Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C.

Abstract

Although patients with thromboembolic disease frequently have family histories of thrombosis, well-defined defects such as inherited deficiencies of anticoagulant proteins are found only in a minority of cases. Based on the hypothesis that a poor anticoagulant response to activated protein C (APC) would predispose to thrombosis, a set of new coagulation assays was developed that measure the anticoagulant response in plasma to APC. A middle-aged man with a history of multiple thrombotic events was identified. The addition of APC to his plasma did not result in a normal anticoagulant response as measured by prolongation of clotting time in an activated partial thromboplastin time (APTT) assay. Four of the proband's relatives had medical histories of multiple thrombotic events, and they and several other family members responded poorly to APC in the APTT-based assay. Subnormal anticoagulant responses to APC were also found in factor IXa- and Xa-based assays. Several possible mechanisms for the observed phenomenon were ruled out, such as functional protein S deficiency, a protein C-inhibitory antibody, or a fast-acting protease inhibitor against APC. Moreover, restriction fragment-length polymorphism analysis excluded possible linkage of the underlying molecular defect to factor VIII and von Willebrand factor genes. We now describe a previously unrecognized mechanism for familial thromboembolic disease that is characterized by poor anticoagulant response to APC. This would appear to be explained best by a hypothesized inherited deficiency of a previously unrecognized cofactor to APC. As we have identified two additional, unrelated cases with thrombosis and inherited poor anticoagulant response to APC, this may constitute an important cause for familial thrombophilia.

Factor VLeiden

“…Some studies attribute more than 95% of cases of APC resistance to the FV Leiden mutation [3,9,12]. FV Leiden is present in heterozygous form in 5% of the general Caucasian population and is less common or rare in other ethnic groups [13][14][15][16][17][18].…”

“…APC also indirectly promotes fibrinolysis [2]. APC resistance, caused by FV Leiden , was first reported in 1993 by D€ ahlback et al and currently represents the most common known hereditary predisposition to venous thrombosis [3,4]. FV Leiden -induced APC resistance accounts for 20% of unselected patients with first-episode thrombosis, 50% of familial thrombosis, and 60% of thrombotic patients known to have normal levels of protein S, protein C, antithrombin, and antiphospholipid antibodies [5][6][7].…”

Luteinizing hormone-releasing hormone analogue: leuprorelin acetate for the prevention of menstrual bleeding in premenopausal women undergoing stem cell transplantation

“…These modifications induce a thrombophilic state which may be further amplified by genetically determined prothrombotic defects which occur fairly commonly in the general population and include activated protein C resistance related to factor V Leiden, or antithrombin III deficiency. 5 Thus, the use of estroprogestinics after stem cell transplantation may increase the risks of toxicity in patients already prone to metabolic complications and they may play a role in the development of veno-occlusive disease after transplantation.…”

The Factor V Leiden mutation is associated with a higher blood haemoglobin concentration in women below 50 of the Malmö Thrombophilia Study (MATS)

“…Since the discovery of APC resistance and the FVL in 1993 [5,3,6], knowledge about hereditary thrombophilia has increased remarkably. We now know that venous thromboembolism (VTE) is a multi-causal disease which occurs often when genetic and acquired risk factors are present at the same time [7].…”