Role of factor XII in thrombin generation and fibrinolysis during cardiopulmonary bypass

The Lancet ◽  
1994 ◽  
Vol 344 (8931) ◽  
pp. 1192-1193 ◽  
Author(s):  
J.F. Burman ◽  
H.I. Chung ◽  
J.C.R. Lincoln ◽  
D.A. Lane ◽  
H. Philippou ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Thrombin Generation ◽  
Factor Xii

Dual role of collagen in factor XII–dependent thrombus formation

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 881-890 ◽  
Author(s):  
Paola E. J. van der Meijden ◽  
Imke C. A. Munnix ◽  
Jocelyn M. Auger ◽  
José W. P. Govers-Riemslag ◽  
Judith M. E. M. Cosemans ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Type I Collagen ◽  
Factor Viia ◽  
Thrombus Formation ◽  
Dual Role ◽  
Type I ◽  
Factor Xii ◽  
Glycoprotein Vi

Abstract In vivo mouse models have indicated that the intrinsic coagulation pathway, initiated by factor XII, contributes to thrombus formation in response to major vascular damage. Here, we show that fibrillar type I collagen provoked a dose-dependent shortening of the clotting time of human plasma via activation of factor XII. This activation was mediated by factor XII binding to collagen. Factor XII activation also contributed to the stimulating effect of collagen on thrombin generation in plasma, and increased the effect of platelets via glycoprotein VI activation. Furthermore, in flow-dependent thrombus formation under coagulant conditions, collagen promoted the appearance of phosphatidylserine-exposing platelets and the formation of fibrin. Defective glycoprotein VI signaling (with platelets deficient in LAT or phospholipase Cγ2) delayed and suppressed phosphatidylserine exposure and thrombus formation. Markedly, these processes were also suppressed by absence of factor XII or XI, whereas blocking of tissue factor/factor VIIa was of little effect. Together, these results point to a dual role of collagen in thrombus formation: stimulation of glycoprotein VI signaling via LAT and PLCγ2 to form procoagulant platelets; and activation of factor XII to stimulate thrombin generation and potentiate the formation of platelet-fibrin thrombi.

scholarly journals Stimulated Platelets but Not Endothelium Generate Thrombin Via a Factor XIIa-Dependent Mechanism Requiring Phosphatidylserine Exposure

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 258-258 ◽  
Author(s):  
Pavan K. Bendapudi ◽  
Karen Deceunynck ◽  
Secil Koseoglu ◽  
Roelof Hendrik Bekendam ◽  
Shauna D Mason ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Thrombin Generation ◽  
Thrombus Formation ◽  
Specific Inhibitor ◽  
Unexpected Finding ◽  
Factor Xii ◽  
Fibrin Formation ◽  
Platelet Accumulation

