Unusually Large Von Willebrand Factor Research Articles

Thrombotic Thrombocytopenic Purpura: Evidence That Infusion Rather Than Removal of Plasma Induces Remission of the Disease

Plasma exchange has recently been reported to be more effective than plasma infusion for the treatment of thrombotic thrombocytopenic purpura (TTP). However, in the only available controlled study, the plasma infused during the exchange procedure was three times that given by infusion alone. Here we report the case of a patient with chronic relapsing TTP who had 21 relapsing episodes in the last 3 years. During 18 relapses, infusion of plasma, as infusion alone or in the context of an exchange procedure, invariably induced remission of the disease. By contrast, plasma removal alone (replaced with albumin and saline) was ineffective in three further consecutive relapses so that infusion was eventually necessary to induce remission. We concluded that the effective component of plasma exchange in TTP is infusion, rather than removal of plasma. Unusually large von Willebrand factor (ULvWF) multimers were found during both acute and remission phases, possibly reflecting intravascular leakage from ongoing endothelial cell injury. A relative increase of the 176-kd fragment and a relative decrease of the 225-kd subunit were demonstrated during the acute phase, indicating in vivo proteolytic vWF fragmentation. Since in vitro evidence is available that such fragments of vWF induce platelet aggregation, it is speculated that protease inhibitors of normal plasma help restore normal vWF processing activity in the circulation, which explains remission of the disease associated with the plasma infusion.

Granulocyte proteases do not process endothelial cell-derived unusually large von willebrand factor multimers to plasma vWF in vivo

The unusually large von Willebrand factor (ULvWF) multimers present within endothelial cells and platelets are larger than the vWF multimers normally found in adult human plasma. Furthermore, ULvWF multimers are cleared rapidly from the circulation if they are released by intense endothelial cell stimulation. The mechanisms by which the ULvWF multimers are processed to large plasma vWF multimers are not known. It has been demonstrated that granulocyte proteases are capable of decreasing vWF multimer size in vitro, and that some patients with myeloproliferative syndromes have a relative absence of large plasma vWF multimers in sodium citrate-anticoagulated plasma samples. In order to assess the influence of granulocyte proteases on vWF multimer size, we evaluated the vWF multimeric patterns in 94 plasma samples from 60 patients with neutrophil counts that were either considerably elevated or extremely reduced. In 83 of 94 plasma samples, the vWF multimeric patterns were normal. No patients with very low neutrophil counts had ULvWF multimers present. These observations suggest that granulocyte proteases are not likely to be involved in vivo in the processing of ULvWF multimers from endothelial cells to the smaller vWF forms in circulation.

Effectiveness of the cryosupernatant fraction of plasma in the treatment of refractory thrombotic thrombocytopenic purpura

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.