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Eleven of fifty serum samples collected from patients with a diagnosis of thrombotic microangiopathy (TMA), from 1979 to 1991, tested positive for antiretroviral antibodies. Seven had human immunodeficiency virus (HIV) infection, and four had human lymphotrophic virus, type I (HTLV-I) infection. All patients were treated with plasma exchange and/or infusion, but only two of the HIV-infected patients obtained a complete response (CR) and one of them died after a few months. Combined results from the literature indicate that most patients with HIV infection survive less than one year from the initial diagnosis of TMA. In the setting of HIV infection, TMA is a treatable condition, but survival for most patients is less than 12 months. Three of the four HTLV-I infected patients with TMA had a CR. These observations strongly suggest that both HIV and HTLV-I infections are associated with TMA, but rigorous epidemiologic studies will be needed to determine the relative risk for each. Retroviral infections should be considered in patients with TMA, especially if the patient has associated risk factors and demographic characteristics.

Many patients with thrombotic thrombocytopenic purpura (TTP) satisfactorily respond to plasma therapy (plasmapheresis and/or plasma infusion). Some, however, respond either not at all or only transiently and incompletely. Evidence indicates that platelets and endothelial cell-derived unusually large von Willebrand factor (ULvWF) multimers, as well as the largest vWF multimers in plasma, form thrombi which are deposited in the microvascular circulation. Accordingly, platelet transfusions are avoided unless there is intra-cranial or other life-threatening hemorrhage. The largest plasma multimers of vWF are, however, replenished by the infusion of large volumes of whole plasma. We postulated that under conditions of massive plasma replacement, plasma depleted of the largest multimers of vWF might be preferable for the treatment of TTP episodes. The largest vWF multimers sediment in the cryoprecipitate, and the cryoprecipitate-poor fraction of plasma (cryosupernatant) is depleted of these forms. Seven patients responding inadequately to intensive plasma therapy were switched to receive cryosupernatant in place of whole plasma. All patients improved quickly following this change in therapy, and the TTP syndrome resolved in all seven.

Whole plasma infusion, in our experience, has been highly effective in the management of patients with thrombotic thrombocytopenic purpura. The effectiveness of plasma infusion in the treatment of this severe disorder implies the deficiency of a factor in the patient's plasma. Furthermore, we have observed that when platelets are suspended in plasma obtained during active, untreated thrombotic purpura, aggregation occurs. This effect is neutralized by preincubation of the thrombotic thrombocytopenic purpura plasma with normal plasma. Thus, there is both a correlation with the clinical pathogenic mechanism, disseminated platelet aggregation, and with the therapeutic response to plasma infusion. Based upon our experience and the concept that thrombotic thrombocytopenic purpura is a plasma factor deficiency state, we recommend initial infusion of a full plasma volume equivalent over the first 24 hours. This should be done under an intensive care setting. After this initial plasma infusion, we advise the infusion of 3 units of plasma daily until a full remission is obtained. When the clinical situation has stabilized, we stop the daily plasma infusions and cautiously observe for recurrence of the manifestations of thrombotic thrombocytopenic purpura. If there is a recurrence, plasma is again infused in substantial quantity during the first 24 hours and then 3 units daily until a full remission is again evident. Whether the plasma requirement might be attenuated or the course of the disease shortened by the concomitant use of antiplatelet agents, corticosteroids or other means remains to be determined.

Remission plasma samples of some patients with chronic relapsing thrombotic thrombocytopenic purpura (TTP) contain unusually large von Willebrand factor (vWF) multimers similar to those produced by normal human endothelial cells in culture. The infusion of the cryosupernatant fraction of normal plasma is as effective as normal fresh-frozen plasma (FFP) in the treatment or prevention of TTP episodes in patients with the chronic relapsing form of TTP. Three patients with chronic relapsing TTP during remission have unusually large vWF multimers present in their plasma. Two of the patients were transfused once with FFP, one of the two received cryosupernatant on three occasions, and the third patient was studied before and immediately after plasma exchange. Unusually large vWF multimers decreased or disappeared from patient plasma samples within 1/2 to 1 1/2 hours following the transfusion of FFP (on two occasions) or cryosupernatant (on two of three occasions), and immediately after plasma exchange (on one occasion). The patient who received cryosupernatant was studied serially after the infusions. Unusually large vWF multimers returned to her plasma within ten to 24 hours and persisted thereafter. Unusually large vWF multimers did not disappear from patient remission plasma samples, or from the culture medium removed from normal human endothelial cells, when these fluids were incubated in vitro with either normal FFP or cryosupernatant. We conclude that an activity in FFP, and its cryosupernatant fraction, promoted the rapid in vivo disappearance of unusually large vWF multimers from the plasma of two patients with chronic relapsing TTP in remission, and plasma exchange reversed the abnormality in a third patient who was in partial remission. Neither FFP nor cryosupernatant directly converted unusually large multimers to smaller vWF forms in vitro in the fluid phase. These results indicate that an activity in the cryosupernatant fraction of normal plasma is involved in vivo in controlling the metabolism of unusually large vWF multimers, and that this process is defective in some chronic relapsing TTP patients.

