An underestimated combination of opposites resulting in enhanced thrombotic tendency

Abstract

Heterozygous carriers of factor V (FV) Leiden who also carry FV deficiency often develop venous thromboembolism, but the thrombosis risk associated with this rare condition (pseudohomozygous activated protein C resistance) is still unclear. The thrombosis risk of genetically characterized pseudohomozygotes (n ‫؍‬ 6) was compared with that of FV Leiden heterozygotes (n ‫؍‬ 683) and homozygotes (n ‫؍‬ 50) recruited within a large cohort study on familial thrombophilia. Both thrombin generation and Kaplan-Meier thrombosis-free survival analyses were performed in different FV genotype groups. FV Leiden pseudohomozygotes showed significantly higher thrombosis risk than heterozygotes. The thrombin generation test in pseudohomozygotes showed a pattern similar to homozygotes. Accordingly, early thrombotic manifestations occurred in pseudohomozygotes at a similar rate as in homozygotes. Thus, failure to recognize FV deficiency in FV Leiden heterozygotes may result in an underestimate of the thrombosis risk and inadequate management of affected patients. (Blood.

Increased thrombin generation after acute versus chronic coronary disease as assessed by the thrombin generation test

“…Recently,an ew methodology hasb ecomea vailablet oa ssess the endogenous thrombin potential in vivo (3,4). Thrombinactivity can be registered by continuous measuring of chromogenico rf luorescent substratecleavage, resulting in athrombin generation curve.The endogenous thrombin potential is obtained upon activation of coagulation by small amountso ft issue factor (TF)a nd phospholipids, and it has beenassociatedwith risk of venous thromboembolism and hypercoagulable states (5,6).…”

Factor V Leiden pseudo‐homozygotes have a more pronounced hypercoagulable state than factor V Leiden homozygotes

“…Based on APC resistance measurements, FV Leiden pseudo-homozygotes are generally considered to have a hypercoagulable state similar to that of FV Leiden homozygotes [4][5][6]. Their risk of venous thrombosis is not well established and was found to be similar to that of FV Leiden heterozygotes in a previous study [7] and to that of homozygotes in another study [6]. However, both studies may have been biased by the inclusion of probands in the analysis.…”

“…A previous case series suggested that patients diagnosed with saddle PE need aggressive therapy, such as surgical embolectomy, owing to an increased risk of mortality [1]. However, other contemporary studies have suggested that saddle PE is not associated with worse short-term clinical outcomes [4][5][6].…”

“…Measurements at high TF were performed in the absence and presence of APC (Innovative Research, Novi, MI, USA). As the low APC concentration (approximately 5 nM) normally used in the thrombin generation-based APC resistance test has relatively little effect on thrombin generation in FV Leiden homozygous plasma, precluding discrimination between homozygotes and pseudohomozygotes [5,6], a higher APC concentration (16 nM) was used in the present study. This APC concentration completely abolished thrombin generation in pooled normal plasma and reduced the endogenous thrombin potential (ETP) of a FV Leiden homozygous plasma pool (prepared by pooling plasma from five FV Leiden homozygotes: one male and four females, mean age 37.8 years) to approximately 30% of the ETP measured in the absence of APC.…”

“…The rare FV Leiden heterozygotes that carry a loss-of-function mutation on the counterpart FV allele (FV Leiden pseudo-homozygotes), express only the FV Leiden allele and have plasma FV levels of approximately 50% [4]. Based on APC resistance measurements, FV Leiden pseudo-homozygotes are generally considered to have a hypercoagulable state similar to that of FV Leiden homozygotes [4][5][6]. Their risk of venous thrombosis is not well established and was found to be similar to that of FV Leiden heterozygotes in a previous study [7] and to that of homozygotes in another study [6].…”