Major strides have been made in understanding the intrinsic coagulation pathway, producing potential new targets for therapies designed to prevent thrombus formation, according to a three-part State of the Art session held Tuesday at the ISTH 2015 Congress. Thrombi induced by medical devices are among the potential targets of effective inhibitors of the intrinsic coagulation pathway.

From left, Jeffrey Weitz, moderator Harry R. Buller, and Patricia Liaw.

From left, Jeffrey Weitz, moderator Harry R. Büller, and Patricia Liaw.

The session, titled “Evolving Role of the Intrinsic Pathway,” included an update on the role of histones and extracellular DNA in the emerging field of immunothrombosis as well as compelling data on the importance of polyphosphate in accelerating thrombin generation. Both suggest that the classic diagrams of clotting pathways may need to be revised to accommodate a more sophisticated and complex array of clotting mediators.

As opposed to the extrinsic coagulation pathway, which is largely mediated by tissue factor, the intrinsic pathway, also known as the contact activation pathway, is triggered when prekallikrein and factor XII assemble, as reviewed by James Morrissey, Biochemistry Department, University of Illinois, Champaign-Urbana, U.S.A. He explained that the intrinsic pathway is not required for hemostasis, but once activated, it does trigger the conventional pathways of clot formation, and it is important for a complete understanding of the risks of both thromboembolism and bleeding.

Immunothrombosis

Many roles of the intrinsic pathway are just now being identified. One such role is immunothrombosis, which is a term recently coined to recognize the role of intravascular thrombi in recruiting immune cells and platelets to prevent infection, according to Patricia Liaw, Division of Hematology and Thromboembolism, McMaster University, Hamilton, Canada.

Reviewing a variety of evidence indicating that this clotting “is important for preventing the dissemination of invading microbes,” Liaw presented evidence that extracellular DNA and histones “exert procoagulant, pro-inflammatory, and anti-fibrinolytic effects.” In some situations, these effects would be expected to be beneficial, but Liaw also outlined how these processes contribute to disease pathology, particularly in mediating organ damage associated with sepsis.

These processes have important implications for both enhancing the immunoprotective effects of clotting and preventing adverse consequences. In a review of the factors that mediate these processes, Liaw identified several potential therapeutic targets. In addition to extracellular DNA and histones, these targets could include the inflammatory mediators released by neutrophils or other immunoregulatory cells.

Polyphosphate

Polyphosphate, which appears to have broad roles in biology, is also a major focus of research in the intrinsic coagulation pathway, according to Morrissey. While microbial polyphosphate is “a very potent trigger of the contact pathway” that may have an important role in mediating host response to pathogens, there has been growing attention to the role of polyphosphate released by activated platelets in accelerating clotting, he said.

In addition to the evidence that polyphosphate released by activated platelets is capable of inhibiting the activity of tissue factor pathway inhibitor (TFPI) and enhancing fibrin clot structure, Morrissey said that there is now intriguing evidence that polyphosphate amplifies factor XI and may be an important co-factor for this pro-coagulatory loop.

Proof-of-principle studies investigating the potential for inhibitors of polyphosphate to attenuate clot formation have already been completed, according to Morrissey. These studies demonstrated prevention of clot formation in mouse models of arterial and venous thrombosis. Although initial compounds were toxic, Morrissey said that recent work with better tolerated polyphosphate inhibitors have suggested that these treatments may provide antithrombotic efficacy comparable to heparin, but with a reduced bleeding risk.

Medical Device-Induced Thrombosis

Preventing thrombi caused by medical devices may be one of the most important potential applications of therapies that inhibit the intrinsic coagulation pathway. In an explanation of the underlying pathogenic process of device-induced clotting, Jeffrey Weitz, executive director, Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Canada, provided a broad array of compelling evidence that activation of factor XII to factor XIIa plays a central role. Indeed, he identified this among critical targets for novel therapies.

“Emerging strategies for inhibition of components of the intrinsic pathway, including inhibitory antibodies against factor XIIa, XIa and small molecular inhibitors of factor XIa, or factor XII or XI antisense oligonucleotides, have the potential to inhibit the root cause of device-associated thrombosis more safely than anticoagulants such as heparin or warfarin,” Weitz reported.

A number of other strategies also have potential for reducing device-associated thrombi, particularly the development of novel biomaterials with reduced propensity to generate the intrinsic coagulation pathway. Weitz suggested that work in understanding this pathway has broad implications for developing strategies to improve outcomes in the large patient populations who depend on these devices.

 

By Ted Bosworth |June 23, 2015