Abstract To inhibit pathological thrombus formation without impairing hemostasis is the holy grail of anticoagulant therapy. Recent data from animal models have indicated that factor XII (FXII) may be a promising new antithrombotic target that is particularly intriguing due to the longstanding clinical observation that severe congenital FXII deficiency is not associated with a bleeding diathesis in humans. FXII is thought to participate in thrombus formation after being activated in high shear arterial environments. FXIIa then initiates downstream activation of the contact pathway, culminating in thrombin generation. However, the relevant cell surface for FXII activation remains unclear. Here we compare the role of platelets versus endothelial cells in FXII activation and study the function of surface phospholipids in this process. To explore the effect of FXII inhibition on thrombus formation in vivo, we used antibody X210-C01, a novel human IgG1 developed using phage-display technology that blocks both mouse and human FXIIa. Using a mouse laser injury model of arterial thrombosis, we showed that X210-C01 inhibited both fibrin formation and platelet accumulation at sites of vascular injury. Plasma removed from animals after completion of these experiments was used to quantify the concentrations of X210-C01 achieved in vivo at a given dose. FXII inhibition was somewhat more potent in preventing platelet accumulation (IC50 dose = 27 mg/kg, R2=0.93) than fibrin formation (IC50 dose = 43 mg/kg, R2=0.95). Importantly, treatment with X210-C01 at 100 mg/kg did not prolong bleeding times or increase total blood loss in a tail bleeding assay. To evaluate the mechanism underlying our in vivo observations, we studied the differential role of FXII in thrombin generation by stimulated platelets and endothelium. X210-C01 did not globally inhibit SFLLRN-induced platelet aggregation or granule release. We next performed a fluorogenic thrombin generation assay (TGA) using human platelets treated with the peptide agonist SFLLRN. X210-C01 inhibited platelet-based thrombin generation in a dose-dependent fashion, whereas anti-tissue factor (TF) and anti-factor VIIa (FVIIa) antibodies did not. By contrast, in a similar TGA using SFLLRN-stimulated endothelial cells, X210-C01 had no effect, while anti-TF antibodies abrogated thrombin generation. These results indicate that stimulated endothelium generates thrombin by a mechanism distinct from that of platelets. FXII is known to be activated in vitro by anionic surfaces. Because phosphatidylserine (PS) is a negatively-charged phospholipid expressed on the surface of stimulated platelets, we reasoned that PS may serve as the platelet-based activator of FXII. To test this hypothesis, we used lactadherin, a potent and specific inhibitor of PS, in the platelet-based TGA and showed that PS blockade inhibited platelet-based thrombin generation at concentrations as low as 10 nM. We then used a chromogenic FXIIa activity assay to test the ability of PS-containing liposomes to activate FXII. Liposomes containing 80% phosphatidylcholine (PC) and 20% PS (PC-PS 80/20) failed to activate FXII at concentrations as high as 100 µM. In this assay, SFLLRN-stimulated platelets led to significantly greater FXII activation than either resting platelets or the PC-PS 80/20 liposomes tested. In summary, we have made the unexpected finding that thrombin generation on the surface of stimulated platelets proceeds by a FXIIa-dependent pathway and does not require FVIIa or TF. By contrast, thrombin generation on endothelium requires TF but not FXIIa. Additionally, surface PS is necessary but not sufficient for platelet-based FXII activation and thrombin generation, pointing to the involvement of a second platelet component. Further studies will be directed towards investigating the in vivo role of platelet-based FXII activation in arterial thrombus formation. Disclosures Mason: Shire Pharmaceuticals: Employment. Kenniston:Shire Pharmaceuticals: Employment.

scholarly journals Contact system activation and high thrombin generation in hyperthyroidism

2017 ◽  
Vol 176 (5) ◽  
pp. 583-589 ◽  
Author(s):  
Namhee Kim ◽  
Ja-Yoon Gu ◽  
Hyun Ju Yoo ◽  
Se Eun Han ◽  
Young Il Kim ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Thrombin Generation ◽  
Contact System ◽  
Factor Vii ◽  
Factor Xii ◽  
Free T4 ◽  
Thrombotic Risk ◽  
Double Stranded Dna ◽  
System Activation ◽  
Normal Controls

BackgroundHyperthyroidism is associated with increased thrombotic risk. As contact system activation through formation of neutrophil extracellular traps (NET) has emerged as an important trigger of thrombosis, we hypothesized that the contact system is activated along with active NET formation in hyperthyroidism and that their markers correlate with disease severity.Subjects and methodsIn 61 patients with hyperthyroidism and 40 normal controls, the levels of coagulation factors (fibrinogen, and factor VII, VIII, IX, XI and XII),D-dimer, thrombin generation assay (TGA) markers, NET formation markers (histone–DNA complex, double-stranded DNA and neutrophil elastase) and contact system markers (activated factor XII (XIIa), high-molecular-weight kininogen (HMWK), prekallikrein and bradykinin) were measured.ResultsPatients with hyperthyroidism showed higher levels of fibrinogen (median (interquartile range), 315 (280–344) vs 262 (223–300),P = 0.001),D-dimer (103.8 (64.8–151.5) vs 50.7 (37.4–76.0),P < 0.001), peak thrombin (131.9 (102.2–159.4) vs 31.6 (14.8–83.7),P < 0.001) and endogenous thrombin potential (649 (538–736) vs 367 (197–1147),P = 0.021) in TGA with 1 pM tissue factor, neutrophil elastase (1.10 (0.39–2.18) vs 0.23 (0.20–0.35),P < 0.001), factor XIIa (66.9 (52.8–87.0) vs 73.0 (57.1–86.6),P < 0.001), HMWK (6.11 (4.95–7.98) vs 3.83 (2.60–5.68),P < 0.001), prekallikrein (2.15 (1.00–6.36) vs 1.41 (0.63–2.22),P = 0.026) and bradykinin (152.4 (137.6–180.4) vs 118.3 (97.1–137.9),P < 0.001) than did normal controls. In age- and sex-adjusted logistic regression analysis, fibrinogen, factor VIII, IX and XIIa,D-dimer, peak thrombin, neutrophil elastase, HMWK and bradykinin showed significant odds ratios representing hyperthyroidism’s contribution to coagulation and contact system activation. Free T4 was significantly correlated with factors VIII and IX,D-dimer, double-stranded DNA and bradykinin.ConclusionThis study demonstrated that contact system activation and abundant NET formation occurred in the high thrombin generation state in hyperthyroidism and were correlated with free T4 level.

