Reduced Activity of Protein S in Plasma: A Risk Factor for Venous Thromboembolism in the Japanese Population

The quantitative assay of protein S can help in rapidly identifying carriers of abnormal protein S molecules through a simple procedure (by determining the total protein S mass, total protein S activity, and protein S-specific activity in blood), without genetic testing. To clarify the relationship between venous thromboembolism (VTE) and protein S-specific activity, and its role in the diagnosis of thrombosis in Japanese persons, the protein S-specific activity was measured and compared between patients with thrombosis and healthy individuals. The protein S-specific activity of each participant was calculated from the ratio of total protein S activity to total protein S antigen level. Plasma samples were collected from 133 healthy individuals, 57 patients with venous thrombosis, 118 patients with arterial thrombosis, and 185 non-thrombotic patients. The protein S-specific activity of one-third of the patients with VTE was below the line of Y = 0.85X (−2 S.D.). Most protein S activities in the plasma of non-thrombotic patients were near the Y = X line, as observed in healthy individuals. In conclusion, it was clearly shown that monitoring protein S activity and protein S-specific activity in blood is useful for predicting the onset and preventing venous thrombosis in at least the Japanese population.

Anticoagulant protein S in COVID-19: low activity, and associated with outcome

Introduction. COVID-19 disease was associated with both thrombo-embolic events and in-situ thrombi formation in small vessels. Antiphospholipidic antibodies were found in some studies.Aim. Assessment of protein S activity in patients with COVID-19 as a cause of this prothrombotic state, and of the association of protein S activity with worse outcome.Methods. All patients admitted for COVID-19 disease in a university hospital between 15th of May and 15th of July 2020 were prospectively enrolled into this cohort study. Patients treated with antivitamin K anticoagulants and with liver disease were excluded. All patients had protein S activity determined at admission. The main outcome was survival, while secondary outcomes were clinical severity and lung damage.Results. 91 patients were included, of which 21 (23.3%) died. Protein S activity was decreased in 65% of the patients. Death was associated with lower activity of protein S (median 42% vs. 58%, p < 0.001), and the association remained after adjustment for age, inflammation markers and ALAT. There was a dose-response relationship between protein S activity and clinical severity (Kendall_tau coefficient = –0.320, p < 0.001; Jonckheere-Terpstra for trend: p < 0.001) or pulmonary damage on CT scan (Kendall_tau coefficient = –0.290, p < 0.001; Jonckheere-Terpstra for trend: p < 0.001). High neutrophil count was also independently associated with death (p = 0.002).Conclusion. Protein S activity was lower in COVID-19 patients, and its level was associated with survival and disease severity, suggesting that it may have a role in the thrombotic manifestations of the disease.

Apixaban Does Not Interfere With Protein S or Activated Protein C Resistance (Factor V Leiden) Testing Using aPTT-Based Methods

Context.— Apixaban causes a false increase in activated protein C resistance (APCR) ratios and possibly protein S activity. Objective.— To investigate whether this increase can mask a diagnosis of factor V Leiden (FVL) or protein S deficiency in an actual population of patients undergoing apixaban treatment and hypercoagulation testing. Design.— During a 4.5-year period involving 58 patients, we compared the following 4 groups: heterozygous for FVL (FVL-HET)/taking apixaban, wild-type/taking apixaban, heterozygous for FVL/no apixaban, and normal APCR/no apixaban. Patients taking apixaban were also tested for protein S functional activity and free antigen (n = 40). Results.— FVL-HET patients taking apixaban had lower APCR ratios than wild-type patients (P &lt; .001). Activated protein C resistance in FVL-HET patients taking apixaban fell more than 3 SD below the cutoff of 2.2 at which the laboratory reflexes FVL DNA testing. No cases of FVL were missed despite apixaban. In contrast to rivaroxaban, apixaban did not interfere with the assessment of protein S activity (mean activity 93.9 IU/dL, free antigen 93.1 IU/dL, P = .39). A total of 3 of 40 patients (8%) had low free protein S antigen (30, 55, and 57 IU/dL), with correspondingly similar activity results (27, 59, and 52 IU/dL, respectively). Apixaban did not cause a missed diagnosis of protein S deficiency. Conclusions.— Despite apixaban treatment, APCR testing can distinguish FVL-HET from healthy patients, rendering indiscriminate FVL DNA testing of all patients on apixaban unnecessary. Apixaban did not affect protein S activity.

Influence of hyperinsulinemic – hypoglycemic clamp on induced platelet aggregation, activity of physiological anticoagulants and von Willebrand factor in patients with type I diabetes

Background. Intensive glycaemic control in patients with type 1 diabetes may lead to hypoglycaemia and thus increase the risk of cardiovascular and cerebrovascular events. Platelet activation and/or decreased activity of physiological anticoagulants during hypoglycaemia may play a role in the development of cardiovascular or cerebrovascular complications. Aims. To investigate induced platelet activity, the activity of physiological anticoagulants, and the von Wil-lebrand factor in patients with type 1 diabetes with the hyperinsulinaemichypoglycaemic clamp. Materials and methods. We examined 11 patients with type 1 diabetes without macro- and micro-vascular complications (6 males, 5 females, mean age 23.7 5.6 years, A1C 9.7 2.3%). Induced platelet aggregation, physiological anticoagulants (Protein S, Protein C, AT III) and the von Willebrand factor were studied at hyperglycaemic, euglycaemic, and hypoglycaemic stages during use of a hyperinsulinaemic (1 mU/kg/min) hypoglycaemic clamp. Results. Platelet aggregation to all agonists increased significantly during the hypoglycaemic stage, compared with the euglycaemic or hyperglycaemic stages. There was no difference in platelet aggregation between the euglycaemic and hyperglycaemic stages. Platelet aggregation to all agonists increased during the hypoglycaemic stage compared with the hyperglycaemic period: thrombin23.9%, ADP30.6%, arachidonic acid30.9%, collagen69.4% and ristocetin70.8%. During hypoglycaemia aggregation to ADP, arachidonic acid and collagen remained within normal limits (upper quartile); aggregation to thrombin was significantly above normal limits and aggregation to ristocetin remained significantly below lower limits. Protein S activity was significantly increased during hypoglycaemia compared with euglycaemia (p = 0.046) and hyperglycaemia (p = 0.046). Antithrombin-III activity decreased significantly at the euglycaemic and hypoglycaemic stages, compared with the hyperglycaemic period, but still remained significantly elevated above the upper threshold. Protein C and vWf activity did not change significantly. Conclusions. In patients with type 1 diabetes platelet aggregation and protein S activity increases significantly at the hypoglycaemic stage of the hyperinsulinaemichypoglycaemic clamp. Platelet activation is directly caused by hypoglycaemia and not by decreasing glucose levels. Increased protein S activity is a compensatory response to platelet activation.