Jennifer A. Bell, Michael Huo, Jay R. Lieberman.
Response/Recommendation: There are 5 classic thrombophilias that have a genetic predisposition for venous thromboembolism (VTE). A large proportion of the inherited risk factors for VTE remain undiscovered and many new loci associated with VTE risk continue to be identified.
Strength of Recommendation: Strong.
Rationale: VTE, comprising deep venous thrombosis (DVT) and pulmonary embolism (PE), is a multifactorial disease with many known acquired and inherited risk factors. Family history of VTE has been estimated to have an odds ratio (OR) of 2.2 to 2.71,2. Over the last 60 years, many gene variations that affect VTE risk have been identified through family-based studies. Initial reports of familial aggregation of VTE was first described in the 1990s. Five thrombophilias have been described including: hereditary antithrombin deficiency; protein C deficiency; protein S deficiency; Factor V Leiden and prothrombin mutation. These classic thrombophilias have been associated with increased VTE risk and familial aggregation of VTE3,4. Other loci such as non-O blood (ABO), fibrinogen gamma (FGC) and hyperhomocystenemia (MTHFR) have since been associated with increased VTE risk. Many more loci associated with increased VTE risk continue to be discovered through genome-wide association5–9.
Protein C, protein S and antithrombin are natural coagulation inhibitors and deficiencies result in a hypercoagulable state. Mutations are typically due to loss of function mutations in the PROC, PROS1 and SERPINC1 genes encoding proteins C, protein S and antithrombin, respectively. Protein C and protein S are vitamin K-dependent glycoproteins that inhibit Factor VIIIa and Factor Va, cofactors in the activation for Factor X and prothrombin, respectively10. Protein C and protein S deficiency are both autosomal dominant traits and present in less than 1% of the general population and 2-3% in patients with VTE4. Patients with DNA analysis confirmed protein C deficiency have been reported to have relative risk of 6.5 for VTE, compared to control subjects11. In a family study, first-degree relatives with protein S deficiency had a 5 times greater risk of thrombosis compared to subjects with normal PROS1 gene12. In a case-control study comparing patients with first time VTE to controls, patients with S levels in the 2.5th percentile and <0.10th percentile had an OR of 2.31(95% confidence interval [CI], 1.06-5.05) and 5.44 (95% CI, 0.61-48.78), respectively13.
Antithrombin is a serine protease inhibitor and functions to inhibit thrombin and activated Factor X (FXa), resulting in decreased generation and half-life of thrombin. The SERPIN1 gene is located at chromosome 1q 23-25, and the most common mutations are missense and nonsense mutations. Of the 5 classic thrombophilias, antithrombin deficiency is the least common, present in less than 0.2% of the general population and 1% in patients with VTE4. A meta-analysis evaluating VTE in antithrombin deficient individuals compared to controls found an OR of 14.0 (95% CI, 5.5 to 29.0) for the first VTE and the annual VTE risk in antithrombin deficient subject to be 2.3% (95% CI, 0.2-6.5%)14. While antithrombin deficiency is the least common of the classic thrombophilias, deficiencies result in high relative risk of a first VTE and recurrence.
Factor V and prothrombin are coagulation factors and gain of function mutations result in hypercoagulable state. Factor V Leiden is due to resistance to activated protein C (APC-resistance) on Factor V. When inactivated protein C attaches to thrombin, APC is formed and inactivates Factor Va and VIIIa by cleaving specific sites. The most common mutation, rs6025, is due to a single-point mutation that replaces arginine with glutamine at the APC cleavage site5,15. Factor V Leiden mutation is the most common thrombophilia, and has been estimated to be associated with up to 20% of patients with first VTE events11. Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study evaluated patients with a first VTE event, heterozygous mutations were found in 14.8% of patients and 5.2% of controls, and homozygous mutations in 0.7% and 0.2%, respectively. Subjects with Factor V Leiden mutation had an OR of 3.3 compared to control subjects (95% CI, 2.6-4.1)16.