Role of Metalloproteinases and Tissue Inhibitors of Metalloproteinases During Cardiopulmonary Bypass in Rats

ASAIO Journal ◽  
2012 ◽  
Vol 58 (3) ◽  
pp. 204-211 ◽  
Author(s):  
Ralf Guenzinger ◽  
Harald Lahm ◽  
Michael Wottke ◽  
Ruediger Lange
Keyword(s):  
Cardiopulmonary Bypass ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Tissue Inhibitors

Surgical setup for cardiopulmonary bypass through central cannulation

2021 ◽  
Keyword(s):  
Cardiac Surgery ◽  
Cardiopulmonary Bypass ◽  
Surgical Care ◽  
Heart Lung Machine ◽  
American College Of Surgeons ◽  
History Of ◽  
Central Cannulation ◽  
First John ◽  
Clinical Advances

The introduction of cardiopulmonary bypass was one of the most important clinical advances of 1952. In that year, John Gibbon performed the first successful cardiac surgery using cardiopulmonary bypass. The procedure has been described as “One of the most impressive evidences of the role of investigative surgery in the history of medicine in the persevering efforts of Dr. Gibbon for more than 20 years, which finally culminated in a practical heart-lung machine”, at the first John H. Gibbon, Jr. Lecture at the annual meeting of the American College of Surgeons. Due to on-going advancements in cardiopulmonary bypass, many patients with complex heart disease requiring surgical care undergo cardiac surgery while the other organs remain adequately oxygenated and perfused. This tutorial discusses the access, surgical technique, and initiation of cardiopulmonary bypass through central cannulation and describes the safeguards and pitfalls.

Fibrillar type I collagens enhance platelet-dependent thrombin generation via glycoprotein VI with direct support of α2β1 but not αIIbβ3 integrin

2005 ◽  
Vol 94 (07) ◽  
pp. 107-114 ◽  
Author(s):  
Christelle Lecut ◽  
Martine Jandrot-Perrus ◽  
Marion A. H. Feijge ◽  
Judith M. E. M. Cosemans ◽  
Johan W. M. Heemskerk
Keyword(s):  
Thrombin Generation ◽  
Type I Collagen ◽  
Platelet Rich Plasma ◽  
Procoagulant Activity ◽  
Type I ◽  
Platelet Surface ◽  
Glycoprotein Vi ◽  
Collagen Receptors ◽  
Fibrillar Collagens

SummaryThe role of collagens and collagen receptors was investigated in stimulating platelet-dependent thrombin generation. Fibrillar type-I collagens, including collagen from human heart, were most potent in enhancing thrombin generation, in a way dependent on exposure of phosphatidylserine (PS) at the platelet surface. Soluble, non-fibrillar type-I collagen required pre-activation of integrin α2β1 with Mn2+ for enhancement of thrombin generation. With all preparations, blocking of glycoprotein VI (GPVI) with 9O12 antibody abrogated the collagen-enhanced thrombin generation, regardless of the α2β1 activation state. Blockade of α2β1 alone or antagonism of autocrine thromboxane A2 and ADP were less effective. Blockade of αIIbβ3 with abciximab suppressed thrombin generation in platelet-rich plasma, but this did not abolish the enhancing effect of collagens. The high activity of type-I fibrillar collagens in stimulating GPVI-dependent procoagulant activity was confirmed in whole-blood flow studies, showing that these collagens induced relatively high expression of PS. Together, these results indicate that: i) fibrillar type-I collagen greatly enhances thrombin generation, ii) GPVI-induced platelet activation is principally responsible for the procoagulant activity of fibrillar and non-fibrillar collagens, iii) α2β1 and signaling via autocrine mediators facilitate and amplify this GPVI activity, and iv) αIIbβ3 is not directly involved in the collagen effect.

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