Protein C and protein S changes in GH-deficient adults on r-HGH replacement therapy: Correlations with PAI-1 and t-PA plasma levels

Background: In the rat liver, growth hormone (GH) affects the synthesis of vitamin-K-dependent factors, including Protein C (prot.C) and protein S (prot.S), two natural anticoagulants that prevent hypercoagulable states. Adults with GH deficiency (GHD) are at risk of thrombotic events. High circulating levels of PAI-1 and t-PA, that reflect hypercoagulable states, may contribute to such risk. In GHD adults on replacement therapy with recombinant human GH (r-HGH), %Δ PAI-1 and %Δ t-PA are related to %Δ insulin changes. Objectives: To evaluate changes in vitamin-K-dependent factors in GHD on r-HGH replacement. Methods: In 60 GHD adults, to relate plasma levels of vitamin-K-dependent factors with those of PAI-1, t-PA and insulin before and after 6-month (6-mo) replacement therapy with r-HGH. Results: After 6-mo r-HGH replacement, %Δ insulin enhancements occurred in 36/60 subjects. PAI-1, t-PA, Prot.C, Prot.S and FVIIact did not change in them. In the 24/40 subjects that experienced %Δ insulin reductions, Prot.C (p = 0.025), Prot.S (p = 0.031) and FVIIact (p = 0.049) decreased significantly. PAI-1 (p = 0.019) and t-PA antigen (p = 0.009) behaved similarly. In a multivariate analysis, %Δ PAI-1 (β = 0.436, p <0.01) was the strongest predictor of %Δ prot.S, wheras %Δ t-PA (β = 0.385, p <0.008) and %Δ insulin (β = 0.429, p <0.004) were the strongest predictors of %Δ prot.C. In all cases, regardless of %Δ insulin changes, FII, FVII Ag and FIX levels did not change from baseline. Conclusions: In GHD adults on r-HGH replacement, changes in vitamin-K-dependent factors reflect a subtle adaptation of the natural anticoagulant system to PAI-1 and t-PA changes, via the response of insulin to r-HGH.