AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

The hemostatic system consists of platelets, coagulation factors, and the endothelial cells lining the blood vessels. The platelets arise from the cytoplasmic fragmentation of megakaryocytes in the bone marrow and circulate in blood as disk-shaped anucleate particles.

Under normal circumstances, the resistance of the endothelial cell lining to interactions with platelets and coagulation factors prevents thrombosis. When endothelial continuity is disrupted and the underlying matrix is exposed, a coordinated series of events are set in motion to seal the defect (primary hemostasis). Platelets play a primary role in this process, interacting with subendothelium-bound von Willebrand factor (vWf) via the membrane glycoprotein Ib complex. This initial interaction (platelet adhesion) sets the stage for other adhesive reactions that allow the platelets to interact with each other to form an aggregate (see Image 1).

The platelet glycoprotein (glycoprotein IIb/IIIa) complex mediates platelet-to-platelet interactions (platelet aggregation). On resting platelets, glycoprotein IIb/IIIa is unable to bind fibrinogen or vWf. Platelet activation allows binding of these proteins, which bridges adjacent platelets. Morphologically, the platelets change dramatically from disks to spiny spheres in a process called shape change.

Platelets contain 2 unique types of granules, the alpha granules and the dense granules. The alpha granules contain hemostatic proteins such as fibrinogen, vWf, and growth factors (eg, platelet-derived growth factor). The dense granules contain proaggregatory factors such as adenosine 5'-diphosphate (ADP), calcium, and 5-hydroxytryptamine (serotonin). During activation, the granules are centralized and their contents are discharged into the lumen of the open canalicular system, from which they are then released to the exterior (the release reaction).

Following activation, platelets have 2 major mechanisms to recruit additional platelets to the growing hemostatic plug. They release proaggregatory materials (eg, ADP) by the release reaction, and they synthesize thromboxane A₂ from arachidonic acid. Thus, the release reaction and prostaglandin synthesis act to consolidate the initial hemostatic plug by promoting the participation of other platelets in the growing hemostatic plug. In addition, when platelets are activated, negatively charged phospholipids move from the inner to the outer leaflet of the membrane bilayer. This negative surface provides binding sites for enzymes and cofactors of the coagulation system, resulting in the formation of a clot (secondary hemostasis).

Pathophysiology

Platelet disorders lead to defects in primary hemostasis and have signs and symptoms different from coagulation factor deficiencies (disorders of secondary hemostasis). The body's reaction to vessel wall injury is rapid adhesion of platelet subendothelium. The initial hemostatic plug, composed primarily of platelets, is stabilized further by a fibrin mesh generated in secondary hemostasis. The arrest of bleeding in a superficial wound, such as the bleeding time wound, almost exclusively results from the primary hemostatic plug.

Hence, primary hemostatic disorders are characterized by prolonged bleeding time, and the characteristic physical examination findings are petechiae and purpura. In comparison, defects in secondary hemostasis exhibit delayed deep bleeding (eg, muscles and joints) and the characteristic physical examination finding is hemarthrosis. Hemarthrosis and muscle hematomas are not present in primary hemostatic disorders.

Autoimmune thrombocytopenias

Immune thrombocytopenic purpura

Immune thrombocytopenic purpura (ITP) is one of the most common autoimmune disorders. It occurs in 2 distinct clinical types, an acute self-limiting form observed almost exclusively in children (5 cases per 100,000 persons), and a chronic form, observed mostly in adults (3-5 cases per 100,000 persons) and rarely in children.

This disease is caused by autoantibodies to platelets. The antigenic target in most patients appears to be the platelet glycoprotein IIb/IIIa complex. Platelets with antibodies on their surface are trapped in the spleen, where they are efficiently removed by splenic macrophages. The mechanism of origin of these antibodies is not known. These antibodies may be directed towards the viral antigens and then cross-react with platelet antigens. They persist because of the failure of immune surveillance mechanisms to repress these antibodies. These antibodies can also react with the developing megakaryocytes in bone marrow, leading to decreased protection of platelets (ineffective thrombopoiesis).

ITP occurs commonly in otherwise healthy individuals and only rarely as the initial manifestation of lupus and other autoimmune disorders. HIV infection is often associated with immune thrombocytopenia in both adults and children.

Acute ITP

This is a disease that occurs exclusively in children. It affects both sexes equally and has a peak incidence in children aged 3-5 years. Most patients have a history of antecedent acute viral syndrome.

Onset is sudden, with symptoms and signs depending on the platelet count. Bleeding is usually mild unless the platelet count drops below 20,000/µL. With platelet counts from 20,000-50,000/µL, petechiae and ecchymoses are observed following mild trauma. With platelet counts below 10,000/µL, generalized petechiae, ecchymoses, and mucosal bleeding occur. With platelet counts below 2000/µL, widespread ecchymoses, hemorrhagic bullae, and retinal hemorrhage occur.

Physical examination reveals only the presence of petechiae and ecchymoses. The presence of lymphadenopathy or splenomegaly suggests other secondary causes of thrombocytopenia rather than ITP.

The peripheral smear shows a decreased number of platelets. Often, the smear shows giant platelets, which is a reflection of increased thrombopoietin-induced stimulation of the bone marrow. At times, the smear may show eosinophilia and lymphocytosis, possibly reflecting hypersensitivity to the inciting viral antigens. The bone marrow shows an increase in the number of megakaryocytes and signs of thrombopoietin-induced megakaryocyte stimulation (increase in number and ploidy, decrease in cytoplasm) resulting in large platelets in the periphery.

Thrombocytopenia in an otherwise healthy child with normal white and red blood cell counts almost always results from ITP. Findings from a careful history and physical examination help exclude other causes of thrombocytopenia, such as lupus and HIV infection. Acute leukemia is unlikely to manifest as an isolated thrombocytopenia without any abnormalities in the smear. Bone marrow examination is necessary only if atypical features (other abnormalities in the smear, sternal tenderness, lymphadenopathy, splenomegaly) or an unusual clinical course is evident.

Chronic ITP

This is typically observed in adults aged 20-40 years. It has an insidious onset, and a history of an antecedent infection need not be present. Unlike childhood ITP, chronic ITP is more common in females than in males. As in childhood ITP, the bleeding manifestations depend on the platelet count.

