Impact of fibrinogen concentration in severely ill patients on mechanical properties of whole blood clots

Dempfle, Carl-Erik; Kälsch, Thorsten; Elmas, Elif; Suvajac, Nenad; Lücke, Thomas; Münch, Elke; Borggrefe, Martin

doi:10.1097/mbc.0b013e32830f1b68

Cited by 50 publications

(38 citation statements)

References 17 publications

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“…Our in vivo observations are supported by ex vivo and in vitro cell-based experiments that recapitulate aspects of the murine thrombosis models. Notably, these findings are consistent with studies demonstrating fibrin network density, mechanical stability, and resistance to lysis are positively correlated with fibrinogen concentration in clots triggered by exogenous thrombin 24,30,36,37 but extend these findings to a more physiologically relevant model in which clotting was initiated by TF-bearing primary cells. The vascular cells used in the current study model both arterial (atherosclerotic) disease where plaque rupture exposes blood to subendothelial cells (eg, SMCs) and venous disease where clots are thought to arise on intact but inflamed endothelium (eg, TNF-␣-HSVECs).…”

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confidence: 80%

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Causal relationship between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice

Machlus

Cardenas

Church

et al. 2011

Blood

178

160

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Epidemiologic studies have correlated elevated plasma fibrinogen (hyperfibrinogenemia) with risk of cardiovascular disease and arterial and venous thrombosis. However, it is unknown whether hyperfibrinogenemia is merely a biomarker of the proinflammatory disease state or is a causative mechanism in the etiology. We raised plasma fibrinogen levels in mice via intravenous infusion and induced thrombosis by ferric chloride application to the carotid artery (high shear) or saphenous vein (lower shear); hyperfibrinogenemia significantly shortened the time to occlusion in both models. Using immunohistochemistry, turbidity, confocal microscopy, and elastometry of clots produced in cell and tissue factor-initiated models of thrombosis, we show that hyperfibrinogenemia increased thrombus fibrin content, promoted faster fibrin formation, and increased fibrin network density, strength, and stability. Hyperfibrinogenemia also increased thrombus resistance to tenecteplase-induced thrombolysis in vivo. These data indicate that hyperfibrinogenemia directly promotes thrombosis and thrombolysis resistance and does so via enhanced fibrin formation and stability. These findings strongly suggest a causative role for hyperfibrinogenemia in acute thrombosis and have significant implications for thrombolytic therapy. Plasma fibrinogen levels may be used to identify patients at risk for thrombosis and inform thrombolytic administration for treating acute thrombosis/thromboembolism. IntroductionElevated plasma fibrinogen is associated with risk of cardiovascular disease and arterial and venous thrombosis. [1][2][3][4][5][6][7][8][9] Several studies have detected dose effects, with increased risk of death or thrombosis in subjects with the highest plasma fibrinogen concentrations. [6][7][8][9] The Framingham 7 and Fragmin During Instability in Coronary Artery Disease 8 studies positively correlated fibrinogen levels with risk of cardiovascular disease and incidence of death and/or myocardial infarction, respectively. The Leiden Thrombophilia Study showed that persons with elevated fibrinogen levels (4.0-4.9 vs Ͻ 3.0 mg/mL, 130%-160% of normal) have an adjusted odds ratio for venous thrombosis of 1.6, whereas persons with Ն 5 mg/mL fibrinogen (Ն 170% of normal) have a 4-fold higher thrombotic risk, even after adjusting for C-reactive protein levels. 9 These epidemiologic studies suggest that elevated fibrinogen is an independent risk factor for both arterial and venous thrombosis and therefore a potential diagnostic and therapeutic target for predicting and reducing thrombosis.Importantly, however, epidemiologic studies have not and cannot show a causal relationship between fibrinogen and disease etiology. 2,10,11 Fibrinogen levels increase with age, inflammatory processes, hematocrit, hypertension, glucose intolerance, cigarette smoking, and adiposity, and high fibrinogen levels increase plasma viscosity, a demonstrated risk factor for coronary heart disease. 5,6,12 These potential confounders have not permitted distinction between fibr...

