Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura.
BACKGROUND
Thrombotic thrombocytopenic purpura (TTP) affects 1 in 1600 to 1 in 5000 patients who receive ticlopidine, but little is known about the pathogenesis of this complication.


OBJECTIVE
To investigate whether von Willebrand factor (vWF), which has been associated with idiopathic TTP, is involved in the pathogenesis of ticlopidine-associated TTP.


METHODS
Case series.


METHODS
Three tertiary care, university-affiliated medical centers.


METHODS
Seven patients who developed TTP 2 to 7 weeks after initiation of ticlopidine therapy. Controls were 7 consecutive patients without thrombocytopenia who had been receiving ticlopidine for 3 to 5 weeks and 10 randomly selected hospitalized patients.


METHODS
Platelet-bound vWF in patients' EDTA-anticoagulated whole blood samples; vWF proteinase activity in patients' plasma samples; inhibitory activity of IgG isolated from patients' plasma samples against the proteinase from the controls' plasma samples; and vWF multimeric patterns in patients' EDTA-anticoagulated plasma samples.


RESULTS
Binding of vWF to single platelets was increased in the three patients tested during the most thrombocytopenic phase of TTP episodes. Initial plasma samples from all seven patients lacked the largest vWF multimers and were severely deficient in vWF metalloproteinase. IgG molecules, isolated from plasma samples of five patients, inhibited metalloproteinase in plasma samples from the controls. In patients examined, these abnormalities resolved upon the remission that accompanied plasma exchange and discontinuation of ticlopidine therapy.


CONCLUSIONS
In the patients who developed ticlopidine-associated TTP, autoantibodies to the vWF metalloproteinase were formed; this led to the same type of vWF abnormalities observed in patients with idiopathic acute TTP. The findings suggest that failure to process large and unusually large vWF multimers in vivo caused binding of vWF to platelets, systemic platelet thrombosis, and TTP.
Tsai
H M
HM
Albert Einstein College of Medicine, Bronx, New York, USA.
Rice
L
L
Sarode
R
R
Chow
T W
TW
Moake
J L
JL
D000368:Aged; D000369:Aged, 80 and over; D001323:Autoantibodies / Q000276:immunology; D001792:Blood Platelets / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D020128:Inhibitory Concentration 50; D008297:Male; D008666:Metalloendopeptidases / Q000276:immunology*; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects*; D011485:Protein Binding; D011697:Purpura, Thrombotic Thrombocytopenic / Q000209:etiology*; D013988:Ticlopidine / Q000009:adverse effects*; D014841:von Willebrand Factor / Q000276:immunology* / Q000378:metabolism
D001323:Autoantibodies; D007074:Immunoglobulin G; D010975:Platelet Aggregation Inhibitors; D014841:von Willebrand Factor; D008666:Metalloendopeptidases; D013988:Ticlopidine