The diagnosis of ITP is established by the exclusion of other causes of thrombocythemia. The peripheral blood film should be examined to rule out thrombotic thrombocytopenic purpura (TTP) (fragments) or spurious thrombocytopenia resulting from clumping. Often, the smear shows giant platelets, which is a reflection of the increased thrombopoietin-induced stimulation of bone marrow. Bone marrow examination, which is not always necessary, shows increased megakaryocytes.

Alloimmune thrombocytopenia

Posttransfusion purpura

Platelet glycoprotein IIb/IIIa is a major antigen in platelets and is polymorphic. Most individuals have leucine at position 33 (phospholipase A₁ [PLA₁]/PLA₁ or human platelet alloantigen [HPA]–1a). A small number of individuals, approximately 1-3% of random populations, have proline at position 33. Homozygotes with proline are termed phospholipase-negative (or HPA-1b, PLA₂/PLA₂), and, when they receive blood products from HPA-1a–positive individuals, they produce an antibody reactive against HPA-1a. This alloantibody destroys the transfused platelets and the patient's own platelets, leading to a severe form of thrombocytopenia that lasts for several weeks and, sometimes, several months.

Posttransfusion purpura typically occurs 10 days following a transfusion. This syndrome can be induced by a small amount of platelets contaminating a red blood cell transfusion or, occasionally, following fresh frozen plasma transfusion. The thrombocytopenia responds to intravenous immunoglobulin (IVIG). Other platelet alloantigens are occasionally implicated in posttransfusion purpura.

Neonatal alloimmune thrombocytopenia

The prevalence of neonatal alloimmune thrombocytopenia is approximately 1 case in 200 term pregnancies; for clinically apparent disease, the prevalence is 1 case in 1500 term pregnancies. It is the most common cause of severe neonatal thrombocytopenia. Maternal antibodies against the fetal platelet antigens, inherited from the father but absent in the mother, cross the placenta and induce severe thrombocytopenia. Most cases of neonatal alloimmune thrombocytopenia are due to platelet antigens HPA-1a observed in mothers who are HPA-1b. Less commonly, other platelet antigens, such as HPA-5b, are responsible for neonatal alloimmune thrombocytopenia. Thus, the pathophysiology of this disease is similar to that of the hemolytic disease of newborns. But unlike hemolytic disease, thrombocytopenia occurs during the first pregnancy in half the cases.

Typically, the diagnosis is considered when bleeding or severe thrombocytopenia occurs in a baby after an otherwise uncomplicated pregnancy. The affected infant may have intracranial hemorrhage, and the disorder is associated with a relatively high mortality rate. The platelet count should be checked immediately after delivery and 24 hours later as it continues to fall.

Drug-induced thrombocytopenia

Drugs can induce thrombocytopenia by a number of mechanisms. In addition to the cytotoxic drugs, thiazide diuretics, interferon, and alcohol can cause thrombocytopenia by inhibiting platelet production in the bone marrow. More commonly, drug-induced thrombocytopenia results from the immunological destruction of platelets. Drugs can induce antibodies to platelets, either acting as a hapten or as an innocent bystander. Also, drugs such as gold salts and interferon can induce an ITP-like disorder.

Common drugs associated with thrombocytopenia include quinidine, amiodarone, gold, captopril, sulfonamides, glibenclamide, carbamazepine, ibuprofen, cimetidine, tamoxifen, ranitidine, phenytoin, vancomycin, and piperacillin.

The diagnosis of drug-induced thrombocytopenia is often empirical. A temporal relationship must be present between the administration of the drug and the development of thrombocytopenia, with no other explanations for the thrombocytopenia. Recurrent thrombocytopenia following reexposure to the drug confirms the drug as the cause of thrombocytopenia. Identifying the drug that is causing severe thrombocytopenia in an acutely ill patient who is taking multiple drugs is often challenging. A complete list of all available reports of drug-induced thrombocytopenia is available at Platelets on the Internet.

Heparin causes a unique situation among drug-induced thrombocytopenias in that the antibodies also activate platelets and induce a hypercoagulable state.

Thrombotic thrombocytopenic purpura

TTP is a rare but serious disorder that was initially described as a pentad of thrombocytopenia (with purpura), red blood cell fragmentation, renal failure, neurological dysfunction, and fever. Recent evidence indicates that this disorder results from the abnormal presence of unusually large multimers of von Willebrand protein. These ultra-large precursors, normally synthesized in the endothelial cells, are processed by a plasma enzyme to normal-sized multimers. This enzyme is now identified as ADAMTS13, a metalloproteinase synthesized in the liver.

The sporadic forms of TTP are caused by an antibody or toxin inhibiting the activity of ADAMTS13. The chronic, recurrent form of TTP may result from a congenital deficiency of the enzyme. The ultra-large multimers are thought to induce the aggregation of platelets, causing platelet consumption. Occlusion of microvasculature by the platelets in the brain, kidney, and other organs leads to myriad symptoms. A TTP-like syndrome has been associated with lupus, pregnancy, HIV infection, and certain drugs (eg, quinine, ticlopidine, clopidogrel, cyclosporine, chemotherapeutic agents).

TTP is often associated with an episode of flulike illness 2-3 weeks before presentation. Most patients with TTP do not have the classic pentad. The most common presentation is petechiae and neurological symptoms. The neurologic symptoms can range from headache and confusion to seizures and coma. Fever is present in slightly more than half the patients.

Hemolytic uremic syndrome

Patients with hemolytic uremic syndrome (HUS) have vascular lesions indistinguishable from those observed in patients with TTP, but the renal vasculature endures the most lesions, with minimal neurological dysfunction. This is a catastrophic illness that predominantly affects children aged 4-12 months, sometimes affects older children, and rarely affects adults. It follows an upper respiratory tract infection. In the tropics, epidemics of HUS are frequent and resemble an infectious disease; however, no causative organism has been identified. In North America, Shigella-like toxins (secreted by Escherichia coli serotype 0157:H7 or Shigella dysenteriae serotype I) cause many cases of HUS. Diarrhea and abdominal cramps are very prominent symptoms.

Disorders of platelet function

Functional disorders of platelets are relatively rare, and most of these disorders are mild and may not be recognized early in life.

von Willebrand disease

von Willebrand disease is the most common inherited bleeding disorder. It is autosomal dominant, and its prevalence is estimated to be as high as 1 case per 1000 individuals.

