Complement Regulator Factor H is a Cofactor for Thrombin in Both Pro- and Anticoagulant Roles

Thrombin is central to hemostasis, with both pro- and anticoagulant functions. Interest in interactions between complement and coagulation is increasing. We hypothesized that the complement regulator factor H (FH) influences the action of thrombin. Soluble and membrane-bound complement regulators protect cells and tissues from unintended complement-mediated injury. Complement regulator FH is a soluble complement regulator essential for controlling the alternative pathway in blood and on cell surfaces. Meike Heurich, Ph.D., of Cardiff University in Cardiff, United Kingdom, looked to investigate this further, as it was hypothesized that FH influences the action of thrombin.

This was done by measuring in FH knockout mice tail-bleeding time and blood loss. FH-depleted human plasma was used to measure activated partial thromboplastin time (aPTT), and clot formation was monitored in fibrin generation turbidity assays. Thrombin-mediated activated protein C (aPC) generation was measured in the presence and absence of thrombomodulin. Thrombin-FH binding was investigated in a binding assay and affinity was measured using surface plasmon resonance. Heurich remarked that tail-bleeding time in FH knockout mice was 804 ± 550 seconds, compared with 196 ± 305 seconds in wild type. The aPTT in FH-depleted human plasma was prolonged and restored by the re-addition of FH into depleted plasma. FH enhanced fibrinogen cleavage and fibrin clot generation by shortening lag time and increasing the rate of clot formation in a concentration-dependent manner. Thrombin activation of protein C was shown in an FH concentration–dependent manner in the presence or absence of thrombomodulin. FH complement regulatory function was not altered by thrombin binding.

Heurich concluded based on these findings that the interactions between coagulation and complement systems and the potential impact of their imbalance or dysregulation in disease are important.

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