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Antibody Inhibitors to von Willebrand Factor Metalloproteinase and Increased Binding of von Willebrand Factor to Platelets in Ticlopidine-Associated Thrombotic Thrombocytopenic Purpura

Han-Mou Tsai, MD; Lawrence Rice, MD; Ravindra Sarode, MD; Thomas W. Chow, PhD; and Joel L. Moake, MD
[+] Article, Author, and Disclosure Information

From Albert Einstein College of Medicine, Bronx, New York; Baylor College of Medicine and Rice University, Houston, Texas; and Case Western Reserve University, Cleveland, Ohio.

Grant Support: By grants HL62131 (H-MT) and HL18584 and HL 54169 (JLM) from the National Heart, Lung, and Blood Institute of the National Institutes of Health.

Requests for Single Reprints: Han-Mou Tsai, MD, Division of Hematology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467.

Requests To Purchase Bulk Reprints (minimum, 100 copies): the Reprints Coordinator; phone, 215-351-2657; e-mail, reprints@mail.acponline.org.

Current Author Addresses: Dr. Tsai: Division of Hematology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467.

Drs. Rice and Moake: Department of Medicine/Hematology-Oncology, The Methodist Hospital, 6565 Fannin, MS 902-Main, Houston, TX 77030.

Dr. Sarode: Blood Bank/Pathology, University Hospitals of Cleveland, 11100 Euclid Avenue, RB&C-568, Cleveland, OH 44106.

Dr. Chow: Cox Laboratory for Biomedical Engineering, Rice University, 6100 South Main, Houston, TX 77005.

Author Contributions: Conception and design: H.-M. Tsai, L. Rice, T.W. Chow, J.L. Moake.

Analysis and interpretation of the data: H.-M. Tsai, L. Rice, T.W. Chow, J.L. Moake.

Drafting of the article: H.-M. Tsai, L. Rice, J.L. Moake.

Critical revision of the article for important intellectual content: H.-M. Tsai, L. Rice, R. Sarode, J.L. Moake.

Final approval of the article: H.-M. Tsai, L. Rice, R. Sarode, T.W. Chow, J.L. Moake.

Provision of study materials or patients: H.-M. Tsai, R. Sarode, J.L. Moake.

Statistical expertise: H.-M. Tsai, R. Sarode,

Obtaining of funding: H.-M. Tsai

Administrative, technical, or logistic support: H.-M. Tsai, T.W. Chow, J.L. Moake

Collection and assembly of data: H.-M. Tsai, T.W. Chow, J.L. Moake.

Ann Intern Med. 2000;132(10):794-799. doi:10.7326/0003-4819-132-10-200005160-00005
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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.

Design: Case series.

Setting: Three tertiary care, university-affiliated medical centers.

Patients: 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.

Measurements: 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.

Conclusion: 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.


Grahic Jump Location
Proposed pathophysiology of ticlopidine-associated thrombotic thrombocytopenic purpura (TTP).topvWFbottom

In normal circulation ( ), large and unusually large forms of von Willebrand factor ( ), with cleavage sites exposed by shear stress, undergo proteolysis by von Willebrand factor proteinase. Proteolysis reduces the size of the von Willebrand factor multimers and prevents binding of von Willebrand factor to platelets. In the circulation of patients with TTP ( ), proteolysis is blocked by antibodies to the proteinase. As a result, unfolded large and unusually large multimers of von Willebrand factor accumulate in the circulation and bind to platelet glycoproteins Ib/IX/V and IIb/IIIa. This causes platelet thrombi in capillaries and arterioles. Further increase in shear stress caused by microvascular thrombi results in additional unfolding of von Willebrand factor. This sets off a cycle of systemic arteriolar thrombosis characteristic of the disorder.

Grahic Jump Location




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Summary for Patients

Mechanisms of Thrombotic Thrombocytopenic Purpura (TTP), a Complication Associated with the Drug Ticlopidine

The summary below is from the full report titled “Antibody Inhibitors to von Willebrand Factor Metalloproteinase and Increased Binding of von Willebrand Factor to Platelets in Ticlopidine-Associated Thrombotic Thrombocytopenic Purpura.” It is in the 16 May 2000 issue of Annals of Internal Medicine (volume 132, pages 794-799). The authors are H.-M. Tsai, L. Rice, R. Sarode, T.W. Chow, and J.L. Moake.


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