Angeles University FoundationSchool of MedicineDepartment of Pathology

Basilio, Mary A.December 3, 2014

A. Idiopathic (Autoimmune) Thrombocytopenic Purpura

Idiopathic thrombocytopenic purpura (ITP) is a syndrome in which antibodies against platelet or megakaryocytic antigens cause thrombocytopenia. It is, thus, more fittingly called immune thrombocytopenic purpura. ITP occurs in two forms: an acute, self-limited, hemorrhagic syndrome in children and a chronic bleeding disorder in adolescents and adults. The autoantibodies often recognize the platelet membrane glycoproteins, Gp IIb/IIIa or Ib/IX, which are involved in platelet adhesion and clot formation.PATHOPHYSIOLOGYLike autoimmune hemolytic anemia, ITP reflects antibody- mediated destruction of platelets or their precursors. In most cases, these are IgGs, but IgM antiplatelet antibodies also occur. Acute ITP typically appears in children of either sex after a viral illness and is likely caused by virus-induced changes in platelet antigens that elicit autoantibodies. Complement bound at the surface lyses platelets in the blood or mediates their phagocytosis and destruction by splenic and hepatic macrophages.Chronic ITP occurs mainly in adults (male-to-female ratio of 1:2.6) and may be associated with autoimmune (e.g., systemic lupus erythematosus) or malignant lymphoproliferative (e.g., chronic lymphocytic leukemia) diseases. It is also common in people infected with HIV. The magnitude of thrombocytopenia in ITP reflects the balance between (1) levels of antiplatelet antibodies; (2) the extent to which platelet production in the marrow is impaired, as some antibodies may bind to megakaryocytes; and (3) expression of Fc and complement receptorsat macrophage cell surfaces. This expression is upregulated in infection and pregnancy but is restored by certain drugs, for example, corticosteroids, danazol and intravenous globulin, all of which are used to treat ITP.PATHOLOGYIn acute ITP, the platelet count is typically less than 20,000/uL. In chronic adult ITP, platelet counts vary from a few thousand to 100,000/uL. Peripheral blood smears show many large platelets, owing to accelerated release of young platelets by bone marrow actively engaged in platelet production. Bone marrow thus shows compensatory increases in megakaryocytes. Platelets carry detectable IgG in more than 80% of patients with chronic ITP; in half of these, platelet-associated C3 is also detectable.

CLINICAL MANIFESTATIONSChildren with acute ITP experience sudden onset of petechiae and purpura but are otherwise asymptomatic. Spontaneous recovery occurs within 6 months in over 80% of cases. The major threat (>1% of cases) is intracranial hemorrhage. Treatment is rarely necessary, but with serious disease, corticosteroids and intravenous immunoglobulin may be needed. Glucocorticoids decrease antiplatelet antibody production and downregulate macrophage Fc receptors. Globulin inhibits clearance of IgG-coated platelets from the circulation via multiple mechanisms. Chronic ITP in adults manifests as bleeding episodes, such as epistaxis, menorrhagia or ecchymoses, and excessive bleeding after trauma and minor procedures (e.g., tooth extraction). Life-threatening hemorrhages are uncommon. Occasionally, asymptomatic people are discovered to have thrombocytopenia on a routine blood cell count. Most adults with chronic ITP improve with corticosteroids and intravenous globulin. Danazol (a synthetic anabolic steroid) acts like glucocorticoids. In 70% of patients who do not respond adequately to drug therapy within 23 months, splenectomy produces complete or partial remission. For patients with severe ITP, ongoing studies are testing the efficacy of thrombopoietic agents that activate the TPO receptor.

A section of the bone marrow reveals increased megakaryocytes.

B. Thrombotic Thrombocytopenic PurpuraThrombotic microangiopathies (TMAs) are a heterogeneous group of syndromes that all cause thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, fever and renal impairment. TMAs include TTP and hemolyticuremic syndrome. Their pathology reflects widespread platelet aggregation and deposition of hyaline thrombi in the microcirculation.

PATHOGENESISIn TTP, platelet cross-linking by inappropriate vWF multimers from injured endothelial cells reflects altered cleavage of multimeric vWF multimers. vWF monomers are normally assembled into multimeric molecules of varying size (up to millions of daltons) within endothelial cells and released locally in response to endothelial stimulation. ADAMTS13 is a metalloprotease that normally cleaves large vWF multimers.In TTP, ADAMTS13 is deficient, causing ultra-large vWF multimers to accumulate. These multimers bind platelets, which form thrombi in the microvasculature, depleting platelets and causing thrombocytopenia. ADAMTS13 is genetically absent or defective in familial TTP because of mutations of the ADAMTS13 gene. The protein is inactivated by autoantibodies in idiopathic TTP. Prophylactic plasma infusion, which replaces the missing ADAMTS13, is most effective in familial forms of TTP, and plasma exchange is preferred in acquired types.Although most cases arise in otherwise normal people, TTP may also complicate systemic diseases such as autoimmune collagen vascular disorders (systemic lupus erythematosus, rheumatoid arthritis, Sjgren syndrome), drug-induced hypersensitivity reactions and malignant hypertension. It has also been triggered by infections, cancer chemotherapy, bone marrow transplantation and pregnancy in HELLP syndrome. Other TMA disorders are much less well understood.

PATHOLOGY In TTP, periodic acidSchiff (PAS)- positive hyaline microthrombi deposit in arterioles and capillaries throughout the body, mainly in the heart, brain and kidneys. These microthrombi contain platelet aggregates, fibrin and a few erythrocytes and leukocytes. Unlike immune-mediated vasculitis, there is no inflammation in TTP. Fragmented erythrocytes (schistocytes) always appear in peripheral blood smears and are caused by RBC shearing in vessels narrowed by thrombi. RBC polychromasia is also a feature and reflects an increase in reticulocytes in response to anemia. Hemolysis increases serum LDH and unconjugated bilirubin levels.

CLINICAL MANIFESTATIONSTTP may occur at any age but is most common in women in the 4th and 5th decades. It may be chronic and recurrent for years or, more frequently, occur as an acute, fulminant disease that is often fatal. Most patients present with neurologic symptoms, including seizures, focal weakness, aphasia and alterations in consciousness. Widespread purpura is often present and vaginal bleeding may occur in women. Hemolytic anemia is a constant feature; hemoglobin levels are often below 6 g/dL. Jaundice caused by hemolysis may be severe. Renal dysfunction includes proteinuria, hematuria and mild renal insufficiency.More than half of patients with TTP have platelet counts below 20,000/UL. Despite the presence of aggregated platelets, the coagulation cascade is not activated. Thus, PT, PTT and fibrinogen all remain normal. These parameters distinguish this syndrome from DIC. With plasma infusion and plasmapheresis, about 89% of patients survive this once almost uniformly fatal disease. Microthrombi are present in the brain (L) and heart (R) of a patient who died of thrombotic thrombocytopenic purpura.