Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology

Abstract

Higher levels of procoagulant factors and factor XII deficiency may be risk factors for first venous thromboembolism (VTE). We studied associations of coagulation factors IX through XIII with risk of future VTE in 2 general population samples. Using a nested case-control study combining the 21 860 participants of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study, we determined antigenic levels of these coagulation factors in primarily pre-event blood samples from 462 participants who subsequently developed VTE and 1047 participants who remained free of VTE. Only elevated levels of factors IX and XI were associated with increased risk of VTE after adjustment for age, sex, race, and study. For factor IX, the odds ratio (OR) was 1.4 (95% confidence interval [CI], 1.0-2.0) comparing the top to bottom quintile. The OR for factor XI was higher: 2.0 (95% CI, 1.4-2.9). With further adjustment for body mass index and diabetes, only elevated factor XI remained associated with VTE risk: OR 1.8 (95% CI, 1.3-2.7). Associations were similar by study and whether the thrombosis was idiopathic or secondary. Factor XII deficiency was not related to VTE risk. Among these procoagulant factors, only elevated factor XI was a risk factor for VTE. (Blood.

Epidemiologic and clinical data linking factors XI and XII to thrombosis

“…John Hageman's death from pulmonary embolism occurred 12 days after he sustained pelvic fractures, during which time he was largely 20 Age Ͼ45 y (462) Low fXII (fXII:Ag) VTE No VTE also not associated with high fXII NPHS-II 24 Males age 50-63 y at intake (2997) Low fXII (fXIIa-C1-INH) IS Yes RATIO 25 Females age 18-50 y with IS (175) High fXII (fXIIa-C1-INH) IS Yes Risk further increased by OCPs RATIO 34 Females age 18-50 y with IS (175) High fXII (fXII:Ag) IS No fXII:Ag not correlated with fXIIa-C1-INH ARIC 26 Age 45-54 y at intake (15 792) High fXII (fXII:c) IS No Case-control within ARIC cohort NPHS-II 29 Males age 50-63 y at intake (2997) High fXII (fXIIa:Ag) CHD Yes NPHS-II 24 Males age 50-63 y at intake (2997) High fXII (fXIIa-C1-INH) CHD No RATIO 25 Females immobile. 10 Although fXII deficiency per se was considered to be a risk factor for VTE, 11 in retrospect, this conclusion was likely explained by reporting bias.…”

“…The risk of VTE did not vary across the range of quintiles, indicating that neither fXII deficiency nor excess was associated. 20 Of interest in this regard is the experience in patients with hereditary angioedema (HAE), a disorder in which C1 esterase inhibitor, one of the major physiological inhibitors of fXIIa, is deficient (type I or type II HAE) or fails to inhibit a mutated inactivation-resistant form of fXII (type III HAE). 21 Despite the relative lack of regulation of fXII(a) in vivo, affected patients do not have any thrombotic propensity.…”

Measurement of factor XIII activity in plasma

“…Elevated FXIII-A levels did not infl uence the risk of venous thromboembolism in a recent nested case-control study involving 462 participants who developed venous thromboembolism and 1047 participants who remained free of it (14) . Further studies should explore if there is any gender or age specifi c difference.…”

The effect of time between venipuncture, processing and freezing on the measurement of coagulation factor levels

“…As ABO is one of the strongest genetic risk factors for venous thromboembolism (VTE), it would be tempting to hypothesize that the FUT2 and ALPL loci could also be candidate susceptibility genes for VTE. Further arguments support this hypothesis: (i) high levels of fibrinogen in plasma, composed of fibrinogen a, b and c chains, are a risk factor for VTE; (ii) fibrinogen A-a peptide has been hypothesized to be a marker of thrombin generation associated with thrombotic risk [2]; and (iii) FUT2 polymorphisms (rs492602, rs601338) have previously been found associated with plasma levels of vitamin B12 [3], known to correlate with plasma homocysteine levels [4], a risk factor for VTE [5]. To investigate this hypothesis further, we used the results of two previously published genome-wide association studies (GWAS) for VTE [6,7] and two standard case-control studies for VTE, FARIVE [6] and TEHS, to assess whether single nucleotide polymorphisms (SNPs) at the ALPL and FUT2 could be associated with VTE risk.…”

“…Levels within the upper 10% (> P90) of the population distribution of the procoagulant factors prothrombin, factor VIII, FIX, and FXI, and low levels of anticoagulation proteins, are associated with an increased risk of venous thrombosis [1][2][3][4][5]. Many preanalytic variables may affect the accuracy of these assays, including the duration of time from venipuncture to specimen processing and storage [6,7].…”