The hallmark of von Willebrand disease is defective platelet adhesion to subendothelial components caused by a deficiency of the plasma protein vWf. This factor is a large, multimeric protein synthesized, processed, and stored in the Weibel-Palade bodies of the endothelial cells, and it is secreted constitutively following stimulation. vWf has a major role in primary hemostasis as mediator of the initial shear-stress–induced interaction of the platelet to the subendothelium via the glycoprotein Ib complex. In addition, von Willebrand protein acts as a carrier and stabilizer of coagulation factor VIII by forming a complex in the circulation. In the absence of vWf, the factor VIII level is low. In classic hemophilia A, the factor VIII level is low because of a deficiency of factor VIII itself, whereas in von Willebrand disease, the factor VIII level is low because of a deficiency in its carrier protein.

von Willebrand disease is a relatively mild bleeding disorder, except in the occasional patient who is homozygous for the defect and who has severe bleeding often indistinguishable from classic hemophilia. The bleeding manifestations are predominantly skin-related and mucocutaneous (ie, easy bruising, epistaxis, GI hemorrhage). Most bleeding episodes occur following trauma or surgery. In women, menorrhagia is common, often exacerbated by the concurrent administration of cyclooxygenase inhibitors. Pregnant patients with this disease usually do not have problems.

Bleeding time is prolonged in persons with von Willebrand disease. Because the von Willebrand protein is phase-reactant (ie, increased synthesis in the presence of inflammation, infection, tissue injury, and pregnancy), a mild prolonged bleeding time may be normalized, resulting in difficulty in diagnosis.

In addition to the prolonged bleeding time, characteristic abnormalities in platelet aggregation tests occur. In patients with von Willebrand disease, platelets aggregate normally to all agonists except ristocetin. The antibiotic ristocetin induces binding of the von Willebrand protein to platelets, similar to what happens with platelets following vessel wall injury in vivo. Ristocetin-induced platelet aggregation correlates with the platelet-aggregating activity of the von Willebrand protein. Levels of coagulation factor VIII are also low, resulting from a decrease in vWf.

Variants of von Willebrand disease

While the common form of von Willebrand disease (type I) results from a quantitative deficiency of vWf, the variants result from abnormalities in the von Willebrand protein.

A common variant (type IIA) results from functionally defective vWf that is unable to form multimers. Larger multimers are more active in mediating platelet vessel-wall interaction. In these variants, the factor VIII level may be normal.

In the type IIB variant, the von Willebrand protein has heightened interaction with platelets, even in the absence of stimulation. Platelets internalize these multimers, leading to a deficiency of von Willebrand protein in the plasma. A disorder of platelet glycoprotein Ib has also been described. In this condition, increased affinity for von Willebrand protein in the resting stage leads to the deletion of plasma von Willebrand protein. This disease is called pseudo von Willebrand disease or platelet-type von Willebrand disease.

Type III von Willebrand disease is a severe form of von Willebrand disease characterized by very low levels of vWf and clinical features similar to hemophilia A, but with autosomal recessive inheritance. It results from a homozygous state or double heterozygosity.

Bernard-Soulier syndrome

This syndrome results from a deficiency of platelet glycoprotein protein Ib, which mediates the initial interaction of platelets to the subendothelial components via the von Willebrand protein. It is a rare but severe bleeding disorder. Platelets do not aggregate to ristocetin. The platelet count is low, but, characteristically, the platelets are large, often the size of red blood cells, and may be missed because most automatic counters do not count them as platelets.

Glanzmann thrombasthenia

This results from a deficiency of the glycoprotein IIb/IIIa complex. Platelets do not aggregate to any agents except ristocetin. The more severe type I results from a complete absence of the glycoprotein IIb/IIIa complex, while in the milder type II, some of the glycoprotein IIb/IIIa complex is retained.

Both Bernard-Soulier syndrome and Glanzmann thrombasthenia are characterized by life-long bleeding. Although platelet transfusions are effective, they should be used only for severe bleeding and emergencies because alloantibodies often develop in these patients.

Disorders of secretion and thromboxane synthesis

During primary hemostasis, thromboxane synthesis and released ADP play a major role. A mild bleeding diathesis ensues if these mechanisms are deficient. Thromboxane synthesis disorders are almost always caused by aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs).

Mutations in the enzyme that converts arachidonic acid to thromboxane A₂ have been described and are associated with a life-long bleeding diathesis. Similarly, an absent or defective receptor for thromboxane A₂ also leads to an aspirinlike aggregation defect. In disorders of release reaction, platelets fail to secrete proaggregatory ADP following activation. The defects result from either the absence of granules in platelets or the defective storage of ADP. ADP is present in the dense granules of platelets as a storage pool, which is not used in the normal metabolic activity of platelets (in contrast to the metabolic pool). These disorders are often associated with other systemic abnormalities (eg, Hermansky-Pudlak syndrome).

Disorders of secretion and thromboxane synthesis

These are mild platelet disorders and often respond to desmopressin (DDAVP) infusion, which seems to improve hemostatic function. If severe bleeding is present, these disorders can also be managed effectively with platelet transfusions. Cryoprecipitate has also been reported to be very effective.

Platelet dysfunction in uremia

Abnormal bleeding is common in patients with uremia. The bleeding has the characteristics of a platelet disorder, and GI tract bleeding is the most frequent symptom.

Bleeding time is generally very prolonged in patients with uremia, signifying a major defect in platelet function, which improves after dialysis. A number of dialyzable platelet-inhibitory factors have been shown to inhibit platelet function. Furthermore, uremic platelets synthesize less thromboxane A₂, and the blood vessels taken from patients with uremia produce greater quantities of platelet-inhibitory prostaglandin. Nitric oxide produced by the endothelial cells inhibits platelet function. Because the prolonged bleeding time and the hemostatic abnormalities are partly corrected by red blood cell transfusion or erythropoietin therapy, the failure of hemoglobin to quench excess nitric oxide synthesis has been suggested as partly responsible for the platelet dysfunction.

Frequency

United States

Inherited hemostatic disorders are relatively rare. The prevalence of von Willebrand disease has been estimated at 1 case per 1000-5000 individuals. Acquired hemostatic disorders are common, and ITP is one of the most common autoimmune disorders. It occurs in 2 distinct clinical types, an acute self-limiting form observed almost exclusively in children (5 cases per 100,000 individuals), and a chronic form, observed mostly in adults (3-5 cases per 100,000 individuals) and rarely in children.

