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Thrombotic thrombocytopenic purpura (TTP) is a disorder of systemic platelet aggregation. Evidence has accumulated that the aggregating agonist in TTP of all types is likely to be von Willebrand factor, especially unusually large von Willebrand factor multimers derived from endothelial cells. Recent evidence indicates that a metalloproteinase involved in von Willebrand factor breakdown is not present in adequate amounts in children with chronic relapsing TTP. Chronic relapsing TTP is, therefore, likely to be a congenital deficiency of von Willebrand factor metalloproteinase. In adults with single episode or intermittent types of TTP, the von Willebrand factor metalloproteinase is inhibited by autoantibodies that are present either transiently or intermittently in patient blood. Single episode and intermittent types of TTP in adults are, therefore, autoimmune processes of a short-term and recurrent nature, respectively.

Thrombotic thrombocytopenic purpura (TTP) is a disorder of systemic platelet aggregation. Evidence has accumulated that the aggregating agonist in TTP of all types is likely to be von Willebrand factor (vWf), especially unusually large vWf multimers derived from endothelial cells. Recent evidence indicates that a metalloproteinase involved in vWf breakdown is produced in inadequate amounts in children with chronic relapsing TTP. Chronic relapsing TTP is, therefore, likely to be a congenital enzyme deficiency. In adults with single episode or intermittent types of TTP, the vWf metalloproteinase is inhibited by autoantibodies that are present either transiently or intermittently in patient blood. Single episode and intermittent types of TTP in adults are likely to be short-term or recurrent autoimmune processes, respectively.

Extensive microvascular platelet aggregation is characteristic of thrombotic thrombocytopenic purpura (TTP). Previous studies have indicated that abnormalities of von Willebrand factor (vWf) are often present in TTP patient plasma. There has not been previously any direct evidence linking these abnormalities to the process of intravascular platelet aggregation in TTP. We used flow cytometry to analyze the binding of vWf to single platelets, and the presence of platelet aggregates, in the blood of 4 children with chronic relapsing (CR) TTP and 5 adults with single episode or recurrent TTP. vWf on the single platelets of CRTTP patients at all time points studied was significantly increased compared to controls, and was increased further as platelet counts decreased to levels below 40,000/microl. The single episode and recurrent adult TTP patients had platelet aggregates in the blood, as well as increased vWf on single platelets, before therapy commenced and thereafter until recovery was in process. In the one unresponsive single episode TTP patient, vWf on single platelets remained elevated, and platelet aggregates persisted, until her death. The platelet alpha-granular protein, P-selectin, was not increased on the single platelets of most TTP blood samples, suggesting that it is vWf from plasma (rather than from alpha-granules) that attaches to platelet surfaces in association with platelet aggregation. These results suggest that vWf-platelet interactions are involved in the platelet clumping process that characterizes TTP.

Recent studies indicate that CRTTP patients have excessive shear stress-induced platelet aggregation that is associated with the presence of ULvWF multimers in their plasma and increased vWF-binding to their platelets by flow cytometry. In these CRTTP patients, relapses, excessive shear-aggregation and the presence in their plasma of ULvWF forms are all reversed by the infusion of normal FFP or substances devoid of the largest vWF multimers found in plasma (cryoprecipitate-poor plasma or cryosupernatant; solvent/detergent-treated plasma) without the need for concurrent plasmapheresis. This constellation of observations, along with reports of increased vWF in TTP platelet thrombi, increases the probability that ULvWF multimers derived from injured or abnormal endothelial cells induce aggregation during TTP episodes in high-shear regions of the microcirculation.

Plasma VIII:von Willebrand factor antigen (VIII:vWF) levels were elevated approximately two- to eightfold in seven patients (three adults and four children) during acute episodes of thrombocytopenia, renal failure, and hemolytic anemia (the hemolytic-uremic syndrome, HUS). In all seven patients, there was an alteration in plasma VIII:vWF patterns during these acute HUS episodes, so that the largest VIII:vWF forms were relatively decreased. Plasma VIII:vWF multimer patterns returned to normal, or nearly to normal, as platelet counts returned to preexisting levels, even in the patients whose recovery of renal function was incomplete and whose plasma VIII:vWF antigen level remained above normal. The sister of one of the HUS patients had a similar clinical prodrome (gastroenteritis) that was not followed by thrombocytopenia or renal failure and was not accompanied by an elevated level or abnormal forms of plasma VIII:vWF. These results suggest that an alteration in VIII:vWF metabolism, distribution, or interaction with platelets is associated with acute HUS episodes. In contrast to patients with chronic relapsing thrombotic thrombocytopenic purpura, none of the HUS patients (either during or after the acute HUS episodes) had a defect in the conversion of unusually large VIII:vWF multimers derived from endothelial cells to the VIII:vWF forms found in normal plasma.

