Chapter 109. Disorders of Platelets and Vessel Wall (Part 7)

Thrombotic Thrombocytopenic Purpura TTP and HUS were previously considered overlap syndromes. However, in the past few years the pathophysiology of inherited and idiopathic TTP has become better understood and clearly differs from HUS. TTP was first described in 1924 by Eli Moschcowitz and characterized by a pentad of findings that include microangiopathic hemolytic anemia, thrombocytopenia, renal failure, neurologic findings, and fever. The full-blown syndrome is less commonly seen now, probably due to earlier diagnosis. The introduction of treatment with plasma exchange markedly improved the prognosis in patients, with a decrease in mortality from 85–100% to 10–30%.The pathogenesis of inherited...
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Chapter 109. Disorders of Platelets and Vessel Wall (Part 7) Chapter 109. Disorders of Platelets and Vessel Wall (Part 7) Thrombotic Thrombocytopenic Purpura TTP and HUS were previously considered overlap syndromes. However, inthe past few years the pathophysiology of inherited and idiopathic TTP hasbecome better understood and clearly differs from HUS. TTP was first describedin 1924 by Eli Moschcowitz and characterized by a pentad of findings that includemicroangiopathic hemolytic anemia, thrombocytopenia, renal failure, neurologicfindings, and fever. The full-blown syndrome is less commonly seen now,probably due to earlier diagnosis. The introduction of treatment with plasmaexchange markedly improved the prognosis in patients, with a decrease inmortality from 85–100% to 10–30%. The pathogenesis of inherited (Upshaw-Schulman syndrome) andidiopathic TTP is related to a deficiency of, or antibodies to, a metalloprotease thatcleaves vWF and ADAMTS13, respectively. vWF is normally secreted as ultra-large multimers, which are then cleaved by ADAMTS13. The persistence of ultra-large vWF molecules are thought to contribute to pathogenic platelet adhesion andaggregation (Fig. 109-4). This defect alone, however, is not sufficient to result inTTP as individuals with a congenital absence of ADAMTS13 develop TTP onlyepisodically. Additional provocative factors have not been defined. The level ofADAMTS13 activity, as well as antibodies, can now be detected by laboratoryassays. However, assays with sufficient sensitivity and specificity to direct clinicalmanagement have yet to be defined. Figure 109-4 Pathogenesis of thrombotic thrombocytopenic purpura (TTP).Normally the ultra-high molecular-weight multimers of von Willebrand factor(vWF) produced by the endothelial cells are processed into smaller multimers by aplasma metalloproteinase called ADAMTS13. In TTP the activity of the protease isinhibited, and the ultra-high molecular-weight multimers of vWF initiate plateletaggregation and thrombosis. (From Vesely et al., Copyright American Society ofHematology.) Idiopathic TTP appears to be more common in women than in men. Nogeographic or racial distribution has been defined. TTP is more common inpatients with HIV infection and in pregnant women. Medication-related TTP maybe secondary to antibody formation (ticlopidine and possibly clopidogrel) or directendothelial toxicity (cyclosporine, mitomycin C, tacrolimus, quinine), althoughthis is not always so clear, and fear of withholding treatment, as well as lack ofother treatment alternatives, results in broad application of plasma exchange.However, withdrawal, or reduction in dose, of endothelial toxic agents maydecrease the microangiopathy. Thrombotic Thrombocytopenic Purpura: Treatment TTP is a devastating disease if not diagnosed and treated promptly. Inpatients presenting with new thrombocytopenia, with or without evidence of renalinsufficiency and other elements of classic TTP, laboratory data should beobtained to rule out DIC and to evaluate for evidence of microangiopathichemolytic anemia. Findings to support the TTP diagnosis include an increasedlactate dehydrogenase and indirect bilirubin, decreased haptoglobin, and increasedreticulocyte count, with a negative direct antiglobulin test. The peripheral smearshould be examined for evidence of schistocytes (Fig. 109-1D). Polychromasia isusually also present due to the increased number of young red blood cells, andnucleated RBCs are often present, which is thought to be due to infarction in themicrocirculatory system of the bone marrow. Plasma exchange remains the mainstay of treatment of ITP. ADAMTS13antibody–mediated TTP (idiopathic TTP) appears to respond best to plasmaexchange. Plasma exchange is continued until the platelet count is normal andsigns of hemolysis are resolved for at least 2 days. While never evaluated inclinical trial, the use of glucocorticoids seems a reasonable approach, but theyshould only be used as an adjunct to plasma exchange. Additionally, otherimmunomodulatory therapies have been reported to be successful in refractory orrelapsing TTP, including rituximab, vincristine, cyclophosphamide, andsplenectomy. The role of rituximab in the treatment of this disorder needs to bedefined. A significant relapse rate is noted: 25–45% within 30 days of initialremission and 12–40% with late relapses. Relapses may be more frequent inpatients with severe ADAMTS13 deficiency at presentation.