Role of the coagulation system in acute antibody mediated rejection The activation of the coagulation system of proteins leads to thrombin-activated platelet aggregation with the subsequent conversion of soluble fibrinogen into a stable fibrin plug (Figure 1.6). The system may be activated by local endothelial cell damage or by tissue factor (TF) released by traumatised cells that binds with Factor VIIa, resulting in thrombin generation (extrinsic pathway). Figure 1.6 Activation pathways of the coagulation system via the intrinsic and extrinsic pathways. (TFPI = tissue factor pathway inhibitor) (Source: xxxxx://xxxx0.xxxxxxxxxx.xxx/hematology/111004/coagulation-cascade) Antibody mediated rejection, (amongst other causes including sepsis, complement regulator deficiencies, pregnancy, surgery, malignancies, and severe hypertension) has been shown to be an important cause of thrombotic microangiopathy (TMA) – a condition characterised (in the acute phase) by endothelial cell damage and inflammation, thrombin formation and platelet aggregation and microvascular thrombi (40). In a recent review by Xxxx et al (41), peritubular capillary C4d staining has been reported as being positive in biopsies with TMA due to AMR suggesting that complement activation is a key step in its pathogenesis. In the same review, a group reported that C4d deposits and C4d deposits with C5b-9 occurred in 88 % and 59.5% of TMA confirmed biopsies in 36 patients. Furthermore, they reported that 76 %, 59.9%, 9.5 % of the samples had glomerular, arterioles and PTC, C4d deposits respectively. This would suggest a different distribution of C4d deposition in TMA with the authors suggesting that “C4d and MAC complex should be investigated as possible diagnostic biomarkers in the clinical work-up of patients suspected of having complement-mediated TMA” (42). The activation and regulation of the complement and coagulation systems does not occur as discreet isolated phenomenon. Indeed, thrombin can directly activate complement, independent of the classical pathway and conversely antibody-mediated complement activation can also activate coagulation pathways via increased TF activity. The membrane attack complex (C5b-9) and C5a have been reported to initiate the TF- dependent coagulation pathways by increasing TF synthesis by endothelial cells (26)(43)(44)(45)(46). MASP-2 (a lectin pathway enzyme) has been shown to cleave prothrombin to thrombin which can further cleave factor XIII and fibrinogen to form a crosslinked fibr...
