Reincarnation of ancient links between coagulation and complement

Abstract

To cite this article: Conway EM. Reincarnation of ancient links between coagulation and complement. J Thromb Haemost 2015;13 (Suppl. 1): S121-S32.Summary. Throughout evolution, organisms have developed means to contain wounds by simultaneously limiting bleeding and eliminating pathogens and damaged host cells via the recruitment of innate defense mechanisms. Disease emerges when there is unchecked activation of innate immune and/or coagulation responses. A key component of innate immunity is the complement system. Concurrent excess activation of coagulation and complement -two major blood-borne proteolytic pathways -is evident in numerous diseases, including atherosclerosis, diabetes, venous thromboembolic disease, thrombotic microangiopathies, arthritis, cancer, and infectious diseases. Delineating the cross-talk between these two cascades will uncover novel therapeutic insights.

Complement in disease: a defence system turning offensive

“…Moreover, the alternative pathway can be divided into at least two arms: one that initiates complement activation and invokes pattern recognition (that is, by properdin) or hydrolysis of C3 (that is, by tick-over), and one that mediates amplification independent of the initiating mechanism. Finally, ‘extrinsic’ proteases that are not traditionally associated with the complement system, in particular those from the coagulation cascade (for example thrombin and plasmin) can directly activate C3 and/or C5, thereby providing an additional, context-specific pathway of complement activation 31,178 . Although the differentiation of the classical, lectin and alternative pathways remains helpful in many circumstances, this distinction should be used with care.…”

“…Cooperation between the complement and coagulation systems has many potential implications for health and disease 31 . Both cascades are driven by tiered, serine protease-mediated activation steps, and examples of each pathway activating the other have been reported.…”

“…The release of complement components such as FD from the α-granules of activated platelets might fuel convertase-mediated complement turnover. Platelets themselves are well-protected from complement damage through the expression and engagement of complement regulators 31,34 ; however, the generation of complement effectors could be important in enhancing platelet activation. Soluble MAC (that is, sC5b–9) can trigger the secretion of the platelets’ α-granules, and C1q induces the expression of P-selectin, among other effects 34 .…”

“…Although C3aR and C5aR1 are barely detectable on resting platelets, both are strongly upregulated upon platelet activation. The physiological effects of complement–platelet crosstalk on the defensive actions of complement or on platelet clearance remains debated, but current observations suggest that tempered complement activation on activated platelets by effector-mediated stimulation serves to sustain or amplify platelet activation 31 .…”

HUS and atypical HUS

“…[95][96][97] In addition, numerous molecular interactions between complement and coagulation proteins have been described. 98,99 The physiological relevance of most of these interactions has not been proven. Some interactions, such as cleavage of C5 by thrombin, may be clinically relevant.…”