Enhanced proteolysis of plasma von Willebrand factor in thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome

Abstract

To examine whether enhanced in vivo proteolysis of von Willebrand factor (vWF) would account for the reported loss of larger multimers in acute thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), we studied eight patients with acute TTP/HUS whose blood samples were collected into an anticoagulant containing a cocktail of protease inhibitors to impede in vitro proteolysis. In all, enhanced proteolytic degradation of vWF was expressed as a relative decrease in the intact 225-Kd subunit of vWF and a relative increase in the 176-Kd fragment. However, instead of the loss of larger forms of normal multimers reported by other investigators, the plasma of all but one of our patients (whether they had TTP or HUS) contained a set of larger than normal (supranormal) multimers. Hence, although proteolytic fragmentation of vWF was enhanced during acute TTP/HUS, this phenomenon was not associated with the loss of larger multimers. In the five patients who survived the acute disease and underwent plasma exchange (three with HUS and two with chronic relapsing TTP), subunits and fragments returned to normal values, and supranormal multimers were no longer detected in plasma. In conclusion, even though vWF proteolysis is enhanced in acute TTP/HUS, it does not lead to loss of larger multimers.

Diagnosis of thrombotic thrombocytopenic purpura based on modulation by patient plasma of normal platelet adhesion under flow condition

“…Thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia, haemolytic anaemia, neurological and renal abnormalities, and fever (Amorosi & Ultmann, 1966;Moake, 1997). Unusually large multimers of von Willebrand factor (VWF) have been found in the plasma of TTP patients (Moake et al, 1982;Mannucci et al, 1989). These multimers easily adhere to the vessel wall and promote platelet adhesion and aggregation, especially at elevated levels of shear stress, leading to thrombotic microangiopathy, thrombocytopenia and microangiopathic haemolytic anaemia (Kakishita, 2000).…”

“…There are several studies demonstrating the presence of large VWF multimers in the plasma of TTP patients (Moake et al, 1982;Mannucci et al, 1989;Raife & Montgomery, 2000). The large VWF multimers found in most TTP patients confer an increased capacity of plateletplatelet and platelet-vessel wall interaction (Moake et al, 1986).…”

Extracorporeal Plasma Treatment in Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome: A Review

“…There has been a growing body of evidence that in familial relapsing TTP there is a primary lack of this MP's activity (14). Furthermore, ULvWF in plasma was only detectable in remission, but not during relapse when it was most probably consumed by the formation of microthrombi (9). In contrast, in ac-quired TTP (e.g., by viral infection), IgG antibodies against MP were found during the active phases of the disease, but not during remission.…”

Laboratory abnormalities in thrombotic thrombocytopenic purpura

“…The pathophysiology of TTP remains uncertain and debated. Many pathological findings have been reported, including abnormalities of von Willebrand factor (VWF) (Mannucci et al, 1989;Moake & McPherson, 1989) and the presence of a platelet aggregating factor in the plasma during the acute illness (Lian et al, 1979;Kelton et al, 1987). It has been postulated that either or both of these findings might be useful for diagnostic or prognostic purposes or as clues to the pathophysiology of TTP.…”