The Enemy of My Enemy: Inhibiting TFPI in Hemophilia
Published on: July 01, 2012
Dr. Flaumenhaft indicated no relevant conflicts of interest.
Maroney, SA, Cooley BC, Ferrel, JP et al. Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia. Proc Natl Acad Sci USA. 2012;109:3927-3931.
A great mystery in hemostasis and thrombosis has been why patients with hemophilia have such severe spontaneous bleeding despite having a fully functional extrinsic pathway of blood coagulation. The answer lies in the activity of a protein called tissue factor pathway inhibitor (TFPI). Following vascular injury, coagulation is mediated by tissue factor (TF), a central component of the extrinsic pathway, which binds factor VIIa. This complex (TF-VIIa) activates factor X to Xa, which, in concert with factor Va, generates a thrombin burst. TFPI almost immediately blocks the extrinsic pathway, but the combination of the thrombin burst along with activation of factor XI to XIa by TF-VIIa is sufficient to activate the intrinsic pathway. In this way, activation of factor X to Xa by the factor VIIIa/factor IXa complex counteracts the activity of TFPI, allowing coagulation to proceed. If factor VIIIa and factor IXa are deficient, as in hemophilias A and B, the activity of TFPI is unopposed and the combination of complete blockade of the extrinsic pathway and a non-functional intrinsic pathway results in uncontrolled bleeding. These observations raise the possibility that direct inhibition of TFPI in the setting of hemophilia might mitigate bleeding complications and has prompted investigators to develop TFPI inhibitors. Blocking antibodies or aptamers (oligonucleotide or small peptide inhibitors) directed at TFPI improve hemostasis in animal models of hemophilia, but inhibition of total intravascular TFPI poses a thrombotic risk. Platelets express an isoform of TFPI that is different from that expressed in vascular beds. Therefore, finer control of hemostasis could potentially be obtained by selectively inhibiting TFPI from one source and not another. Yet, whether the roles in hemostasis of TFPI from different cellular sources are distinct is incompletely understood.
Investigators working in the laboratory of Alan E. Mast at the Blood Research Institute of Wisconsin have created a series of genetically modified mice, and studies using these animals suggest an unexpected role for platelet TFPI in hemostasis. Initially, Maroney and colleagues attempted to breed FVIII/TFPI-double-null mice. However, like single TFPI-null mice, these double-null mice were not viable. Next, the investigators generated hemophilic mice (FVIII-null mice) that were also heterozygous for TFPI, but these mice were not protected from excess bleeding. However, when TFPI was neutralized using a blocking antibody in the hemophilic mice, an antibody concentration-dependent increase in protection against bleeding was observed. Notably, protection against bleeding continued to increase even after all plasma TFPI was neutralized, suggesting the existence of an extra-plasmic pool of the inhibitor. To identify this putative alternative source, the investigators generated a hemophilic mouse with hematopoietic cells that lacked TFPI and observed protection against bleeding with demonstration of fibrin generation at injury sites.
These studies provide further evidence that inhibition of TFPI can decrease bleeding in a mouse model of hemophilia. Unexpectedly, they also demonstrate that TFPI derived from a hematopoietic cell, presumably platelets, serves an essential function in inhibiting TF following vasucular injury.
Hemophilia is the most common cause of inherited coagulopathy. Current treatment includes recombinant or purified factor therapy. However, these treatments are expensive and require intravenous infusion; and formation of inhibitors is common. Small moleculebased therapies targeting natural anticoagulants have the potential advantages of lower cost, oral administration, and absence of inhibitor formation. Yet the optimal targets for this strategy are incompletely defined, and the risk of thrombosis remains a concern. Inhibition of TFPI represents a potential new strategy for mitigating the bleeding risk associated with hemophilia, and the animal models developed by Maroney and colleagues provide valuable insights into how the TFPI system functions in vivo.
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