October, 1998
| THROMBOTIC THROMBOCYTOPENIC PURPURA SYNDROME Valerie A. Lyons, M.D., Resident in Pathology Joseph E. Kiss, M.D., Medical Director, Hemapheresis and Blood Services INTRODUCTION Thrombotic thrombocytopenic purpura (TTP) is a clinical syndrome which consists of microangiopathic hemolytic anemia, thrombocytopenia, and fever, along with a variable degree of renal insufficiency and fluctuating neurologic abnormalities. Cases with more pronounced renal involvement and little CNS findings are often referred to as Hemolytic Uremia Syndrome (HUS). TTP occurs in a heterogeneous group of patients with an increased incidence and association with pregnancy, autoimmune conditions, infections, malignancy and certain medications. Historically, the mortality rate of TTP was in excess of 95%. With increased awareness of symptomatology, understanding of pathophysiologic mechanisms and treatment of milder forms of disease, today the mortality is less than 10%.1 Pathophysiology The cardinal pathological finding in TTP is microvascular occlusion of terminal arterioles and capillaries. The lesions consist predominantly of platelet aggregates and von Willebrand Factor (vWF), without significant amounts of fibrin or evidence of inflammation, unlike disseminated intravascular coagulation and vasculitis, respectively. Passage of red blood cells through partially occluded vessels results in fragmentation or the characteristic schistocyte. Under normal conditions, endothelial cells release large vWF multimers into plasma. Plasma proteases cleave these large vWF multimers into smaller multimers, which allow platelets to bind to subendothelium. Unusually large vWF multimers are found in the plasma of patients with TTP, which have an increased capacity to bind to platelets. The origin of these unusually large multimers is unclear. It has been suggested that excessive release of vWF multimers from injured endothelium overwhelms plasma proteases, resulting in abnormally large multimeric forms. Direct platelet aggregation through GPIX and GPIIb-IIIa sites on platelets, may account for the reversible formation of microthrombi which lodge in small vessels.1 These events help explain the transient neurologic manifestations of TTP.
Clinical manifestations TTP remains a clinical diagnosis. No laboratory test or microscopic examination is diagnostic. Many patients do not present with the classic pentad. Acceptable guidelines for the initiation of therapy include thrombocytopenia and microangiopathic hemolytic anemia unexplained by the patient’s underlying medical condition. An increase in serum lactate dehydrogenase (LDH) level and the presence of schistocytes support the diagnosis of TTP. Schistocytes reflect an active microangiopathic hemolytic process; however, a normal red blood cell morphology does not preclude therapy in a symptomatic patient or a patient with a recent diagnosis of TTP. LDHs are cytoplasmic enzymes that leak into the serum in response to cellular injury. LDH can be separated into five different isoenzymes by appropriate electrophoretic techniques, with the fraction of greatest mobility LDH1, found predominantly in myocardium and red blood cells.2 Although LDH is released from hemolyzed red blood cells in TTP, the major proportion in blood is a result of tissue ischemia secondary to microvascular occlusion. Clinical response to the management of TTP is dependent upon the etiology, with cancer and chemotherapy-associated TTP being less responsive to conventional therapy. No definitive predictors of relapse have been reported. However, relapse seems to be most frequent within the first 60 days following the initiation of treatment.3 Management The mainstay of treatment is plasma exchange (PEX). This procedure is thought to remove unusually large vWF multimers or replace deficient plasma proteases felt to play a significant role in the etiology of TTP. Prompt initiation of PEX is essential because TTP can be rapidly progressive and delay has been shown to correlate with the likelihood of treatment failure.1 If delay is unavoidable, plasma infusion has been shown to be of some benefit, but should not be considered an acceptable alternative. Controversial issues surround the management of TTP, including the volume and type of replacement fluid, duration of treatment, efficacy of concomitant drug therapy, and the utility of tapering PEX after clinical stabilization. Guidelines for the treatment of TTP generally include a 1-1.5 plasma volume exchange using fresh frozen plasma (FFP) daily until resolution of clinical symptoms and normalization or near-normalization of the platelet count and LDH level. Once clinical remission is attained, tapering PEX to every other day for several days may be beneficial in preventing relapse. Published estimates of relapse rates vary between 30-40%. A recent retrospective study found no statistical difference in the rate of relapse when comparing taper to no-taper apheresis schedule. However, using a tapering schedule for PEX, the relapse rate for patients treated by ITxM is approximately 20%. Platelet transfusions are contraindicated because they exacerbate platelet aggregation, causing microthrombi formation which may manifest as rapid clinical deterioration. Serious hemorrhage is rare in TTP.4 FFP is standard replacement fluid for patients with TTP. A virally-inactivated pooled-plasma product, solvent-detergent plasma, has been recently approved by the Food & Drug Administration for this indication. Cryosupernatant, the residual plasma fraction after separation of cryoprecipitate from FFP, has also been used successfully as a replacement fluid, including cases which initially did not respond to FFP. Replacement using non-plasma-derived fluids alone is not efficacious. High doses of glucocorticoids have been shown to be of benefit in some patients; however, prior to the induction of PEX, the response rate to glucocorticoids alone was approximately 10%. Antiplatelet agents have not proved particularly beneficial in the treatment of TTP. Recent reports have associated the use of the platelet inhibitor ticlopidine with the development of TTP in patients undergoing coronary artery stenting or for the treatment of stroke.5,6 Vincristine has been found to be beneficial as a second-line therapy. Splenectomy is usually performed as salvage therapy for patients with chronic forms of TTP, or persistent TTP refractory to plasma exchange.
Summary Although the pathophysiology of TTP remains uncertain, increased recognition and the use of intensive PEX has markedly improved the outlook for patients with this enigmatic disorder.
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For questions regarding Thrombotic Thrombocytopenic Purpura Syndrome, please contact Joseph E. Kiss, M.D., at (412) 209-7326, or by e-mail: jkiss@itxm.org Copyright © 1998, Institute For Transfusion Medicine
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