(10) In addition, Furlan studied two brothers with chronic, relapsing TTP and detected ULVWF multimers with no VWF-cp activity in their plasma." Furlan further found ULVWF multimers to be absent from plasma from their asymptomatic parents who had 50% VWF-cp activity.
In flowing blood, shear forces stretch VWF multimers and expose an A2 domain cleavage site for VWF-cp. Cleavage divides VWF into smaller subunits and releases adhered platelets back to the circulation.
ABBREVATIONS: ADAMTS = a disintegrin-like and metalloprotease domain with thrombospondin type motifs; HUS = hemolytic-uremic syndrome; LD = lactate dehydrogenase; MAHA = microangiopathic hemolytic anemia; PT = prothrombin times; PTT = partial thromboplastin times; TMA = thrombotic microangiopathy; TT = thrombin times; TTP = thrombotic thrombocytopenic purpura; ULVWF = ultralarge VWF; VTEC = verotoxin-producing Ecoli; VWF = Von Willebrand factor; VWF-cp = VWF-cleaving protease.
These ULvWF multimers are cleaved into a series of smaller vWF proteins by the enzyme vWF-cleaving protease (vWF-CP).
These important observations have led to increased use of vWF-CP activity and inhibitor identification in the diagnostic work-up of patients with TMA.
In normal plasma, a vWF-CP has been identified that cleaves the ULvWF multimers between tyrosine 842 and methionine 843 within the monomeric vWF subunits, producing a series of smaller multimers (Figure 1).
Subsequently, a number of studies by Furlan and others have shown extremely low vWF-CP activity in both familial and acquired forms of TTP.
While numerous studies have demonstrated a dramatic decrease or absence of vWF-CP activity in patients with TTP, several of these studies have shown that the protease activity is only moderately decreased and often normal in HUS.
vWF-CP activity can be determined by measurement of the ability of the enzyme from the patient's plasma to degrade vWF multimers.
The principle of this assay is that the degradation of the largest vWF multimers by vWF-CP gives rise to the smaller vWF multimers that bind less to collagen.
vWF-CP activity levels and the presence or absence of an antibody inhibitor are proving to be valuable laboratory data in establishing a diagnosis in patients with suspected TTP.
Finally, prior to starting a new series of plasma exchanges on her third admission, a sample for vWF-CP assay was collected and, subsequently, showed complete absence of protease activity due to the presence of a strong inhibitor.