Heparin cofactor II (HCII) deficiency was first associated with thrombosis in 1985 by Tran et al. (PMID: 2863444). HCII is a serine protease inhibitor in plasma that rapidly inhibits thrombin in the presence of dermatan sulfate or heparin. However, HCII deficiency may represent only a modest risk of thrombosis, becoming clinically manifest only when additional inherited or acquired thrombogenic conditions are present. In 1987, Andersson et al. (PMID: 2443998) established an autosomal dominant mode of inheritance, which affected individuals having half the normal amount of HCF II. These individuals were molecularly characterized by Blinder et al. (PMID: 2647747) in 1989. At least 8 unique variants (including missense and frameshift variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 7 publications (PMIDs: 8902986, 2647747, 15337701, 31064749, 11204559, 8562924, 29296762). Variants in this gene segregated with HCII deficiency in 23 additional family members. This gene-disease relationship is supported by its biochemical function of inhibiting thrombin (PMID: 6895893), the alteration of expression (PMID: 2863444) and function (PMID: 2647747) observed in patients, and multiple mouse models which recapitulate the HCII deficiency and increased susceptibility to induced thrombosis but can be rescued with human HCII (PMID: 17549254, 11805133). In summary, SERPIND1 is definitively associated with autosomal dominant heparin cofactor II deficiency.
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