Unilateral hyphema, hematuria, and ecchymoses developed in a previously healthy 42-year-old women after the ingestion of aspirin and ethanol. There was no evidence for ocular trauma, disease, or vascular malformation by slit-lamp examination and gonioscopy. Platelet count and coagulation tests were normal. The patient's bleeding time was prolonged and there was impaired platelet aggregation. Delayed (secondary) aggregation in response to collagen, adenosine diphosphate, and epinephrine was decreased, as was aggregation induced by thrombin and serotonin. These data indicate that the qualitative platelet defect was induced by both aspirin and ethanol. Anterior chamber hemorrhage subsided after discontinuation of aspirin and ethanol, and the hyphema subsequently resolved. Bleeding time and platelet aggregation were normal two weeks after the patient's initial presentation. A prolonged bleeding time in association with normal platelet count, prothrombin time, and partial thromboplastin time indicated a qualitative platelet defect, which is most commonly drug-induced. Defective platelet function resulted in spontaneous hyphema.

Sudden thrombocytopenia that was temporally related to the administration of morphine sulfate developed in a 23-year-old woman. A morphine-dependent platelet antibody was found in her serum by chromic chloride Cr 51 platelet lysis. The antibody was complement dependent, present in the IgG immunoglobulin fraction, and its drug-dependent platelet lytic activity was demonstrable with several narcotic analgesics in addition to morphine. The antibody activity declined over an eight-month period following recovery from thrombocytopenia. To our knowledge, morphine-induced immune thrombocytopenia has not previously been described.

To analyze and review von Willebrand factor (vWF) multimeric patterns in patients with single-episode thrombotic thrombocytopenic purpura (TTP), intermittent TTP (episodes at infrequent, irregular intervals), chronic relapsing TTP (episodes at frequent, regular intervals), and the hemolytic-uremic syndrome (HUS).Platelet-poor plasma samples were obtained in EDTA, citrate, or citrate-hirudin-aprotinin-leupeptin from 36 patients with single-episode TTP, eight patients with intermittent TTP, four patients with chronic relapsing TTP, and 26 patients with HUS. The samples were separated by sodium dodecyl sulfate-agarose gel electrophoresis, overlaid with rabbit 125I-anti-human vWF IgG, and analyzed by autoradiography.Abnormalities of vWF multimers were found in platelet-poor plasma samples from 31 of 36 found in platelet-poor plasma samples from 31 of 36 patients (86%) at the onset of and during their single TTP episode. vWF multimers larger than those in normal plasma, and similar to vWF forms observed within normal human endothelial cells (unusually large vWF multimers), were demonstrated in 31% of the patients; 19% had either unusually large vWF multimers or a relative decrease in the largest plasma vWF forms in different serial samples; 36% had a relative decrease in the largest plasma vWF forms. These results imply that endothelial cell injury or intense stimulation, along with the attachment of unusually large vWF multimers and the largest plasma vWF forms to platelets, occurred during the single TTP episodes in most patients. Patterns of vWF multimers were normal in 92% of patients with single-episode TTP studied after recovery. All eight patients with intermittent TTP and the four patients with chronic relapsing TTP had unusually large vWF multimers in their plasma between episodes, and these multimers decreased or disappeared during relapses. Of 26 children and adults with HUS, 14 had a relative decrease in the largest plasma vWF multimeric forms and one had unusually large vWF multimers during the episode (vWF multimeric abnormalities in 58% of the patients).It is probable that vWF was involved in the pathophysiology of TTP in most of these patients with the single-episode, intermittent, or chronic relapsing types of TTP, and in more than 50% of the patients with HUS.