Prothrombin is a precursor to thrombin, that is proteolytically cleaved by Xa to form thrombin. The most common mutation of gene F2 is G20210A, a point mutation that substitutes adenosine for guanosine and results in a gain-of-function mutation17. Patients who are heterozygote for prothrombin G20210A have higher levels of plasma prothrombin, however, the exact mechanism of increased VTE risk is not well understood. In a case-control study, the prothrombin A20210 allele was found in 8.01% of VTE patients compared to 2.29% control subjects (p<0.001), and was associated with an increased risk of VTE (OR 3.88; 95% CI, 2.23 to 6.74)18. Other case-control series have reported similar OR from 2.8 to 3.817,19.
A large proportion of VTE’s heritability remains undiscovered. There is a continued effort to identify loci associated with VTE through genome-wide association studies (GWAS), which compare the DNA of large cohorts of patients with VTE to control subjects. In three recent GWAS, 14, 22, and 20 susceptibility genes for VTE have been discovered, respectively7–9. Previously identified and novel single nucleotide polymorphisms (SNPs) identified in these three studies can be found in Table 1. Many previously known VTE loci are associated with the coagulation cascade. Herrera-Riveor et al., identified 20 susceptibility genes for VTE that do not participate directly in the coagulation cascade and proposed increased VTE risk was due to possible effect on platelet formation or function, cardiovascular development and repair, and/or inflammation7. Ideally, in the future, genetic profiles could be established for surgical patients to assess the risk for developing a VTE. Further studies will need to evaluate mechanism of actions of newly found VTE loci and their potential mechanism of VTE.
The 5 classic inherited thrombophilias include protein C deficiency, protein S deficiency, antithrombin deficiency, Factor V Leiden and prothrombin G20210A. Protein C, protein S, and antithrombin deficiencies are most commonly due to a loss of function mutation, resulting in a hypercoagulable state. Factor V Leiden and prothrombin G20210A are due to gain of function mutations and are more commonly found in unselected patients with VTE. However, the classic thrombophilias make up a small proportion of inherited risk for VTE, and research on new loci and their risk for VTE need to be determined.
Table 1. Genome-wide significant VTE loci from three GWAS8,9,20.
| Gene/Locus | rs ID † | Chromosome | Position ‡ | A1 | A2 | Consequence |
| F5 | rs6025 | 1 | 169519049 | T | C | Arg534Gln |
| C4BPA | rs2842700 | 1 | 207282149 | A | C | intron |
| F5 | rs4524 | 1 | 169511755 | C | T | Lys858Arg |
| KIF26B | rs1756912 | 1 | 245588095 | A | G | intronic |
| RGSL1 | rs55897462 | 1 | 182512200 | G | T | intronic |
| CSRNP1 | rs13084580 | 2 | 127962493 | T | C | 5’UTR |
| PROS1 | rs6795524 | 2 | 68619981 | G | A | intron |
| POLE4 | rs74965230 | 2 | 75182831 | C | T | intergenic |
| RP11-122C5.1 | rs16867574 | 3 | 39188182 | C | T | downstream |
| STXBP5 | rs7739314 | 3 | 93650604 | C | A | downstream |
| FGG | rs2066865 | 4 | 155525276 | A | G | downstream |
| F11 | rs4253417 | 4 | 187199005 | C | T | intron |
| FGG | rs2066864 | 4 | 155525695 | A | G | intron |
