Measurement of plasma and platelet tissue factor pathway inhibitor, factor V and Protein S in people with haemophilia

Abstract

Introduction Tissue factor pathway inhibitor (TFPI) is a naturally occurring anticoagulant found in plasma, where it circulates bound to lipoproteins, factor V (FV) or Protein S (PS), and in platelets. Therapeutic agents targeting TFPI are under development for the treatment of haemophilia A and haemophilia B. Aim To begin to understand how TFPI, FV and PS interact to modulate haemophilia bleeding. Methods Plasma and platelet antigen concentrations of these factors were determined in 73 people with haemophilia A and 18 with haemophilia B. Using multiple regression models, these were compared to the same analytes measured in 224 male blood donors. Results There were no differences in plasma or platelet TFPI, FV or PS concentrations between haemophilia types or severities. However, compared to blood donors, people with haemophilia had approximately one‐third lower plasma PS, 9% lower plasma TFPIα, 50% higher platelet FV and 26% lower platelet Protein S. Conclusion Together, the presented data suggest that individuals with haemophilia may have a compensatory procoagulant response of both plasma and platelet proteins to the decreased concentrations of FVIII or FIX.

Anticoagulant protein S—New insights on interactions and functions

“…In contrast, protein S levels were reduced both in plasma (33%) and in platelets (26%). 98 Prince and colleagues showed that blocking protein S anticoagulant functions in plasma of individuals with hemophilia normalized their thrombin generation in vitro. 97 Together, these findings suggest that the reduction in protein S levels helps partially rebalance their coagulation.…”

“…They showed that platelet TFPIα and FV levels were increased (21% and 50%, respectively) compared to healthy blood donors, while only minor differences were seen in plasma. In contrast, protein S levels were reduced both in plasma (33%) and in platelets (26%) 98 . Prince and colleagues showed that blocking protein S anticoagulant functions in plasma of individuals with hemophilia normalized their thrombin generation in vitro 97 .…”

Factor V east Texas variant causes bleeding in a three‐generation family

“…2,4,5 However, platelet TFPIα and FV concentrations do not correlate, which is consistent with their different locations within the platelet. 16,23 Here, we found that platelet TFPIα in two individuals with the FV east Texas variant was normal, indicating that FV-short does not alter platelet TFPIα, and implicating elevated plasma TFPIα as the cause of the bleeding disorder. Human platelet FV is adsorbed from plasma.…”

“…21,22 Platelet TFPIα does not localize to α-granules where FV is located, but instead appears to be in the cytoplasm. 22 The plasma concentrations of FV and TFPIα correlate 16,23 and increases in plasma FV-short greatly increase plasma TFPIα. 2,4,5 However, platelet TFPIα and FV concentrations do not correlate, which is consistent with their different locations within the platelet.…”

Longitudinal observations of TFPI levels in paediatric Haemophilia A patients

“…Whereas one study's results indicate that haemophilia B patients have lower free TFPI levels than Haemophilia A patients, 14 other studies showed no significant difference in TFPI levels between patients with Haemophilia A and haemophilia B 15 . 30 Whereas in one of these studies 15 there was no difference between TFPI levels in haemophilia patients and healthy individuals, in the second study 30 a mild decrease in plasma TFPIα in haemophilia patients when compared to blood donors was observed. Nevertheless, there is lack of published information specifically on the TFPI levels in paediatric haemophilia subjects.…”