HPE CSL Managing Perioperative Bleeding handbook - Page 8

Pathophysiology 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- 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 includes sepsis, chronic inflammatory states in atherosclerosis, pregnancy, smoking, acute exercise, exposure to extracorporeal membrane oxygenation, or cardiopulmonary bypass (after an initial decline). “Coagulation and complement systems descend from a common ancestral pathway and have an extensive crosstalk” 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). 8 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 hospitalpharmacyeurope.com 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 procedures, trauma and delivery. Clinical manifestations of dysfibrinogenemia are very heterogeneous, ranging from absence of clinically relevant symptoms to major bleeding, and even thrombosis. The evidence of thromboembolic complications in patients with fibrinogen deficiency (in around 30% of the subjects 5 ) is difficult to explain, given the pro-coagulant properties of fibrinogen. The main interpretation is that the low levels of fibrinogen may promote a weak clot, more susceptible to the lytic effects of plasmin. This could result in a partial or total clot breakdown, with embolisation of clot parts. More common are the acquired conditions, which may derive from liver disease, disseminated intravascular coagulation (DIC), thrombolytic therapy, haemodilution or consumption. Basically, acquired hypofibrinogenemia results from a reduced synthesis (liver disease), excessive activation of the haemostatic system with consumption of the substrates (disseminated intravascular coagulation), severe haemodilution (heart