A 21-year-old primigravida in her 20th week of pregnancy developed TTP. She was managed with weekly or semiweekly plasma infusions and delivered a healthy 1.6 kg baby 2 weeks prior to the expected date of delivery. After delivery she continued to have active TTP with thrombocytopenia which responded repeatedly to plasma infusion though their frequency gradually decreased to about one unit every 3-4 weeks. Three years after the birth of the first child she conceived again and was easily managed with repeated plasma infusions although the frequency and amount of plasma required to prevent thrombocytopenia were increased. She delivered a normal 3.4 kg term baby after which she again had a decreased plasma requirement. This is the first report of a woman with 5 years of active TTP managed with plasma alone. She experienced two pregnancies in which both mother and infant survived. We believe that the use of plasma in the management of TTP during pregnancy will improve the survival rate of both mother and infant. At the time of second birth, the platelet count was low in the mother but normal in the baby. This suggests that the platelet depressing factor of this patient does not cross the placental barrier.

Thrombotic thrombocytopenic purpura (TTP) and the haemolytic-uraemic syndrome (HUS) are caused by platelet thrombi in the microcirculation (i.e. arterioles and capillaries) throughout the body (TTP) or predominantly in the kidneys (HUS). Plasma factors that induce intravascular platelet agglutination have been a focus of investigation into the pathogenesis of these disorders. Von Willebrand factor (vWF) multimeric forms that are larger than those present in normal plasma are found in the plasma of patients with the chronic relapsing form of TTP. These unusually large vWF multimers are similar to those produced by normal human endothelial cells, but never allowed into the normal circulation. Unusually large vWF multimers in chronic relapsing TTP patients are most apparent in plasma during remission. They disappear, presumably in the process of attaching to platelets and inducing the formation of platelet thrombi, during relapses in chronic TTP. The disappearance of the largest plasma vWF multimeric forms during acute episodes of non-relapsing TTP and HUS has also been seen. These syndromes may be the result of damage to systemic or renal endothelial cells. A cofactor which induces the attachment of large vWF multimers to platelets during episodes of TTP has recently been detected, but not yet characterized biochemically. The cryosupernatant (i.e. vWF-depleted) fraction of normal plasma contains an activity that converts, or potentiates the conversion of, unusually large vWF multimers to the somewhat smaller circulating vWF forms as the bloodstream. There is clinical evidence that an autoantibody may prevent the effect of this 'unusually large vWF depolymerase' in some chronic relapsing TTP patients. Transfusions of normal plasma or cryosupernatant as prophylaxis against, or therapy for, episodes of TTP may transiently provide this missing unusually large vWF depolymerase activity, as well as additional plasma proteins to bind and eliminate the vWF cofactor proposed as the inciting agent of TTP episodes. In some patients, partial removal of unusually large vWF multimers (and possibly the inciting vWF cofactor) by plasmapheresis may be required along with the transfusion of normal plasma or cryosupernatant, in order to control in vivo platelet agglutination. Plasma manipulation has greatly improved the survival of patients with relapsing and non-relapsing forms of TTP. Corticosteroids may also be beneficial. The effectiveness of ancillary measures (splenectomy, vinca alkaloids or other immunosuppressive drugs) is not precisely defined. There is no convincing evidence that aspirin, dipyridamole or PGI2 are helpful in TTP.(ABSTRACT TRUNCATED AT 400 WORDS)

A patient with thrombotic thrombocytopenic purpura (TTP) showed for the first time catastrophic signs and symptoms of CNS involvement immediately after infusion of platelets. Postmortem examination revealed extensive deposits of platelet aggregates within the small blood vessels of the brain, whereas lesions elsewhere in the body consisted of platelets as well as fibrin and were associated with endothelial proliferation and microaneurysm formation. These findings are consistent with the view that the initial event in TTP may be platelet aggregation. The plasma of this patient contained platelet-aggregating activity. We conclude that platelet transfusions in patients with TTP may aggravate the disease process.

Three patients with thrombotic thrombocytopenic purpura (TTP) were treated by infusion of normal plasma with dramatic responses. The plasmas collected from these patients during relapse induced in vitro aggregation of washed platelets from both normal donors and the patients during remission. The platelet aggregating factor was not dialyzable or adsorbable by Al(OH)3 and was not inactivated by diisopropylfluorophosphate, hirudin, or heparin in the presence of normal amounts of antithrombin. In contrast to the platelet aggregation induced by platelet isoantibody, the platelet aggregating activity of TTP plasma diminished as a function of time when it was incubated with normal plasma at 37 degrees C. These observations suggest that at least some instances of TTP appear to be due to deficiency of a plasma inhibitor to counteract a platelet aggregating factor demonstrated to be present in the plasma of these patients.