Isolation and study of an acquired inhibitor of human coagulation factor V.

Abstract

A coagulation Factor V inhibitor developed in a man 75 yr of age in association with an anaplastic malignancy and drug treatment (including the aminoglycoside antibiotic, gentamicin). The patient did not bleed abnormally, despite both surgical challenge and plasma Factor V activity of <1%. The inhibited plasma had grossly prolonged prothrombin and activated partial thromboplastin times, but a normal thrombin time. Mixing studies indicated progressive coagulation inhibition with normal plasma, but not with Factor V-deficient plasma, and reversal of coagulation inhibition by the addition of bovine Factor V to the patient's plasma. 1 ml of patient plasma inhibited the Factor V activity of 90 ml of normal human plasma. The inhibitor was isolated by sequential affinity chromatography on protein A-Sepharose and Factor V-Sepharose. The IgG isolate markedly inhibits the activity of prothrombinase assembled from purified Factors Xa and Va, calcium ion, and phospholipid vesicles, and partially inhibits prothrombinase assembled from purified Factor Xa, calcium ion, and normal platelets. The Factor V of platelets, however, appears relatively inaccessible to the antibody, inasmuch as platelets isolated from whole blood supplemented for 8 h with the antibody functioned normally with respect to platelet Factor V-mediated prothrombinase function. The absence of obvious hemorrhagic difficulties in the patient, the total inhibition of plasma Factor V by the inhibitor, and the apparent inaccessibility of platelet Factor V to the inhibitor specifically implicate platelet Factor V in the maintenance of hemostasis.

Platelets and platelet-derived factor Va confer hemostatic competence in complete factor V deficiency

“…16 Thus, these combined observations suggest that despite a complete absence of a plasma-derived FV and the presence of ;7% normal levels of platelet-derived FV/Va, the persistence of the highly procoagulant cofactor in the patient's platelets confers hemostatic competence. The importance of platelets and platelet-derived FV/Va in sustaining normal hemostasis is supported by several studies.…”

“…on May 13, 2018. by guest www.bloodjournal.org From inhibitor to plasma-but not platelet-derived FV showed no bleeding tendency following extensive surgical challenge. 16 In contrast, individuals with platelet-derived FV/Va inhibitors exhibit severe GI bleeding. 17,18 Other reports describe the success of platelet transfusions in the cessation of severe bleeding resulting from FV deficiency 19,20 or FV inhibitors.…”

Genotype-phenotype correlation in combined deficiency of factor V and factor VIII

“…38 Our results would predict that other conditions that alter plasma FV level should also alter the platelet level, including severe liver diseases or autoimmune clearance of plasma FV. Although a number of patients with FV inhibitor antibodies have been described, [39][40][41][42] bleeding symptoms are highly variable, and direct measurement of platelet FV antigen in this setting has not been reported.…”

An acquired factor V inhibitor associated with defective factor V function, storage and binding to multimerin 1

“…In humans, 80% of FV is found in plasma, and the remainder is stored in platelets, complexed to multimerin 1 (MMRN1), after FV is endocytosed from plasma [2][3][4]. Acquired FV inhibitors, although rare, can cause serious bleeding [5][6][7][8][9]. We investigated an acquired FV inhibitor associated with bleeding, using calibrated automated thrombograms (CATs) [10,11] to evaluate platelet and plasma FVa-dependent thrombin generation, and enzyme-linked immunosorbent assays (ELISA) to measure FV antigen, FV storage and FV binding to MMRN1.…”