Sex

• Unlike hemophilia, most inherited disorders of platelets are not X-linked and are equally distributed in both sexes.
• Chronic autoimmune thrombocytopenia is more common in females than in males.
• Acute ITP is observed equally in both sexes.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• History and physical examination findings help distinguish between primary and secondary hemostatic disorders and whether the disorder is inherited or acquired.
• Epistaxis is common in individuals with primary hemostatic disorders, but it is also common in healthy individuals. Details about the frequency, duration, packing requirement, and prior treatment (cautery or transfusion) are helpful for assessing the severity of bleeding.
• Bleeding gums is a common symptom in persons with primary disorders of hemostasis. Bleeding could be spontaneous or could be associated with brushing or flossing.
• Bleeding from tooth extractions is possible. A molar tooth extraction is a traumatic procedure. Uneventful extraction of a molar is unlikely in a patient with a severe bleeding disorder.
• Hemoptysis, hematemesis, hematuria, hematochezia, and melena are rarely the initial symptoms of a bleeding disorder. However, these may be exacerbated by an underlying bleeding disorder.
• Menstrual history is important. Metromenorrhagia is often observed in individuals with primary hemostatic disorders. This is especially common in patients with von Willebrand disease and is often exacerbated by the NSAIDs used to treat dysmenorrhea.
• Bleeding after childbirth may be the first manifestation of a mild bleeding disorder.
• Bleeding in the joints is the hallmark of hemophilia and other secondary hemostatic disorders.
• Details of previous surgery, including the amount of blood transfused, if any, are helpful.
• In males, excessive bleeding following circumcision is often the initial manifestation of a congenital bleeding disorder.
• Delayed bleeding from the umbilical stump is characteristic of a factor XIII deficiency.
• Defective wound healing is observed in individuals with a factor XIII deficiency and abnormal fibrinogens.
• Medication history findings may be helpful because aspirin often accentuates a preexisting bleeding disorder. A history of previous iron therapy for anemia may be useful.

Physical

• A careful physical examination often reveals signs of a hemostatic disorder (see Image 2).
• Bruising is common in individuals with a platelet disorder.
• Petechiae are pinpoint hemorrhages (<2 mm) in the skin, and purpura (0.2-1 cm) and ecchymoses are larger hemorrhages. The purpura is not palpable, in contrast to the palpable and sometimes tender purpura observed in patients with vasculitis. Initially, purpura tends to form in the areas of increased venous pressure, such as the legs. Petechiae and purpura may develop following the application of a sphygmomanometer.
• Splenomegaly is not observed in the typical patient with ITP. The spleen can engulf platelets and be several times normal size without becoming palpably enlarged.
• Hemarthrosis and deep muscle hematomas are unusual in patients with primary hemostatic disorders.

Causes

• Platelet defects can be considered either as a decreased number of platelets (thrombocytopenia) or as defective platelets. Platelet aggregation tests are useful in differentiating various disorders of platelet function. Spurious thrombocytopenia can occur due to aggregates forming in the specimen. Also, dilutional thrombocytopenia may occur in situations of fluid replacement or blood component replacement without platelet support. In all cases of thrombocytopenia, the peripheral blood smear must be reviewed to confirm the thrombocytopenia. This review is crucial.
• Thrombocytopenia can be further divided into increased destruction or decreased production. Thrombocytopenia resulting from increased destruction occurs either by an immune mechanism or increased consumption. Platelets are consumed intravascularly by the activation of the coagulation process (diffuse intravascular coagulation [DIC]) or by deposition on damaged endothelial cells (microangiopathy). Production defects result from those diseases that cause bone marrow failure, such as aplastic anemia, infiltration by leukemia or another malignancy, fibrosis or granulomatous disorders, or tuberculosis.
• Functional disorders of platelets can be inherited (rare) or acquired (common).
• Causes of thrombocytopenia related to increased destruction include (1) immune thrombocytopenias (eg, autoimmune, alloimmune, drug-induced) and (2) increased consumption (eg, DIC, TTP).
• Causes of thrombocytopenia related to decreased production include bone marrow depression.
• Disorders of platelet function are as follows:
• • Disorders of platelet adhesion (von Willebrand disease, Bernard-Soulier syndrome)
  • Disorders of aggregation (Glanzmann thrombasthenia)
  • Disorders of secretion
  • Disorders of thromboxane synthesis
  • Acquired disorders of platelet function (drugs, eg, aspirin, NSAIDs, alcohol)
  • Uremia
  • Paraproteins
  • Fibrin degradation products
  • Myelodysplasia or a myeloproliferative syndrome

