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The cause of platelet agglutination in thrombotic thrombocytopenic purpura has been an enigma. Current evidence indicates that the interaction of platelets with a platelet-aggregating factor or unusually large multimers of factor VIII:von Willebrand factor, or both, may cause the abnormal platelet agglutination. Recent success in the treatment of thrombotic thrombocytopenic purpura with intravenous infusion of immunoglobulin suggests that the abnormal platelet agglutination in thrombotic thrombocytopenic purpura may reflect a deficiency of immunoglobulins that normally inhibit platelet-aggregating factors or large multimers of factor VIII:von Willebrand factor.

In 1924, Moschcowitz initially described a fulminant febrile illness in a 16-year-old girl characterized by the diffuse deposition of hyaline thrombi in terminal arterioles. In this original description of thrombotic thrombocytopenic purpura (TTP), Moschcowitz reported pallor, petechiae, fever, and slight paralysis. Laboratory studies revealed anemia and proteinuria. Nucleated erythrocytes were present in the peripheral blood smear; no schistocytes were described. No platelet count was obtained. At autopsy, hyaline thrombi were seen in "every section of heart muscle"; occasional thrombi were present in the spleen, liver, and kidneys. Moschcowitz stated, incorrectly, that the hyaline thrombi resulted from the agglutination of erythrocytes. He concluded that a toxin with pronounced hemolytic and agglutinating properties was the cause of the diffuse thrombotic process. TTP is a very rare disease. Petitt calculated an incidence of about one case per million population in Olmsted and Fillmore counties in his review of the Mayo Clinic experience for a 30- year period (1950 through 1979). The peak incidence is in the fourth decade of life, and 60% of cases occur in women.

MANIFESTATIONS

The characteristic clinical pentad of TTP consists of thrombocytopenic purpura, microangiopathic hemolytic anemia, varying neurologic symptoms or signs, renal disease, and fever.

Clinically, the thrombocytopenia, which is attributable to diffuse platelet agglutination, may produce various bleeding complications such as petechiae, purpura, epistaxis, and cerebral and retinal hemorrhages. Neurologic manifestations include headache, confusion, aphasia, transient paresis, ataxia, sensory disturbances, and coma. Hematuria, proteinuria, and renal insufficiency (occasionally, acute renal failure) are the renal abnormalities. The cause of the moderate increases in body temperature is unknown. Anemia is frequently severe, the hemoglobin concentration being less than 5.5 g/dl in 30% of the patients.

Consistent with this nonimmune intravascular hemolytic process, the peripheral blood smear demonstrates schistocytes without spherocytes. The indirect bilirubin, lactate dehydrogenase, reticulocyte count, and plasma hemoglobin values are increased, and hemosiderin is present in the urine. Additionally, haptoglobin is decreased or absent, and the direct Coombs test is negative. Thrombocytopenia is pronounced; platelet counts seldom exceed 20,000/mm3. Marrow megakaryocytes are normal or increased. Although fibrinogen may be consumed inadvertently during the process of diffuse platelet agglutination, mild disseminated intravascular coagulation is uncommon. Other clinical manifestations may include cardiac dysfunction, hepatosplenomegaly, and pancreatitis.

DIAGNOSIS

The diagnosis of TTP is suggested by the aforementioned clinical pentad; no specific diagnostic test exists. The presence of hyaline thrombi in biopsy specimens of skin, subcutaneous tissue, muscle, bone marrow, gingiva, or lymph nodes lends support to the diagnosis. These microvascular occlusions are evidence of the diffuse platelet agglutination that characterizes TTP. The differential diagnosis of TTP includes the hemolytic uremie syndrome, disseminated intravascular coagulation, autoimmune hemolytic anemia, immune thrombocytopenic purpura, Evans' syndrome, immune-mediated microangiopathy (such as systemic lupus erythematosus), subacute bacterial endocarditis, nonbacterial thrombotic endocarditis, meningococcemia, disseminated carcinomatosis, malignant hypertension, eclampsia, and the HELLP (/lemolysis with elevated Ziver enzymes and Zow platelet count) preeclamptic syndrome.6 The hemolytic-uremic syndrome may occur in adults; although similar to TTP clinically, the platelet agglutination is primarily limited to the kidney. The local absence of fibrinolytic activity in thrombosed vascular lesions distinguishes TTP from other disseminated intravascular coagulopathies.

ETIOLOGY AND PATHOGENESIS

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Judy L Schmidt, MD, FACP is triple board certified in Internal Medicine, Hematology, and Medical Oncology. She received her Hematology / Medical Oncology training at the Mayo Clinic from 1985 to 1988.

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