It has become increasingly evident that inflammatory processes are intimately linked with the hemostatic system. In this joint session, these interactions are highlighted in three talks focusing on recent progress in the field of coagulation, vascular biology and platelet research. Coagulation activation is a driving force for vascular dysfunction in sickle cell disease. Conversely, genetic predisposition leading to vascular dysfunction in cerebral cavernous malformations promotes hemorrhage by overactivation of the anticoagulant pathway. The autoimmune pathology of heparin-induced thrombocytopenia is moreover critically dependent on the activation of the humoral complement defense pathway. The session will discuss implications of these links for therapies of thrombotic and vascular disorders.

Dr. Rafal Pawlinski will discuss the interplay between coagulation and inflammation in sickle cell disease (SCD). Contribution of vascular inflammation and hypercoagulable state to the pathology of SCD has been recently recognized. Chronic activation of coagulation not only leads to the increased incidence of pro-thrombotic complications, but it is also an important mediator of vascular inflammation and end-organ damage observed in SCD. Preliminary data from Dr. Pawlinski’s lab indicates that inhibiting the activation of the intrinsic coagulation and/or contact pathways by targeting factor XIIa could provide benefits associated with reduced thrombosis, vascular inflammation and end-organ damage in SCD without increasing risk of bleeding complications.

Dr. Mark Ginsberg will discuss vascular signaling in the pathology of cerebral cavernous malformations (CCM). CCM are common brain vascular malformations prone to acute and chronic hemorrhage with significant clinical sequelae. Endothelial cell specific deletion of CCM susceptibility genes (Krit1, Pdcd10) in mice identified upregulation of transcription factors KLF2 and KLF4 as the cause for elevated expression of anticoagulant endothelial receptors. The resulting excessive generation of activated protein C(APC) contributes to CCM hemorrhage and blocking antibodies to anticoagulant endothelial receptors reduce CCM hemorrhage. Plasma levels of soluble thrombomodulin may represent a biomarker for hemorrhagic risk in CCMs and regulators of the Protein C pathway are potential targets for reducing hemorrhage in CCM. 

Dr. Gowthami Arepally will discuss the role of complement activation in the pathogenesis of heparin induced thrombocytopenia (HIT). HIT is an aggressive thrombotic disorder initiated by ultra-large immune complexes (ULICs) containing IgG antibodies to a multivalent antigen composed of platelet factor 4 (PF4) and heparin (H). Patients with HIT remain at risk of death and major morbidity despite optimum anticoagulation. The mechanisms underlying thrombosis in HIT are only partially understood. HIT ULICs activate cellular FcgRIIA to initiate diverse cellular effector functions that engender a prothrombotic environment. However, ULICs also exert other biologic effects. HIT serum and IgG robustly activate complement leading to its deposition on endothelial cells and circulating platelets. To what extent these disparate activities of HIT ULICs contribute to the hypercoagulable state in HIT is not known. In this session, Dr. Arepally will review recent data showing that the complement activating effects of HIT antibodies essentially mediate FcgR-dependent cellular activation. Using in vitro and in vivo models, they demonstrate that HIT ULICs activate complement via the classical pathway, mediate cellular activation via FcgRIIA and support the procoagulant effects of HIT antibodies. These studies provide a rationale for developing non-anticoagulant interventions in HIT and insights into the contribution of complement to other immune-complex mediated thrombotic disorders.