WORKUP

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Peripheral smear
• • Careful examination of the peripheral smear is essential in a patient with thrombocytopenia.
  • Spurious thrombocytopenia due to platelet clumping or platelets adhering to neutrophils (platelet satellitism) can be seen in the smear (see Image 3).
  • Giant platelets are often seen in persons with ITP (see Image 4).
  • Rare disorders, such as Bernard-Soulier syndrome, can be diagnosed based on the results from the peripheral smear (see Image 5). Examination of the smear is essential to exclude TTP and rare instances of acute leukemia.
  • In TTP, a striking degree of red blood cell fragmentation is seen in addition to thrombocytopenia (see Image 6).
• Platelet-associated immunoglobulin G
• • The autoantibodies responsible for autoimmune thrombocytopenia do not induce complement-mediated lysis. Furthermore, when platelets are destroyed in the circulation, they internalize plasma proteins, including immunoglobulin. Platelets also have low affinity to the crystallizable fragment (Fc) receptor, FcgRIIa, that binds immunoglobulin.
  • In patients with autoimmune thrombocytopenia, the larger platelets have proportionately more membrane surface than the Fc receptor.
  • For these reasons, the detection of increased platelet-associated immunoglobulin is not specific for ITP because it is observed in a variety of conditions associated with thrombocytopenia, which limits the value of this test in the diagnosis of ITP. Specialized tests to identify antibodies reacting specifically against platelet membrane glycoproteins are not clinically available.
• Test of primary hemostasis bleeding time
• • This is a valuable test for disorders of primary hemostasis.
  • It is performed by measuring the duration required for bleeding to stop from a fresh superficial cut (1 mm deep, 1 cm long) made on the volar surface of the forearm using a template under standard conditions.
  • Under these conditions, the cessation of bleeding results from the formation of a primary hemostatic plug. A fairly linear correlation exists between bleeding time and platelet counts of 10,000-100,000/µL.
  • A prolonged bleeding time with a normal platelet count is very significant and indicates a qualitative platelet disorder.
  • In disorders of secondary hemostasis (eg, hemophilia A and B), bleeding time is almost invariably normal.
  • Bleeding time is prolonged when platelet counts indicate fewer than 75,000/µL and do not provide any further information.
  • This test should not be performed on patients with thrombocytopenia.
  • This test is highly operator-dependent and is not recommended as a routine screening test.
• In vitro platelet function analyzer 100
• • The platelet function analyzer 100 (PFA-100) is a bench-top automated instrument that assesses primary hemostasis under shear stress.
  • The PFA-100 uses a disposable test cartridge that contains a membrane impregnated with collagen plus ADP (Col/ADP membrane) or epinephrine (Col/Epi membrane). A blood sample of 0.8 mL of citrated blood is placed in a cup and is aspirated through the aperture. The shear stress and the agonists in the membrane activate platelets, leading to platelet aggregation.
  • The end point, expressed as closure time, is when blood flow stops because of occlusion of the aperture by platelet aggregates.
  • The platelet aggregate formation depends on (1) vWf binding to collagen-coated nitrocellulose membranes, (2) platelet adhesion to vWf via platelet glycoprotein Ib platelet activation, and (3) platelet aggregation mediated by the interaction of glycoprotein IIb/IIIa with vWf and fibrinogen.
  • Normal closure times range from 77-133 seconds for the Col/ADP membrane and 98-185 seconds for the Col/Epi membrane.
  • The PFA-100 has been tested in persons with bleeding disorders. The closure time using the Col/Epi cartridge is abnormal in patients with congenital platelet function defects, von Willebrand disease, or aspirin ingestion, while the closure time with the Col/ADP cartridge is abnormal mainly in patients with von Willebrand disease or congenital disorders.
  • Aspirin prolongs the closure time 94% of the time with the Col/Epi cartridge and only 27% of the time with the Col/ADP cartridge. Glanzmann thrombasthenia, Bernard-Soulier syndrome, and most mild von Willebrand diseases are associated with a prolonged closure time with both cartridges, while a storage pool defect and giant platelet thrombopathy have a prolonged closure time only with the Col/Epi cartridge.
  • The advantages of this instrument include simplicity and reproducibility. The PFA-100 has been reported to have a coefficient of variation of less than 10%. It may be useful for determining global platelet function and for assessing the efficacy of antiplatelet therapy.
• Platelet aggregation
  • Platelet aggregation is measured by turbidimetric methods.
  • When platelets aggregate, the opalescent suspension of platelet-rich plasma becomes clearer and allows more light transmission. The extent of aggregation is determined by measuring the increase in light transmission.
  • Small doses of ADP ( <1 µmol) induce a reversible form of platelet aggregation (primary wave), unaccompanied by thromboxane synthesis or release of intraplatelet ADP. However, with increasing doses of ADP, sufficient stimulation of platelets occurs and leads to the release of intraplatelet ADP and the synthesis of thromboxane A₂ from arachidonic acid, thus resulting in more pronounced irreversible aggregation (secondary wave).
  • Ristocetin induces platelet aggregation by inducing von Willebrand protein binding to the platelet glycoprotein Ib complex.
  • Platelet aggregation tests are useful in distinguishing different disorders of platelet function. They are also particularly useful in the diagnosis of von Willebrand disease, in which ristocetin-induced platelet aggregation is defective.

Imaging Studies

• Imaging studies are not necessary to diagnose uncomplicated ITPs.
• Rarely, platelet survival studies may be necessary to document decreased platelet survival before splenectomy in a patient with possible bone marrow hypofunction. Typically, the platelet half-life is decreased from the normal 5-7 days. A normal platelet survival curve is not consistent with increased splenic destruction.
• In a patient who has relapsed following splenectomy, an indium-labeled platelet imaging study is sometimes useful for localizing an accessory spleen.

Other Tests

• Bone marrow examination is not necessary in most cases of platelet disorders. The isolated presence of large platelets in the peripheral blood, in the absence of any other signs of bone marrow dysfunction, is very suggestive of normal marrow activity.
• Bone marrow examination is necessary in patients who have an atypical course, have splenomegaly, or will undergo splenectomy.
• Bone marrow examination in patients with ITP shows megakaryocytic hyperplasia (see Image 7). Quantifying the megakaryocytes in the bone marrow is technically difficult. Usually, 2-3 megakaryocytes are present in each spicule in typical marrow. Clusters of immature megakaryocytes are often observed in patients with ITP.

