Recent reports demonstrate an increased risk of thrombosis in families with a second genetic abnormality. Most reports have described a combination of FV-R506Q with abnormalities of PC, PS, or AT. These findings begin to shed light on the marked variability in clinical expression of these syndromes. The effect of genetic dosage has long been evident from the severely affected neonates with homozygous PC and PS deficiency. Homozygous AT deficiency appears to be incompatible with survival.
Once one moves away from the well-defined homozygous cases, the risk and severity appear to vary with the type and number of underlying genetic abnormalities1 (Table 11). High risk is conferred by the following: (1) types I and II AT deficiency, especially in combination with FV-R506Q; (2) heterozygous PC and PS deficiency in combination with FV-R506; and (3) in homozygotes for FV-506Q. Mild-to-moderate risk is associated with isolated heterozygous PC and PS deficiency and AT deficiency due to mutations in the heparin binding site. More recent studies are beginning to suggest that either hyperhomocysteinemia or the prothrombin polymorphism, in association with another risk factor, confer additive risk for VTE disease, probably similar to the combination of FVR506Q with other biochemical risk factors described above,164-167 although the results have been mixed. Multigenic risk is best demonstrated with the combination of AT deficiency, and FV-R506Q is more varied in PC and PS deficiencies associated with FV506Q.’ In general, in affected families with heterozygous mutations, the earliest onset is at midteenage years, with childbirth causing a clustering of women in their late teens and early twenties. Diagnosis of patients with suspected inherited thrombophilia should include a panel of tests including at least PC, PS, AT, and FV-R506Q. Many laboratories also add the prothrombin polymorphism G20219A and a homocysteine level. asthma medications inhalers
Table 11—Frequency of VTE in Members of Families With Combined Thrombophilias
|Associated With FV-R506Q||Sole Defect||FV-R506Q Only||Neither Defect||Source of Extracted Data|
|Thrombophilia||No. VTE, %||No.||VTE, %||No.||VTE, %||No.||VTE, %|
|Protein C deficiency (6 families)||23 70||34||35||20||10||30||7||Koeleman et al,1994262|
|Protein S deficiency (7 families)||18 72||21||19||21||19||44||2||Zoller et al, 1995162|
|Antithrombin III deficiency (6 families)||12 92||7||57||5||20||11||0||Van Boven et al, 1996163|