Hypercoagulable States in Cardiovascular Disease

Chan, Mark Y.; Andreotti, Felicita; Becker, Richard C.

doi:10.1161/circulationaha.108.778837

Cited by 114 publications

(87 citation statements)

References 108 publications

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“…On the other hand, although there were no significant differences in the serum levels of Hcy among the MTHFR and CBS genotypes when analyzed alone, the interactions among MTHFR C677T, MTHFR A1298C and CBS844ins68 polymorphisms were significant, corroborating the multifactorial phenotype of the thrombosis (Chan et al, 2008;Guimarães et al, 2009;Miranda-Vilela, 2012), where each gene locus has a small but consistent contribution, and different mutations in different genes interact with each other and with environmental factors to cause the event. Hcy levels in the inherited hypercoagulable phenotypes are a good example of the challenges faced, as discussed below.…”

Section: Discussionmentioning

confidence: 72%

Interactions among methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS) polymorphisms - a cross-sectional study: multiple heterozygosis as a risk factor for higher homocysteine levels and vaso-occlusive episodes

et al. 2017

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ABSTRACT. High plasma homocysteine (Hcy) levels may be responsible for vaso-occlusive episodes and may have acquired and/or genetic causes. This cross-sectional study aimed to investigate the role of methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C) and cystathionine-b-synthase (CBS; T833C/844ins68, G919A) polymorphisms in serum levels of folic acid, vitamin B12 and Hcy, and to verify a possible association between these polymorphisms and the clinical variability. Blood samples of Brazilian patients with a diagnosis of thrombosis were submitted to genotyping by PCR-based methods and serum dosages of folic acid, vitamin B12 and Hcy. Except for the CBS G919A polymorphism, all other genetic markers were in HardyWeinberg equilibrium. An increased risk for venous thrombosis was found for the MTHFR 1298CC carriers (OR = 1.688; 95%CI = 0.839-3.398, P = 0.018) and those homozygously mutant for the CBS haplotype 844ins68/T833C (OR = 2.488; 95%CI = 0.501-12.363, P = 0.031), while heterozygous for this CBS haplotype showed an increased risk for higher Hcy levels (OR = 5.900; 95%CI = 1.003-34.691, P = 0.030). Significant interactions were observed among the MTHFR C677T, MTHFR A1298C and CBS haplotype 844ins68/T833C polymorphisms in the results for Hcy levels (P = 0.000), where heterozygous had higher values. Interactions among these polymorphisms can affect serum Hcy levels, where multiple heterozygosis could be a risk factor for vasoocclusive episodes.

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Section: Discussionmentioning

confidence: 72%

Interactions among methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS) polymorphisms - a cross-sectional study: multiple heterozygosis as a risk factor for higher homocysteine levels and vaso-occlusive episodes

et al. 2017

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“…Age is one of the factors modifying both the frequency of thrombotic events as well as the causative factors. The influence of inherited risk factors decreases with age whereas acquired factors begin to cumulate (21).…”

Section: Discussionmentioning

confidence: 99%

Thrombophilia genetic testing in Romanian young women with acute thrombotic events: role of Factor V Leiden, Prothrombin G20210A, MTHFR C677T and A1298C polymorphisms / Evaluarea genetică a trombofiliilor la femei tinere din România cu evenimente acute trombotice: rolul Factorului V Leiden, Protrombinei G20210A, polimorfismelor MTHFR C677T și A1298C

Daraban

Popp

Botezatu

et al. 2016

Revista Romana De Medicina De Laborator

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“…Furthermore, a murine deficiency of PF4 aggravated LPS-induced lethality, which was suggestive of diminished protein C activation as transgenic overexpression of human PF4 in protein C ϩ/Ϫ heterozygote mice corrected the LPS-susceptible phenotype associated with expression of low protein C levels in these mice (17). These results suggest that the application of PF4 to boost the deteriorating protein C pathway in inflammatory disease and sepsis seems ultimately feasible, especially as PF4 has been 2 The abbreviations used are: TM, thrombomodulin; APC, activated protein C; APTT, activated partial thromboplastin time; BK, bradykinin; CPI, carboxypeptidase inhibitor; NAc-Hep, N-acetylheparin; deN-Hep, de-N-sulfated heparin; PF4, platelet factor 4; PC, 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine; PS, 1,2-dioleoyl-sn-glycero-3-phosphatidylserine; PE, 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine; TAFI, thrombinactivatable fibrinolysis inhibitor; TAFIa, activated TAFI; rl-TM, TM from rabbit lung; tPA, tissue-type plasminogen activator; MES, 4-morpholineethanesulfonic acid.…”

mentioning

confidence: 86%

“…A well coordinated balance between coagulation, anticoagulation, fibrinolysis, and inflammation is essential to maintain normal hemostasis, as evident from the pathological manifestations associated with disproportional activation of either system (1,2). The endothelial cell receptor thrombomodulin (TM; 2 CD141) controls key regulatory steps for these systems (3)(4)(5).…”

mentioning

confidence: 99%

Platelet Factor 4 Inhibits Thrombomodulin-dependent Activation of Thrombin-activatable Fibrinolysis Inhibitor (TAFI) by Thrombin

Mosnier

2011

Journal of Biological Chemistry

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Thrombomodulin (TM) is a cofactor for thrombin-mediated activation of protein C and thrombin-activatable fibrinolysis inhibitor (TAFI) and thereby helps coordinate coagulation, anticoagulation, fibrinolysis, and inflammation. Platelet factor 4 (PF4), a platelet ␣-granule protein and a soluble cofactor for TM-dependent protein C activation, stimulates protein C activation in vitro and in vivo. In contrast to stimulation of protein C activation, PF4 is shown here to inhibit activation of TAFI by thrombin-TM. Consequences of inhibition of TAFI activation by PF4 included loss of TM-dependent prolongation of clot lysis times in hemophilia A plasma and loss of TM-stimulated conversion of bradykinin (BK) to des-Arg 9 -BK by TAFIa in normal plasma. Thus, PF4 modulates the substrate specificity of the thrombin-TM complex by selectively enhancing protein C activation while inhibiting TAFI activation, thereby preventing the generation of the antifibrinolytic and antiinflammatory activities of TAFIa. To block the inhibitory effects of PF4 on TAFI activation, heparin derivatives were tested for their ability to retain high affinity binding to PF4 despite having greatly diminished anticoagulant activity. Nacetylated heparin (NAc-Hep) lacked detectable anticoagulant activity in activated partial thromboplastin time clotting assays but retained high affinity binding to PF4 and effectively reversed PF4 binding to immobilized TM. NAc-Hep permitted BK conversion to des-Arg 9 -BK by TAFIa in the presence of PF4. In a clot lysis assay on TM-expressing cells using hemophilia A plasma, NAc-Hep prevented PF4-mediated inhibition of TAFI activation and the antifibrinolytic functions of TAFIa. Accordingly, NAc-Hep or similar heparin derivatives might provide therapeutic benefits by diminishing bleeding complications in hemophilia A via restoration of TAFIa-mediated protection of clots against premature lysis.

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Hypercoagulable States in Cardiovascular Disease

Cited by 114 publications

References 108 publications

Interactions among methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS) polymorphisms - a cross-sectional study: multiple heterozygosis as a risk factor for higher homocysteine levels and vaso-occlusive episodes

Interactions among methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS) polymorphisms - a cross-sectional study: multiple heterozygosis as a risk factor for higher homocysteine levels and vaso-occlusive episodes

Platelet Factor 4 Inhibits Thrombomodulin-dependent Activation of Thrombin-activatable Fibrinolysis Inhibitor (TAFI) by Thrombin

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