TREATMENT

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• Treatment of acute ITP in children
  • Because acute ITP in children is self-limited, most physicians do not routinely treat it.
  • Treatment is necessary only to prevent intracranial or other serious internal hemorrhage. The rate of intracranial hemorrhage is very low, possibly less than 0.1%, and occurs with platelet counts of 10,000-20,000/µL. Most physicians arbitrarily treat children with ITP when their platelet count indicates fewer than 20,000/µL.
  • Intravenous immunoglobulin G (IgG) (0.8-1 g/kg for 2 d) results in a prompt rise in the platelet count, and this response confirms the diagnosis. The mechanisms of action of intravenous gamma globulins are not clear. Suggested mechanisms include blocking the macrophage Fc receptors, suppressing autoantibody production by providing antiidiotypes, and stimulating the clearance of autoantibodies. The adverse effects of IgG include fever, nausea, vomiting, and, occasionally, renal failure. IgG is also very expensive compared with prednisone and is not available in all countries.
  • Oral prednisone (4 mg/kg, with tapering and discontinuation by day 21) or intravenous methylprednisolone (30 mg/kg for 3 d) is also effective, although intravenous IgG provides the quickest recovery. The mode of action of prednisone is probably multifold, decreasing antibody production, increasing platelet formation, decreasing macrophage-mediated clearance of platelets in the spleen, and immunomodulating the immune response.
  • The combination of steroids and IVIG is synergistic and can be used in patients with imminent hemorrhage.
  • Inducing a mild hemolytic state by administering anti-D immunoglobulin (25-50 mcg/kg for 2 d) is also effective in individuals who are Rh positive. This therapy is less expensive than IVIG, and the limitations include a dose-dependent mild anemia, inapplicability in individuals who are Rh negative, and a limited response in patients who have undergone splenectomy.
  • With these modalities, the platelet counts in most children could be maintained at more than 30,000/µL until spontaneous remission occurs.
  • Other supportive measures include avoiding drugs that impair platelet function (eg, aspirin) and avoiding competitive contact sports.
  • A small minority of children do not undergo spontaneous remission and have a chronic course with remissions and relapse similar to adult-onset chronic ITP.
  • These patients are treated similarly to adults with chronic ITP, except that splenectomy should be avoided if possible because spontaneous remissions frequently occur. Furthermore, splenectomy when the patient is younger than 6 years is associated with severe postsplenectomy sepsis. The American Society of Hematology recommends splenectomy for children only if they have had ITP longer than 1 year and their bleeding results in platelet counts below 30,000/µL.
  • These children should receive pneumococcal and Haemophilus influenzae vaccines before splenectomy, and many physicians recommend a prophylactic antibiotic regimen after splenectomy. Long-term therapy with repeated infusions of intravenous IgG or anti-D immunoglobulin is being tried, with the hope that it can induce a lasting remission and eliminate the need for splenectomy.
• Treatment of chronic ITP in adults
  • No consensus has been reached regarding when to start steroid therapy for chronic ITP in adults and how long to treat it.
  • Most physicians elect to not treat patients unless their platelet count is below 50,000/µL or bleeding manifestations are present.
  • A course of steroid therapy is often administered upon the initial diagnosis in an effort to induce a sustained remission. The treatment of choice is oral prednisone, usually administered in a dose of 1 mg/kg. Approximately two thirds of patients can be expected to show a therapeutic response with steroid therapy.
  • Steroids are usually continued until the platelet count reaches normal or over 50,000, and then they are gradually tapered in 4-6 weeks.
  • Methylprednisone (30 mg/kg IV days 1-3, tapered every third day to 1 mg/kg) has also been used with similar results.
  • In a more recent study, a 4-day course of high-dose dexamethasone (40 mg/d) has been reported as an effective initial therapy for adults with ITP, with 50% of patients showing sustained platelet count of over 50,000.
  • In general, only 15-25% of patients are expected to have lasting remission; the remainder have disease characterized by frequent relapses and remissions.
  • Unlike in children, IVIG does not induce an early rise in platelet counts in adults and does not have an advantage over steroids as an initial therapy.
  • Even if the platelet count normalizes, many patients can maintain platelet counts of more than 20,000-30,000/µL with lower doses of steroids during times of relapse. However, in approximately one third of patients with chronic ITP, steroids are not effective, either because of a failure in response or a steroid requirement that leads to unacceptable adverse effects (eg, glucose intolerance, GI bleeding).
  • The second line of treatment for the management of steroid failures is splenectomy. Splenectomy is considered for any patient who does not respond to steroids (or who cannot receive steroids) and has clinically significant bleeding manifestations.
  • The appropriate time to perform the splenectomy is controversial. Most physicians wait for 3-6 months before recommending splenectomy because sometimes ITP goes into spontaneous remission, especially in younger patients. Often, other clinical considerations (eg, coexistence of diabetes or peptic ulcer disease) may influence the decision for earlier splenectomy.
  • Splenectomy is effective because it removes the major site of destruction and the major source of antiplatelet antibody synthesis.
  • Before splenectomy, patients should receive a pneumococcal vaccine.
  • Even if complete remission is not achieved, the platelet count will be higher after splenectomy.
  • Intravenous IgG (1 g/kg/d for 1-2 d) induces a short-term increase in the platelet count, starting within several days and lasting approximately 2-3 weeks, both in patients who have undergone splenectomy and in those who have not. No clear evidence indicates that repeated infusions induce a lasting remission. Significant adverse effects include hypotension and renal failure.
  • Anti-D immunoglobulin (WinRho, 50-75 mcg/kg IV) is also as effective as intravenous immunoglobulin in Rh positive adults with an intact spleen. Rarely, massive intravascular hemolysis with disseminated intravascular coagulation and occasional death has occurred with use of anti-D immunoglobulin.
  • Both intravenous IgG and anti-D immunoglobulin are relatively expensive therapy for adults compared with steroids and is primarily used to on an interim basis during a crisis (eg, before splenectomy or major surgery).
  • Approximately 10-20% of patients who undergo splenectomy remain thrombocytopenic and continue to have a bleeding risk that requires continued treatment. Both steroid therapy and splenectomy are considered failures in these patients, and the patients are challenging to treat. An accessory spleen should be excluded as the cause of treatment failure after splenectomy.
  • Limited benefit may be observed using immunosuppression with cytotoxic agents. Azathioprine (150 mg/d) or cyclophosphamide (50-100 mg/d) has been used with some success. These cytotoxic drugs can cause myelosuppression, alopecia, hemorrhagic cystitis (cyclophosphamide [Cytoxan]), sterility, and secondary malignancy. These drugs are given for a minimum duration and are withdrawn as soon as remission is achieved. Blood counts must be monitored during therapy.
  • Vincristine infusion (0.02 mg/kg) with a maximum dose of 2 mg every week for 3 weeks has also been shown to induce remission.
  • Rituximab, a monoclonal antibody directed against the lymphocyte antigen, has been reported to induce remission in refractory ITP.