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confidence: 80%

“…Fibrin network structure determines clot viscoelasticity, 24,30 suggesting that elevated fibrinogen alters clot mechanical properties. To For personal use only.…”

Section: Elevated Fibrinogen Increases Clot Mechanical Strengthmentioning

confidence: 99%

Causal relationship between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice

Machlus

Cardenas

Church

et al. 2011

Blood

178

160

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“…20,30,38 A higher target may be appropriate because clot firmness continues to increase with fibrinogen concentration throughout the normal range. 7 The present study has several limitations. Our analysis does not strictly meet the definition for intention to treat.…”

Section: Fibrinogen Concentrate Therapy In Aortic Surgerymentioning

confidence: 99%

“…[6][7][8] Immediately after cardiopulmonary bypass (CPB), fibrin formation is impaired to a greater extent than either thrombin generation or the platelet component of clot strength. 9 The plasma concentration of fibrinogen 10,11 and the firmness (elasticity/ strength) of the fibrin-based clot 9 have been reported to decrease by an average of 34-42% in response to CPB.…”

mentioning

confidence: 99%

Effects of Fibrinogen Concentrate as First-line Therapy during Major Aortic Replacement Surgery

et al. 2013

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Background: Fibrinogen is suggested to play an important role in managing major bleeding. However, clinical evidence regarding the effect of fibrinogen concentrate (derived from human plasma) on transfusion is limited. The authors assessed whether fibrinogen concentrate can reduce blood transfusion when given as intraoperative, targeted, first-line hemostatic therapy in bleeding patients undergoing aortic replacement surgery. Methods: In this single-center, prospective, placebocontrolled, double-blind study, patients aged 18 yr or older undergoing elective thoracic or thoracoabdominal aortic replacement surgery involving cardiopulmonary bypass were randomized to fibrinogen concentrate or placebo, administered intraoperatively. Study medication was given if patients had clinically relevant coagulopathic bleeding immediately after removal from cardiopulmonary bypass and completion of surgical hemostasis. Dosing was individualized using the fibrin-based thromboelastometry test. If bleeding continued, a standardized transfusion protocol was followed. Results: Twenty-nine patients in the fibrinogen concentrate group and 32 patients in the placebo group were eligible for the efficacy analysis. During the first 24 h after the administration of study medication, patients in the fibrinogen concentrate group received fewer allogeneic blood components than did patients in the placebo group (median, 2 vs. 13 U; P < 0.001; primary endpoint). Total avoidance of transfusion was achieved in 13 (45%) of 29 patients in the fibrinogen concentrate group, whereas 32 (100%) of 32 patients in the placebo group received transfusion (P < 0.001). There was no observed safety concern with using fibrinogen concentrate during aortic surgery.

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“…As coagulation progresses the viscoelastic modulus of the blood clot attains a plateau level after the fibrin mesh has been formed. Because fibrin cross-linking is dependent in part on fibrinogen content, the maximum plateau modulus provides information on blood fibrinogen levels [12].…”

Section: Introductionmentioning

confidence: 99%

Assessing blood coagulation status with laser speckle rheology

Tripathi

Hajjarian

Cott

et al. 2014

Biomed. Opt. Express

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Abstract:We have developed and investigated a novel optical approach, Laser Speckle Rheology (LSR), to evaluate a patient's coagulation status by measuring the viscoelastic properties of blood during coagulation. In LSR, a blood sample is illuminated with laser light and temporal speckle intensity fluctuations are measured using a high-speed CMOS camera. During blood coagulation, changes in the viscoelastic properties of the clot restrict Brownian displacements of light scattering centers within the sample, altering the rate of speckle intensity fluctuations. As a result, blood coagulation status can be measured by relating the time scale of speckle intensity fluctuations with clinically relevant coagulation metrics including clotting time and fibrinogen content. Our results report a close correlation between coagulation metrics measured using LSR and conventional coagulation results of activated partial thromboplastin time, prothrombin time and functional fibrinogen levels, creating the unique opportunity to evaluate a patient's coagulation status in real-time at the point of care. (2013). 11. M. Kaibara, "Rheology of blood coagulation," Biorheology 33(2), 101-117 (1996). 12. C. E. Dempfle, T. Kälsch, E. Elmas, N. Suvajac, T. Lücke, E. Münch, and M. Borggrefe, "Impact of fibrinogen concentration in severely ill patients on mechanical properties of whole blood clots," Blood Coagul.

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Impact of fibrinogen concentration in severely ill patients on mechanical properties of whole blood clots

Cited by 50 publications

References 17 publications

Causal relationship between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice

Causal relationship between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice

Effects of Fibrinogen Concentrate as First-line Therapy during Major Aortic Replacement Surgery

Assessing blood coagulation status with laser speckle rheology

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