| F11 | rs2289252 | 4 | 187207381 | T | C | intron |
| F11 | rs2036914 | 4 | 187192481 | T | C | intron |
| F11 | rs4253421 | 4 | 187204937 | A | G | intron |
| HLA-C | rs2074492 | 5 | 38708554 | T | C | upstream |
| OSMR-AS1 | rs4869589 | 5 | 38707871 | T | G | intron |
| SCARA5 | rs10087301 | 6 | 147709180 | A | G | intron |
| GRK5 | rs10886430 | 6 | 31239869 | G | A | intron |
| STXBP5 | rs9373523 | 6 | 147701133 | T | G | intron |
| ZFPM2 | rs4734879 | 8 | 106583124 | A | G | intron |
| MYRF | rs174536 | 8 | 27820792 | A | C | intron |
| ZFPM2 | rs4541868 | 8 | 106590705 | A | C | intron |
| ASH2L | rs149680046 | 8 | 37968307 | T | C | missense |
| ABO | rs9411377 | 9 | 136145404 | A | C | intron |
| ABO | rs8176749 | 9 | 136131188 | T | C | synonymous |
| ABO | rs687289 | 9 | 136137106 | A | G | intron |
| ABO | rs2519093 | 9 | 136141870 | T | C | intron |
| ABO | rs579459 | 9 | 136154168 | C | T | intron |
| TSPAN15 | rs78707713 | 10 | 71245276 | T | C | intron |
| SBNO1 | rs12824685 | 10 | 121010256 | G | T | intron |
| TSPAN15 | rs78707713 | 10 | 71245276 | C | T | intron |
| NRG3 | rs1649936 | 10 | 83969121 | T | C | intronic |
| F2 | rs1799963 | 11 | 46761055 | A | G | 3’UTR |
| VWF | rs216296 | 11 | 61551927 | G | A | intron |
| F2 (LRP4)§ | rs191945075 | 11 | 46933311 | A | G | Downstream (intron) |
| F2 | rs3136516 | 11 | 46760756 | G | A | intron |
| F10 | rs3211752 | 12 | 123817569 | G | A | intron |
| CATSPERB | rs57328376 | 12 | 6154670 | G | A | intron |
| MPHOSPH9 | rs2851436 | 12 | 123667354 | G | T | intron |
| VWF | rs1558519 | 12 | 6153738 | G | A | intron |
| VWF | rs216311 | 12 | 6128443 | T | C | Thr1381Ala |
| PLCG2 | rs12445050 | 13 | 113787459 | T | C | intron |
| SMG6 | rs1048483 | 14 | 92235039 | T | C | intron |
| AGBL1 | rs72755680 | 15 | 87509243 | C | A | ncRNA intronic |
| PEPD | rs731839 | 16 | 81870969 | A | G | intron |
| GP6 | rs1654425 | 17 | 1966457 | C | T | synonymous |
| SLC44A2 | rs2288904 | 19 | 10742170 | G | A | Gln154Arg |
| CYP27C1 | rs7585314 | 19 | 33899065 | T | C | intron |
| PLEK | rs1867312 | 19 | 55538980 | C | A | intron |
| SLC44A2 | rs4548995 | 19 | 10740871 | G | C | intron |
| GP6(NLRP2) § | rs1671135 | 19 | 55511873 | G | C | Downstream (intron) |
| PSG8 | rs59559305 | 19 | 43283623 | A | G | intronic |
| SNRNP70 | 19:49596145 | 19 | 49596145 | C | T | intronic |
| (CD93) | rs6083037 | 20 | 23182559 | A | T | intergenic |
| EDEM2 | rs10747514 | 20 | 33775369 | A | G | intron |
| PROCR | rs6088735 | 20 | 33745676 | T | C | intron |
| PROCR | rs867186 | 20 | 33764554 | G | A | Ser219Gly |
| NCAM2 | rs62207434 | 21 | 22780048 | T | C | intronic |
| A4GALT | rs9607928 | 22 | 43111772 | A | C | intron |
| BRCC3 | rs7051718 | X | 154332656 | T | C | intron |
| F9 | rs6048 | X | 138633280 | A | G | Thr194Ala |
| (BCOR) § | rs3002417 | X | 39708724 | T | C | intergenic |
| F8 | rs143478537 | X | 154424170 | G | C | upstream |
VTE=Venous thromboembolism; GWAS=Genome-wide association studies; A1=Reference Allele; A2: Alternate Allele.
† Reference SNP Cluster ID.
‡Variant position on the chromosome.
§Genes of variants that are outside of protein-coding transcript bounds are shown with the nearest gene in parentheses.
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