential.

• Prednisone therapy is commonly given but may not influence recovery.

• Major bleeding requires urgent intervention as for severe ITP: platelet transfusion, high-dose parenteral methylprednisolone, and possibly IVIG.

Etiology and Pathogenesis

• Pathogenesis is similar to neonatal alloimmune hemolytic disease except that fetal platelets rather than erythrocytes provide the antigenic challenge.

• Destruction of fetal platelets is caused by transplacentally acquired maternal antibodies directed against fetal-platelet–specific antigen inherited from the father.

• The platelet antigen HPA-1a, found in approximately 98% of the general population, provides the most frequent immunogenic stimulus in persons of European ancestry. Other alloantigens are also implicated.

Clinical and Laboratory Features

• First-born children are often affected, indicating that fetal platelets cross the placenta during gestation. Recurrence with subsequent pregnancies is common.

• Because only 2% of the general population lacks the HPA-1a antigen, finding that the mother’s platelets are HPA-1a-negative provides presumptive evidence of alloimmune origin. Neonatal alloimmune thrombocytopenia is in every respect more severe than thrombocytopenia in infants born to mothers with ITP, with death or neurologic impairment occurring in up to 25% of infants.

• Platelet counts usually recover in 1 to 2 weeks.

Prevention and Management

• Antenatal screening for neonatal alloimmune thrombocytopenia has been studied, but the cost-effectiveness of such a program has not been established.

• Management of neonatal alloimmune thrombocytopenia requires platelet transfusion, glucocorticoids, and IVIG.

• Maternal platelets are HPA-1a-negative and should be effective in transfusion. However, they require washing to remove maternal plasma containing antibodies and irradiation to prevent graft-versus-host disease.

• If HPA-1a-negative platelets are unavailable, random donor platelets plus IVIG treatment may be used.

• Management of subsequent pregnancies may require in utero sampling of fetal blood to obtain platelet counts and serial in utero platelet transfusions, procedures with significant risks for the fetus.

• Administration of IVIG and glucocorticoids to the mother may reduce the prevalence of in utero cerebral hemorrhage but is not effective in all patients.

• Delivery by scheduled cesarean section may reduce the risk of neonatal cerebral hemorrhage.

• This acute, severe thrombocytopenia occurs 5 to 15 days after transfusion of a blood product and is associated with high-titer, platelet-specific alloantibodies.

Etiology and Pathogenesis

• Platelet destruction is caused by an alloantibody to a platelet-specific antigen.

• Anti-HPA-1a is present in more than 80% of cases, but alloimmunization to most other platelet-specific antigens has been reported.

• The mechanism of formation of the antibody is well established, but it remains uncertain how anti-HPA-1a antibodies can cause destruction of HPA-1a-negative platelets.

Clinical and Laboratory Features

• Most patients are women, and most are multiparous.

• Severe thrombocytopenia (platelet counts < 5 × 10⁹/L) with major bleeding occurs several days after transfusion of 1 or more units of blood product, usually packed red cells.

• Fever often accompanies the inciting transfusion and the initial presentation.

• Antibodies to a platelet-specific alloantigen can be detected by appropriate serologic methods.

• Only after recovery can the patient’s platelet types be determined.

Treatment, Course, and Prognosis

• Platelet transfusions are essential if there is severe, active bleeding, but these frequently lead to systemic reactions and the platelet count may not be increased.

• Glucocorticoids and IVIG are usually effective.

• Plasma exchange may be effective in 80% of patients.

• Thrombocytopenia begins to resolve after several days in most patients, but may be persistent and severe in some.