HPE CSL Managing Perioperative Bleeding handbook - Page 10

Pathophysiology
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levels is hyperfibrinolysis . Hyperfibrinolysis is reported in a significant percentage of severely injured patients , and is accompanied by a high mortality rate (> 70 %). Aggressive treatment of hyperfibrinolysis with tranexamic acid is the standard of care for severe trauma patients ; replenishment of fibrinogen is also considered within the existing treatment algorithms when low values of fibrinogen are diagnosed ( FibTEM < 7mm ).
Pregnant women have fibrinogen values higher than normal before delivery . In presence of a post-partum haemorrhage ( PPH ), low fibrinogen levels have a negative prognostic value . Values below 2.0g / l or FibTEM < 10mm are predictive of PPH progression and need for massive transfusions . In liver surgery , and namely in liver transplant , the fibrinolytic system is activated during the anhepatic and the reperfusion phases . Additionally , the fibrinogen levels in cirrhotic patients are reduced . Hypofibrinogenemia in these patients is a determinant of severe bleeding . Values below 1.5 – 2.0g / l or FibTEM < 6mm ) should trigger fibrinogen supplementation .
Cardiac surgery is a common clinical scenario for acquired hypofibrinogenemia . Dilution and consumption during cardiopulmonary bypass are the main determinants , but other mechanisms may be involved . Extensive use of cell-saver , with washing of the saved blood , results in a loss of coagulation factors and fibrinogen . Patients undergoing ascending aorta surgery due to acute aortic dissection may form clots inside the false chamber , leading to fibrinogen consumption . Finally , postoperative bleeding from any source ( platelet dysfunction , hyperfibrinolysis , residual heparin , surgical sources and others ) invariably lead to a fibrinogen loss . A study highlighted that postoperative bleeding becomes dependent when fibrinogen levels are below 2.0g / dl , with a 50 % positive predictive value for severe bleeding when the fibrinogen levels fall below 1.15 g / l . 11
Hyperfibrinogenemia High levels of fibrinogen may depend on genetic factors ( G-455A polymorphism ) but is more commonly the result of concomitant inflammatory diseases and lifestyle ( smoking ). Elderly subjects and females have higher fibrinogen values ; 12
seasonal variations have been reported . 13
The most important consequence of increased fibrinogen levels is the concomitant increase in cardiovascular risk . Many studies demonstrated an association between elevated plasma fibrinogen levels and cardiovascular risk . 14 16 Venous thromboembolism can be associated with high fibrinogen levels . It is also true that therapies that reduce the cardiovascular risk ( ACE inhibitors ) simultaneously reduce fibrinogen levels . However , it is not fully established that the link between high fibrinogen levels and cardiovascular events is causative rather than associative . There are several pathways by which fibrinogen triggers acute cardiovascular events . The most intuitive is that fibrinogen is strongly involved in local thrombus formation in the presence of a ruptured atherosclerotic plaque . There are animal models of induced arterial and venous thrombosis demonstrating that higher fibrinogen levels shorten the time to vessel occlusion , and generate a more stable and lysis-resistant clot .
Even chronic atherosclerotic plaque formation can involve fibrinogen . Atherosclerotic plaques contain fibrin ( ogen ) deposits . Fibrin is incorporated in the plaque and contributes to plaque growth and instability . 5
An important link between fibrin ( ogen ) and thrombosis is represented by the contribution of fibrin to the clot physical properties . Different degrees of contribution may result in different clot visco-elastic properties , firmness , and resistance to lysis . Clots characterised by an increased fibrin fibre density ( usually produced by LMW fibrinogen ) are more likely to be associated with cardiovascular events . This was demonstrated in young subjects suffering an acute coronary syndrome . 5
As already mentioned , fibrinogen levels are elevated in a number of conditions characterised by a systemic inflammatory reaction syndrome . It is still unclear if this kind of hyperfibrinogenemia increases the risk of thrombotic events . Of note is that no reports of an increased thrombogenic risk exist in case of exogenous fibrinogen supplementation .
Conclusions Fibrinogen is certainly involved in a number of inflammatory , haemorrhagic , and thrombotic processes . Its peculiar position at the crossroad between
inflammation and coagulation results in dynamic changes in fibrinogen concentration and structural changes of the fibrin network . Many of the conditions where fibrinogen levels are of clinical interest are acute and emergency situations , and fibrinogen levels are often indirectly measured with point-of-care tests in the emergency room , operating room and intensive care unit . The number of studies addressing the role of fibrinogen in both haemorrhagic and thrombotic syndromes is increasing : in the last three years more than 270 articles per year have been published on fibrinogen in bleeding syndromes , and about 300 per year on fibrinogen and thrombosis . Despite this , some results are still conflicting , and there is certainly room available for further studies .
