rs1800595 — F5 HR2 haplotype (H1299R / R2)

Factor V HR2 — The Quiet Modifier of Clotting Risk

Coagulation Factor V is a large plasma protein with a dual role in hemostasis: it accelerates clot formation by amplifying thrombin generation, and it also assists activated protein C (APC) in switching off this cascade. The rs1800595 variant — known as the R2 polymorphism, H1299R, or the HR2 haplotype — subtly shifts that balance toward clotting, but only mildly when inherited alone. Its chief clinical importance emerges when it co-occurs with Factor V Leiden (rs6025) on the opposite chromosome, a combination that amplifies thrombotic risk far beyond what either variant produces independently.

The Mechanism

The F5 gene sits on chromosome 1's minus strand. The rs1800595 C allele (plus-strand) corresponds to a guanine substitution (A4070G) in the coding sequence, replacing histidine with arginine at position 1327 of the mature protein¹¹ position 1327 of the mature protein
Modern NM_000130.5 numbering; older literature used His1299Arg based on an earlier reference transcript; both terms refer to the same variant. This substitution lies in the B domain of Factor V — a large central domain that is cleaved off during activation but influences the protein's interactions with other coagulation factors.

The molecular consequence, described by Castoldi and colleagues in 2004²² described by Castoldi and colleagues in 2004
Castoldi E et al. Impaired APC cofactor activity of factor V plays a major role in the APC resistance associated with the factor V Leiden (R506Q) and R2 (H1299R) mutations. Blood 2004;103:4173-9, is a partial loss of Factor V's anticoagulant cofactor activity: FV(R2) retains only 73% of normal Factor V's ability to assist APC in inactivating Factor VIIIa. This contrasts sharply with Factor V Leiden, which simultaneously resists APC-mediated inactivation of itself AND loses its APC cofactor function entirely. The R2 mechanism is subtler: the protein is still inactivated normally by APC, it simply cooperates less efficiently with APC to shut down the coagulation cascade. Carriers also produce modestly reduced Factor V plasma levels³³ modestly reduced Factor V plasma levels
An increasing frequency of the Arg1299 allele correlates with decreasing mean plasma Factor V activity; homozygotes are not clinically symptomatic.

The Evidence

HR2 alone: Population studies consistently show a borderline or non-significant association between HR2 and venous thromboembolism (VTE) risk in isolation. The largest summary of evidence — a 2003 meta-analysis by Castaman et al. covering 2,696 VTE cases and 7,710 controls⁴⁴ a 2003 meta-analysis by Castaman et al. covering 2,696 VTE cases and 7,710 controls
Castaman G et al. The factor V HR2 haplotype and the risk of venous thrombosis: a meta-analysis. Haematologica 2003 — found a pooled OR of 1.15 (95% CI 0.98-1.36), just crossing statistical significance. One smaller but well-designed study found HR2 was 2.7 times more prevalent in VTE patients who lacked Factor V Leiden⁵⁵ 2.7 times more prevalent in VTE patients who lacked Factor V Leiden
Otrock ZK et al. Factor V HR2 haplotype: a risk factor for VTE in individuals with absence of Factor V Leiden. Ann Hematol 2008 compared to FVL-negative controls (OR 2.7, 95% CI 1.04-7.06), suggesting a detectable independent effect in this subgroup.

HR2 + Factor V Leiden compound heterozygosity: This is where the clinical evidence is clearest. In a family-based prospective cohort reported by Meinardi et al. in Blood 1999⁶⁶ Meinardi et al. in Blood 1999
Meinardi JR et al. Coinheritance of the HR2 haplotype in the factor V gene confers an increased risk of VTE to carriers of factor V R506Q (FV Leiden). Blood 1999;94:3062-6, patients doubly heterozygous for FV Leiden and HR2 had a hazard ratio of 14.0 (95% CI 3.7-53.4) compared to non-carriers — versus 4.2 for FV Leiden alone. The first VTE event occurred an average of 6 years earlier in double heterozygotes than in carriers of FV Leiden alone. This 3- to 4-fold amplification relative to FV Leiden is biologically explained: in compound heterozygous individuals, the FV Leiden chromosome produces a Factor V that resists APC inactivation, while the HR2 chromosome produces a Factor V that provides inferior APC cofactor support — so both copies of Factor V are impaired in anticoagulant function simultaneously.

For recurrent pregnancy loss, the evidence does not support an independent role for HR2. A 2022 meta-analysis of 13 studies⁷⁷ 2022 meta-analysis of 13 studies
Capra AP et al. Systematic review of FV H1299R and recurrent pregnancy loss. Biology 2022;11:1608 found no significant association (OR 1.18, 95% CI 0.78-1.80).

Practical Implications

For the typical HR2 heterozygous carrier without Factor V Leiden, the absolute risk elevation is modest — similar in magnitude to mild thrombophilic polymorphisms like the MTHFR C677T variant. Routine anticoagulation is not indicated; the variant becomes most relevant in the context of acquired provocation (surgery, immobility, pregnancy, hormonal treatments) or when standard thrombophilia workup yields otherwise unexplained VTE in a patient without FV Leiden.

The critical clinical scenario is the patient whose thrombophilia panel shows FV Leiden and who also carries the HR2 C allele. This compound configuration substantially increases lifetime VTE risk and should prompt more proactive management of thrombotic triggers.

Interactions

The most clinically significant interaction is with Factor V Leiden (rs6025, F5 R506Q)⁸⁸ Factor V Leiden (rs6025, F5 R506Q)
The most common inherited thrombophilia in Europeans, present in ~5% of the population; causes complete APC resistance via a different mechanism than HR2. Compound heterozygosity for FV Leiden and HR2 on opposite chromosomes creates a state where neither copy of Factor V functions normally in its anticoagulant role — a multiplicative impairment that approximates the phenotype of FV Leiden homozygosity.

The prothrombin G20210A variant (rs1799963, F2)⁹⁹ prothrombin G20210A variant (rs1799963, F2)
Increases plasma prothrombin 30%, increasing clot-forming capacity; compound risk with any thrombophilic Factor V variant is additive also compounds with the HR2 haplotype, as it increases the procoagulant drive independent of the APC pathway. Any carrier of HR2 should have FV Leiden and prothrombin G20210A status established if a thrombotic event occurs or before high-risk situations.