  • Recently, several studies have reported improved platelet counts in patients with Helicobacter pylori–positive ITP following standard H pylori eradication therapy, with cohorts from Japan and Italy reporting higher response rates. Several explanations, such as molecular and immunomodulation by macrolides, have been provided.
  • A number of treatments have been proposed for splenectomy and steroid failures. Most of them are not based on placebo-controlled studies, and evaluating the efficacy of these treatments in a disease associated with spontaneous remissions and relapse is difficult. The anabolic steroid danazol (400-800 mg/d) has been shown to induce remission in certain patients. Cyclosporine and alfa-interferon have also been used. Plasmapheresis and extracorporeal protein A adsorption have been tried in desperate situations. The autoantibodies responsible for ITP are primarily IgG, and plasmapheresis is of limited value because more than half of the normal IgG pool is in the extravascular space.
  • Refractory ITP has also been treated with combination chemotherapy used for low grade non-Hodgkin lymphoma (6 cycles of cytoxan, vincristine, and prednisone with some success). Other evolving therapies for refractory ITP include autologous hematopoietic stem cell transplantation and anticytokine therapy with etanercept.
• Treatment of alloimmune thrombocytopenia in neonates
  • If left untreated, thrombocytopenia persists from a few days to up to 3 weeks.
  • The treatment of choice is the administration of IVIG and maternally compatible platelets. Maternal platelets should be radiated to avoid graft versus host disease in the infant and washed to reduce the antibody concentration.
  • Response to steroids is rare.
• Therapy for TTP
  • TTP is a medical emergency, and prompt recognition and immediate initiation of plasma exchange is necessary.
  • The minimum criteria for the diagnosis of TTP are thrombocytopenia and microangiopathic hemolytic anemia without an apparent etiology.
  • Examination of the smear shows thrombocytopenia and a microangiopathic picture (characteristic helmet cells and basophilic red blood cells). The lactic dehydrogenase (LDH) level is high, with brisk reticulocytosis. Signs of intravascular coagulation are characteristically absent in patients with TTP.
  • Plasma exchange therapy introduced 20 years ago has changed the outlook of this once serious disorder.
  • Current mortality rates remain approximately 20%, compared with the greater than 90% mortality rate observed before the advent of plasma exchange therapy.
  • Plasma exchange (3-5 L/d) is instituted promptly and continued daily until the patient's platelet count is normalized and the LDH level is within the reference range. Until plasma exchange is instituted, fresh frozen plasma should be administered. Several weeks of plasma exchange may be required before a durable remission is achieved.
  • Antiplatelet agents have not been shown to alter the natural history of the disease.
  • Milder forms of TTP may respond to steroids.
  • Patients who relapse frequently or patients who require large volumes of replacement therapy are candidates for splenectomy. Splenectomy decreases the rate of relapse in patients with chronic relapsing forms of the disease.
  • Anecdotal reports indicate TTP responding to vincristine infusions, intravenous IgG, and staphylococcal protein A adsorption.
  • Therapy for HUS is directed towards the underlying process.
  • Acute and chronic renal failure is managed with fluid and electrolytes and, if necessary, dialysis. Plasma exchange therapy is often administered, but whether this is beneficial remains unclear. Antiplatelet and anticoagulant therapies have been attempted but do not show a marked benefit.
• Severe thrombocytopenia with bleeding
  • A bleeding patient with a very low platelet count is a medical emergency.
  • The presence of hemorrhagic bullae in the buccal mucosa and retinal hemorrhages are harbingers of internal and intracranial bleeding.
  • Diseases that cause such severe thrombocytopenia are ITP, TTP, posttransfusion purpura, drug-induced thrombocytopenia, and aplastic anemia. Differentiating TTP from ITP is very important because platelet transfusions are contraindicated in patients with TTP and plasma exchange therapy should be initiated as soon as possible in patients with TTP.
  • Careful examination of the peripheral smear helps differentiate ITP from TTP. Furthermore, the presence of neurological signs, renal failure, fever, and a high LDH level also helps in the diagnosis of TTP.
  • The patient's medication history should be reviewed, and drug-induced thrombocytopenia should be considered if a temporal relationship exists between thrombocytopenia and drug exposure.
  • Patients with liver disease and those who abuse alcohol often present with severe thrombocytopenia following binge drinking. These patients may have severe thrombocytopenia resulting from splenomegaly, alcohol-induced suppression of platelet production, folate deficiency, and DIC from active liver disease.
  • Aplastic anemia is associated with pancytopenia, and the smear examination findings help differentiate it from ITP.
  • Once the diagnosis of ITP with clinically significant bleeding is established, treatment with steroids (intravenous methylprednisolone at 30 mg/kg) and IVIG should be started immediately.
  • Platelet transfusions are administered to patients with severe clinical bleeding, and a sustained increase in platelet counts is sometimes observed in those with ITP.
  • Currently, emergency splenectomy is rarely necessary and is only considered prior to an emergency operation such as evacuation of an intracranial hematoma.
• von Willebrand disease
  • DDAVP is a vasopressin analog that releases vWf from endothelial cells.
  • Most patients with type I von Willebrand disease can be treated with DDAVP for minor surgeries and dental procedures. The usual dose is 0.3 mcg/kg infused slowly approximately 30 minutes before an operative procedure. This dose can be repeated once a day for 2-3 days, after which it is ineffective because of tachyphylaxis. Other adverse effects occasionally include a hypertensive response and hyponatremia.
  • Recently, an intranasal preparation of DDAVP was made available for individuals with von Willebrand disease and is administered at a dose of 150 mcg or 300 mcg (ie, 150 mcg per nostril). The more diluted preparation is used in patients with diabetes insipidus and does not increase vWf levels.
  • DDAVP does not usually increase factor VIII levels in patients with type IIA and can induce thrombocytopenia in patients with type IIB or pseudo von Willebrand disease.
  • Replacement therapy is used for more extensive surgeries or trauma and for patients with type II and type III disease. The treatment of choice is vWf concentrates. (Humate-P or Alphanate). These preparations are heat-treated, and the solvent is extracted; therefore, they are considered more virally safe. The dose is calculated based on ristocetin cofactor units (usual dose is 50-100 U/kg). The factor VIII level often rises following the infusion of von Willebrand protein concentrate, and it remains elevated for at least for 40 hours, reflecting the half-life of von Willebrand protein rather than factor VIII. The need for further doses is often assessed based on clinical criteria rather than blood test results.
  • Cryoprecipitate has approximately 100 U of factor VIII per bag and has all multimeric forms of vWf. Despite screening tests, patients have a small risk developing viral infections.
  • Highly purified preparations of factor VIII or recombinant factor VIII should not be administered to patients with von Willebrand disease because these preparations have very little von Willebrand protein.
• Uremic bleeding
  • The most effective therapy for this platelet dysfunction is vigorous dialysis.
  • For a more immediate correction, DDAVP and cryoprecipitate have also been shown to be useful in providing hemostasis. These modalities provide a short-term benefit until dialysis corrects the hemostatic defects.
  • In addition to effective dialysis, conjugated estrogen has been shown to decrease bleeding in patients with uremic hemorrhages.