References 1 Lowe GDO , Rumley A , Mackie IJ . Plasma fibrinogen . Ann Clin Biochem 2004 ; 41 : 430 – 40 . 2 Laurens N , Koolwijk P , De Maat MPM . Fibrin structure and wound healing . J Thromb Haemost 2006 ; 4:932 – 9 . 3 Hantgan RR , Francis CW , Marder VJ . Fibrinogen structure and physiology . In : Colman RW et al ( eds ) Hemostasis and Thrombosis : Basic Principles and Clinical Practice . Philadelphia : JB Lippincott Co 1994 ; 277 – 300 . 4 Weisel JW et al . Determination of the topology of factor XIIIa-induced fibrin gamma-chain cross-links by electron microscopy of ligated fragments . J Biol Chem 1993 ; 268:26618 – 24 . 5 Ariens RAS . Fibrin ( ogen ) and thrombotic disease . J Thromb Haemost 2013 ; 11 ( Suppl . 1 ): 294 – 305 . 6 Hoppe B . Fibrinogen and factor XIII at the intersection of coagulation , fibrinolysis and inflammation . Thromb Haemost 2014 ; 112:649 – 58 . 7 Endo Y et al . Interactions of ficolin and mannosebinding lectin with fibrinogen / fibrin augment the lectin complement pathway . J Innate Immun 2010 ; 2:33 – 42 . 8 Egorina EM , Sovershaev MA , Hansen JB . The role of tissue factor in systemic inflammatory response syndrome . Blood Coagul Fibrinolysis 2011 ; 22:451 – 6 . 9 Hoffman M , Monroe DM 3rd . A cell-based model of hemostasis . Thromb Haemost 2001 ; 85:958 – 65 . 10 Kunutsor SK et al . Baseline and long-term fibrinogen levels and risk of sudden cardiac death : A new prospective study and meta-analysis . Atherosclerosis 2016 ; 245:171 – 80 . 11 Ranucci M et al . Fibrinogen levels after cardiac surgical procedures : association with postoperative bleeding , trigger values , and target values . Ann Thorac Surg 2016 ; 102:78 – 85 . 12 Lowe GD et al . Epidemiology of coagulation factors , inhibitors and activation markers : the Third Glasgow MONICA Survey . I . Illustrative reference ranges by age , sex and hormone use . Br J Haematol 1997 ; 97:775 – 84 . 13 van der Bom JG et al . Seasonal variation in fibrinogen in the Rotterdam Study . Thromb Haemost 1997 ; 78:1059 – 62 . 14 Danesh J et al . Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality : an individual participant meta-analysis . JAMA 2005 ; 294:1799 – 809 . 15 Kannel WB et al . Fibrinogen and risk of cardiovascular disease : the Framingham Study . JAMA 1987 ; 258:1183 – 6 . 16 Lowe GD , Rumley A . Fibrinogen and its degradation products as thrombotic risk factors . Ann N Y Acad Sci 2001 ; 936:560 – 5 .
