Excerpt from Platelet Disorders

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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.

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