The contact system contains a series of proteases and cofactors that assemble on cardiovascular cells, platelets, and other inflammatory cells. This system has not been appreciated historically because deficiencies of contact system proteins were not known to be associated with bleeding disorders. During a Plenary session, Professor Thomas Renné presented a captivating talk on the role of the Contact Pathway and its role in thrombosis and hemostasis. He reported results of pivotal studies that highlight this pathway as a target for the development of “safe” anticoagulants that interfere with pathologic thrombosis but do not increase bleeding risk.  In today’s discussion, he described the contact pathway, its activating signals, its role in inflammation, and contribution to coagulation and pathological thrombosis.

Regarding inflammation and the contact pathway, bradykinin appears to be the primary signaling agent, involved in angioedema. Mast cell-heparin activates the contact pathway, mediating capillary leakage via increased bradykinin with resultant angioedema that is seen in mouse models and patients with hereditary angioedema (HAE). Prof. Renné used the example of a case of HAEIII caused by a pathological variant affecting FXII glycosylation that caused excess contact pathway activation to highlight this point.

Prof. Renné illustrated that deficiency of factor XII, although causing an vitro prolonged aPTT, does not result in abnormal hemostasis or bleeding. Rather, the “extrinsic” coagulation pathway mediated via tissue factor appears to be sufficient for hemostasis. Moreover, experiments using FXII deficient mouse models showed that it is possible to block thrombosis without increased bleeding. Taken together, these findings suggest model of hemostasis in which the factors that are important in thrombosis differ to those required for adequate hemostasis, and in which FXII regulating the contact activation pathway, is a key component that offers potential from a therapeutic perspective. This point was demonstrated by research showing that inhibitors against factor XII or its activated form, such as the antibody 3F7, block thrombosis as efficiently as heparin and do not cause increased bleeding. This finding has additional potential implications in the use of ECMO, in cancer-associated thrombosis, and stroke.

Prof Renné went on to describe how Factor XII is activated by the inorganic polymer polyphosphate (PolyP). Platelets have two pools of PolyP, small amounts of short chain soluble molecules that are released to the supernatant; these molecules may support other procoagulant mechanisms. In contrast, insoluble polyphosphate particles (micro-particles) are released from activated platelets and are retained on the platelet surface. These particles potently activate FXII and drive thrombosis in a FXII-dependent manner. Targeting platelet polyphosphates with exopolyphosphates (PPX) interferes with thrombosis, but does not increase bleeding, confirming they operate by FXII activation in vivo.

To close, Dr. Renné suggested that a greater understanding of the contact pathway may lead the way to new anti-thrombotic therapies, without increasing the risk of bleeding whilst also providing additional anti-inflammatory benefits.

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