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Pathophysiology levels is hyperfibrinolysis. Hyperfibrinolysis is reported in a significant percentage of severely injured patients, and is accompanied by a high mortality rate (>70%). Aggressive treatment of hyperfibrinolysis with tranexamic acid is the standard of care for severe trauma patients; replenishment of fibrinogen is also considered within the existing treatment algorithms when low values of fibrinogen are diagnosed (FibTEM <7mm). Pregnant women have fibrinogen values higher than normal before delivery. In presence of a post-partum haemorrhage (PPH), low fibrinogen levels have a negative prognostic value. Values below 2.0g/l or FibTEM <10mm are predictive of PPH progression and need for massive transfusions. In liver surgery, and namely in liver transplant, the fibrinolytic system is activated during the anhepatic and the reperfusion phases. Additionally, the fibrinogen levels in cirrhotic patients are reduced. Hypofibrinogenemia in these patients is a determinant of severe bleeding. Values below 1.5–2.0g/l or FibTEM <6mm) should trigger fibrinogen supplementation. Cardiac surgery is a common clinical scenario for acquired hypofibrinogenemia. Dilution and consumption during cardiopulmonary bypass are the main determinants, but other mechanisms may be involved. Extensive use of cell-saver, with washing of the saved blood, results in a loss of coagulation factors and fibrinogen. Patients undergoing ascending aorta surgery due to acute aortic dissection may form clots inside the false chamber, leading to fibrinogen consumption. Finally, postoperative bleeding from any source (platelet dysfunction, hyperfibrinolysis, residual heparin, surgical sources and others) invariably lead to a fibrinogen loss. A study highlighted that postoperative bleeding becomes dependent when fibrinogen levels are below 2.0g/dl, with a 50% positive predictive value for severe bleeding when the fibrinogen levels fall below 1.15 g/l. 11 10 Hyperfibrinogenemia High levels of fibrinogen may depend on genetic factors (G-455A polymorphism) but is more commonly the result of concomitant inflammatory diseases and lifestyle (smoking). Elderly subjects and females have higher fibrinogen values; 12 hospitalpharmacyeurope.com seasonal variations have been reported. 13 The most important consequence of increased fibrinogen levels is the concomitant increase in cardiovascular risk. Many studies demonstrated an association between elevated plasma fibrinogen levels and cardiovascular risk. 14–16 Venous thromboembolism can be associated with high fibrinogen levels. It is also true that therapies that reduce the cardiovascular risk (ACE inhibitors) simultaneously reduce fibrinogen levels. However, it is not fully established that the link between high fibrinogen levels and cardiovascular events is causative rather than associative. There are several pathways by which fibrinogen triggers acute cardiovascular events. The most intuitive is that fibrinogen is strongly involved in local thrombus formation in the presence of a ruptured atherosclerotic plaque. There are animal models of induced arterial and venous thrombosis demonstrating that higher fibrinogen levels shorten the time to vessel occlusion, and generate a more stable and lysis-resistant clot. Even chronic atherosclerotic plaque formation can involve fibrinogen. Atherosclerotic plaques contain fibrin(ogen) deposits. Fibrin is incorporated in the plaque and contributes to plaque growth and instability. 5 An important link between fibrin(ogen) and thrombosis is represented by the contribution of fibrin to the clot physical properties. Different degrees of contribution may result in different clot visco-elastic properties, firmness, and resistance to lysis. Clots characterised by an increased fibrin fibre density (usually produced by LMW fibrinogen) are more likely to be associated with cardiovascular events. This was demonstrated in young subjects suffering an acute coronary syndrome. 5 As already mentioned, fibrinogen levels are elevated in a number of conditions characterised by a systemic inflammatory reaction syndrome. It is still unclear if this kind of hyperfibrinogenemia increases the risk of thrombotic events. Of note is that no reports of an increased thrombogenic risk exist in case of exogenous fibrinogen supplementation. Conclusions Fibrinogen is certainly involved in a number of inflammatory, haemorrhagic, and thrombotic processes. Its peculiar position at the crossroad between inflammation and coagulation results in dynamic changes in fibrinogen concentration and structural changes of the fibrin network. Many of the conditions where fibrinogen levels are of clinical interest are acute and emergency situations, and fibrinogen levels are often indirectly measured with point-of-care tests in the emergency room, operating room and intensive care unit. The number of studies addressing the role of fibrinogen in both haemorrhagic and thrombotic syndromes is increasing: in the last three years more than 270 articles per year have been published on fibrinogen in bleeding syndromes, and about 300 per year on fibrinogen and thrombosis. Despite this, some results are still conflicting, and there is certainly room available for further studies. References 1 Lowe GDO, Rumley A, Mackie IJ. Plasma fibrinogen. Ann Clin Biochem 2004;41: 430–40. 2 Laurens N, Koolwijk P, De Maat MPM. Fibrin structure and wound healing. J Thromb Haemost 2006;4:932–9. 3 Hantgan RR, Francis CW, Marder VJ. Fibrinogen structure and physiology. In: Colman RW et al (eds) Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia: JB Lippincott Co 1994;277–300. 4 Weisel JW et al. Determination of the topology of factor XIIIa-induced fibrin gamma-chain cross-links by electron microscopy of ligated fragments. J Biol Chem 1993;268:26618–24. 5 Ariens RAS. Fibrin(ogen) and thrombotic disease. J Thromb Haemost 2013;11 (Suppl. 1):294–305. 6 Hoppe B. Fibrinogen and factor XIII at the intersection of coagulation, fibrinolysis and inflammation. Thromb Haemost 2014;112:649–58. 7 Endo Y et al. 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