HHE Sponsored supplement: Managing perioperative bleed - Page 8

Coagulation and complement systems descend from a common ancestral pathway and have an extensive crosstalk (HMW) and low-molecular weight (LMW) fibrinogen. They act differently in terms of fibrin network characteristics and wound healing. HMW fibrinogen produces a fibrin clot with thick fibres and limited fibre density, whereas the LMW fibrinogen produces clots with thin fibres at higher density. 5 The low-density clots produced by HMW fibrinogen promote angiogenesis in wound healing at a better rate than high-density clots. A second very important role of fibrinogen is its ability to cross-link platelets, promoting the platelet aggregation process. Silent platelets may be activated through a number of different receptors and pathways; the protease-activating receptors (PAR) are one of the most powerful activating receptors, and PAR-dependent platelet activation is triggered by thrombin. Once activated, platelets express the integrin αIIb β3 (better known as the GP IIb/IIIa receptor) on their surface. The GP IIb/IIIa receptor binds fibrinogen, producing a cross-link between platelets (platelet aggregation). The haemostatic process is promoted by a thrombin burst which, in turn, results in fibrin polymerisation and platelet aggregation: in both processes, fibrinogen is an essential player. Thrombin is essential to trigger fibrinogen conversion into fibrin; reptile venoms (reptilase, botropase) are able to convert fibrinogen into fibrin independently from thrombin, and this property is used in some point-of-care tests (platelet-mapping thromboelastography) to create a fibrin-dependent, thrombin-independent clot. Fibrinogen-dependent platelet aggregation is blunted by GP IIb/IIIa inhibitors (commonly used in clinical practice). Again, this mechanism is used to separate fibrin(ogen)-dependent and platelet-dependent clot firmness contribution in some visco-elastic, whole blood point-of-care tests (FibTEM at thromboelastometry and Functional Fibrinogen at thromboelastography). Fibrinogen and inflammation Coagulation and complement systems descend from a common ancestral pathway and have an extensive cross-talk. 6 Within this interaction of different pathways, factor XIII has a specific role: it is responsible for generation of complement C5a during plasma clotting. Fibrinogen enhances the activity of the lectin complement pathway. 7 Through this and other mechanisms, coagulation may trigger inflammation. Inflammation, in turn, has important effects on the coagulation process and namely on fibrinogen-dependent processes. Pro-inflammatory cytokines promote tissue factor release from monocytes and endothelial cells 8 and reduce thrombomodulin expression on endothelial cells, decreasing its anticoagulant properties. 9 Fibrinogen synthesis is strongly enhanced by inflammation and is considered an acute-phase protein. Transcription of the three genes producing the fibrinogen chains is enhanced in the early phases of inflammation, in presence of interleukin-6 and glucocorticoids. 2 Fibrinogen levels are increased in patients with elevated levels of C-reactive protein. 10 In the clinical environment, it is common to find elevated fibrinogen levels whenever a systemic inflammatory reaction is present; this 8 HHE 2018 | hospitalhealthcare.com includes sepsis, chronic inflammatory states in atherosclerosis, pregnancy, smoking, acute exercise, exposure to extracorporeal membrane oxygenation, or cardiopulmonary bypass (after an initial decline). Hypofibrinogenemia There are inherited and acquired conditions leading to hypofibrinogenemia. Afibrinogenemia is usually diagnosed at birth following prolonged umbilical cord bleeding. This severe condition is characterised by spontaneous bleeding in all tissues and may not be compatible with life. Hypofibrinogenemia symptoms depend on the severity of the disease, and may be asymptomatic or accompanied by spontaneous bleeding events or severe bleeding following surgical