Thrombotic Thrombocytopenic PurpuraDz

Synonyms: TTP.

ICD9 Code:  TTP 287.31
ICD10 Code:  TTP D69.3

Definition: An acute, severe, occlusive thrombotic microangiopathy characterized by systemic platelet aggregation, vascular occlusion, organ ischemia, thrombocytopenia, and Coombs-negative hemolytic anemia with red blood cell fragmentation.

Etiology: Recent studies have demonstrated TTP to be associated with a deficiency in the von Willebrand factor–cleaving protease ADAMTS13. Deficiency is owing to a genetic/familial absence or an acquired deficiency from autoimmune inhibitors or drug effects. Lack of this protease leads to unusually large von Willebrand factor because ADAMTS13 normally cleaves hyperreactive unusually large von Willebrand factor multimers into smaller and less adhesive von Willebrand factor forms. Thus, the increase in adhesive unusually large von Willebrand factor multimers binds some platelet proteins and promotes aggregation and local thrombosis. Deficiency of ADAMTS13 distinguishes TTP from the hemolytic-uremic syndrome, wherein ADAMTS13 levels are normal. The gene for ADAMTS13 has been localized to chromosome 9 (q34). Drug-induced TTP (and ADAMTS13 deficiency) may be acute immune-mediated (ticlopidine, clopidogrel), dose-related (tacrolimus, penicillin, cyclosporine, oral contraceptives, bleomycin, mitomycin, cisplatin) or may occur with quinine, which causes a hemolytic uremic–like syndrome. Other causes include pregnancy (often third trimester), post-partum, allogeneic bone marrow transplant, or autoimmune disorders (lupus, scleroderma) or HIV infection.

Pathology: Platelet-rich microthrombi occlude arterioles and capillaries (not venules), often with overlying endothelial proliferation. Incomplete occlusion leads to turbulent flow and red blood cell fragmentation and schistocytes. Vascular obliteration occurs systemically with prominent involvement of the kidneys, brain, pancreas, heart, spleen, adrenal glands, and, less commonly, the lung and GI tract.

Demographics: The median age at onset is 35 to 40 years, but it has been reported in infants and elderly. Female:male ratio ranges from 3:2 to 2:1. There is no racial preference. It is estimated there are 1,000 new cases per year.

Cardinal Findings: Initially, patients manifest malaise, fever (without chills), flu-like symptoms, weakness, or abdominal pains associated with nausea, vomiting, or diarrhea. Neurologic features include altered mental status, seizures, coma, or focal neurologic deficit. Some degree of renal impairment is seen in most, usually as microscopic hematuria, proteinuria, and, uncommonly, gross hematuria or rapid progression to acute renal failure. Although thrombocytopenia is profound (>20,000/mm3) and petechiae common, frank bleeding (e.g., CNS, GI) is very uncommon.

Uncommon Findings: Cardiac involvement (congestive heart failure, arrhythmia), acute respiratory distress syndrome, pancreatitis.

Diagnostic Tests: Thrombocytopenia (<20,000 cells/mm3), mild to moderate Coombs-negative anemia with evidence of hemolysis (schistocytes; increased lactate dehydrogenase, bilirubin, and reticulocytes; decreased haptoglobin) and occasional nucleated red blood cells. Mild to moderate leukocytosis (with left shift) is common. Renal studies may show proteinuria, hematuria, or oliguria. Bone marrow is seldom needed but typically shows a reactive picture with an increase in granulocytes and megakaryocytes. In contrast to disseminated intravascular coagulation, studies show normal prothrombin time, PTT, and fibrinogen levels.

Keys to Diagnosis: Thrombocytopenia (<20,000 cells/mm3) with evidence of microangiopathic hemolysis (fragmented cells, schistocytes, elevated lactate dehydrogenase) and of organ ischemia.

Diagnostic Criteria: The classic pentad includes (a) microangiopathic hemolytic anemia, (b) thrombocytopenia, (c) neurologic abnormalities, (d) fever, and (e) renal dysfunction. The classic pentad is uncommon and is not required for the diagnosis.

Differential Diagnosis: TTP should be distinguished from sepsis (e.g., cytomegalovirus, Rocky Mountain spotted fever, meningococcemia), eclampsia, preeclampsia, HELLP syndrome, disseminated malignancy, hemolytic-uremic syndrome, Evan syndrome, malignant hypertension.

Therapy: Prompt use of plasma exchange is essential. Apheresis removes antibodies (to ADAMTS13), unusually large von Willebrand factors and replaces normal metalloproteinase activity. Platelet transfusion is not advised and may worsen the disorder. Adjunctive treatment with low-dose aspirin, ticlopidine, or steroids may be considered, especially when refractory to apheresis. Seldom patients may require the use of cyclophosphamide, vincristine, rituximab, intravenous gammaglobulin, protein A immunoadsorption column pheresis, or splenectomy.

Monitoring: Lactate dehydrogenase is a reliable daily measure of the degree of hemolysis.

Prognosis: In the prepheresis era, TTP carried a mortality rate in excess of 90%. When treated with plasma exchange or plasma infusion, 80% to 90% of patients survive acute TTP. Relapses may occur in 10% to 40% of patients, and a small subset may exhibit chronic TTP and require chronic intermittent plasma exchange.

BIBLIOGRAPHY

Nabhan C, Kwaan HC. Current concepts in the diagnosis and management of thrombotic thrombocytopenic purpura. Hematol Oncol Clin North Am 2003;17:177–199.PMID:12627668

Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 2003;14:1072–1081.PMID:12660343