MEDICATION

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Steroids are the mainstay of the initial treatment of ITP in adults, while intravenous gamma globulins are used in children.

Drug Category: Corticosteroids

Inhibit macrophage-induced platelet phagocytosis and have immunosuppressive effects on antiplatelet antibody production by lymphocytes.

Drug Category: Intravenous immunoglobulins

Impair clearance of platelets by macrophages.

Drug Category: Anabolic steroids

Suppress macrophage-mediated platelet destruction and inhibit platelet antibody production.

Drug Category: Chemotherapeutic agents

Vincristine strongly binds to platelets. Phagocytosis of platelet-bound vincristine by macrophages in ITP delivers drug in high concentration and leads to macrophage dysfunction.

Drug Category: Synthetic hormones

Used to improve platelet function in qualitative disorders.

Drug Category: Immunosuppressive agents

Benefit observed with immunosuppression. Given for minimum duration and withdrawn as soon as remission achieved. Blood counts must be monitored.

Drug Category: Antihemorrhagics

For use in patients with blood-product deficiencies.

Drug Category: Antithrombotic agents

Thrombin, the end product of the coagulation mechanism, initiates transformation of fibrinogen to a fibrin clot and activates platelets.

FOLLOW-UP

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Prognosis

• ITP is generally a benign disorder. Severe ITP with a platelet count of fewer than 5000/µL is occasionally associated with fatal hemorrhages in the brain or internal organs. Patients who are elderly, those whose disease is refractory to treatment who have a prior history of hemorrhage, and patients with concomitant bleeding disorders (hemophilia and uremia) are at higher risk for serious life-threatening hemorrhage.
• TTP is a very serious disorder. With the introduction of plasma exchange therapy, the prognosis is better but mortality rates remain approximately 20%.
• Among congenital bleeding disorders involving platelets, type III von Willebrand disease and type I Glanzmann thrombasthenia are severe diseases associated with life-long hemorrhages. Most other platelet disorders are mild bleeding disorders.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Patients with severe thrombocytopenia and bleeding require emergent medical care. Intracranial bleeding can occur in patients with platelet counts lower than 5000/µL and can be avoided by prompt therapy. TTP should be distinguished from ITP before platelet transfusions because a worsening of clinical manifestations occurs in patients with TTP who receive platelet transfusions. These patients should be admitted and monitored carefully. Reviewing the peripheral smear to exclude spurious thrombocytopenia is crucial, as is identifying the presence or absence of fragmented erythrocytes (schistocytes), an important component of TTP.
• The optimum management of ITP during pregnancy remains controversial. A platelet count of 30,000/µL is adequate for vaginal delivery, and a count lower than 50,000/µL is adequate for cesarean delivery. One of the major concerns in pregnancy is the prevention of intracranial hemorrhage in the infant during delivery. No safe test is available to help predict the outcome in the fetus. Most studies have shown severe neonatal thrombocytopenia is rare.
• Patients who have undergone splenectomy should be warned about the low risk of severe sepsis following splenectomy. These patients should be immunized with pneumococcal vaccine before splenectomy.

Special Concerns

• The major causes of thrombocytopenia in pregnant women are immune thrombocytopenia, incidental thrombocytopenia of pregnancy (gestational thrombocytopenia), and hypertensive disorders of pregnancy.
• ITP during pregnancy
• • The optimal management of ITP during pregnancy is considerably controversial. Most pregnant women with ITP are treated with steroids and have relatively few complications involving the fetus and mother. Patients who are resistant to prednisone can be treated with intravenous gamma globulin. Splenectomy has been performed during pregnancy but should be avoided whenever possible. A platelet count of 50,000/µL is usually sufficient for major surgeries, including splenectomy and cesarean delivery.
  • The overriding concern is thrombocytopenia developing in the fetus. The IgG autoantibodies in ITP can cross the placenta and may cause thrombocytopenia in the fetus. In most recent studies of ITP complicating pregnancy, severe fetal thrombocytopenia is uncommon. However, thrombocytopenia is occasionally observed in infants born from mothers who have thrombocytopenia. No laboratory parameter helps predict the platelet count in the fetus. Prior obstetrical history is the only useful predictor. The platelet count of the fetus before delivery can be determined by fetal scalp sampling or percutaneous cord blood sampling. However, these are invasive procedures associated with serious complications, carrying a risk of intracranial hemorrhage similar to or higher than that of ITP due to neonatal thrombocytopenia. Further, platelets are often clumped, leading to spuriously low platelet count and unnecessary cesarean delivery.
• Gestational thrombocytopenia
  • This form of thrombocytopenia is defined as mild thrombocytopenia in an otherwise healthy pregnancy. How this can be distinguished from a mild form of ITP is not clear.
  • This disorder does not result in infants developing thrombocytopenia.
• Hypertensive disorders of pregnancy
• • These disorders of pregnancy (ie, preeclampsia/eclampsia syndrome) are associated with increased platelet turnover, even when the platelet count is normal. Controlling hypertension and delivering the fetus lead to restoration of the platelet count.
  • Occasionally, thrombocytopenia is associated with hemolysis and elevated liver enzymes (ie, hemolysis, elevated liver enzymes, and low platelet [HELLP] syndrome). This serious disorder often mimics TTP.

MULTIMEDIA

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Media file 1:  Normal hemostasis.
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Media file 2:  Purpuric spots.
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Media file 3:  Spurious thrombocytopenia. Peripheral smear of a patient reported to have platelet counts of 10,000-150,000/mL on various occasions. The smear shows clumping of the platelets and satellitism involving neutrophils and platelets.
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Media file 4:  Examination of the peripheral smears in immune thrombocytopenic purpura often shows giant platelets. These platelets reflect the increased megakaryocytic mass in the marrow.
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Media file 5:  Peripheral smear of a patient with Bernard-Soulier syndrome showing giant platelets. These platelets are not counted as platelets in most particle counters.
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Media file 6:  Examination of the peripheral smear shows red blood cell fragments, basophilic cells, in addition to thrombocytopenia in thrombotic thrombocytopenic purpura.
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Media file 7:  Bone marrow in immune thrombocytopenic purpura. Bone marrow examination reveals an increased number of megakaryocytes.
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REFERENCES

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• Amiral J, Meyer D. Heparin-induced thrombocytopenia: diagnostic tests and biological mechanisms. Baillieres Clin Haematol. Jun 1998;11(2):447-60. [Medline].
• Blanchette V, Imbach P, Andrew M, et al. Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet. Sep 10 1994;344(8924):703-7.