Metabolic consequences of obesity on the hypercoagulable state of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) women have a hypercoagulable state; however, whether this is intrinsically due to PCOS or, alternatively, a consequence of its metabolic complications is unclear. We determined plasma coagulation pathway protein levels in PCOS (n = 146) and control (n = 97) women recruited to a PCOS biobank. Circulating levels of a panel of 18 clotting pathway proteins were determined by Slow Off-rate Modified Aptamer-scan plasma protein measurement. Cohorts were age matched, though PCOS had elevated body mass index (p < 0.001), insulin (p < 0.001) and C-reactive protein (CRP) (p < 0.0001). Eight pro-coagulation proteins were elevated in PCOS: plasminogen activator inhibitor-1 (p < 0.0001), fibrinogen (p < 0.01), fibrinogen gamma chain (p < 0.0001), fibronectin (p < 0.01), von Willebrand factor (p < 0.05), D-dimer (p < 0.0001), P-selectin (p < 0.05), and plasma kallikrein (p < 0.001). However, two anticoagulant proteins, vitamin K-dependent protein-S (p < 0.0001) and heparin cofactor-II (p < 0.001) were elevated and prothrombin was decreased (p < 0.05). CRP, as a marker of inflammation, and insulin resistance (HOMA-IR) correlated with 11 and 6 of the clotting proteins, respectively (p < 0.05). When matched for BMI < 25 (16 PCOS, 53 controls) HOMA-IR remained elevated (p < 0.05) and heparin cofactor-II was increased (p < 0.05). In a multivariate analysis accounting for inflammation, insulin resistance and BMI, there was no correlation of PCOS with any of the coagulation proteins. The hypercoagulable state in PCOS is not intrinsic to the disease as it can be fully accounted for by BMI, inflammation and insulin resistance.

Metabolic Consequences Of Obesity On The Hypercoagulable State Of Polycystic Ovary Syndrome: A Risk For Severe SARS-Cov-2 Infection?

Introduction: Polycystic ovary syndrome (PCOS) women have a hypercoagulable state and are also at high risk for severe COVID-19 leading to thromboembolic complications and increased mortality; however, whether this is intrinsically due to PCOS or, alternatively, a consequence of its metabolic complications is unclear. Methods: We determined plasma coagulation pathway protein levels in PCOS (n=146) and control (n=97) women recruited to a PCOS biobank. Circulating levels of a panel of 18 clotting pathway proteins were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement.Results: Cohorts were age matched, though PCOS had elevated body mass index (BMI)(p<0.001), insulin (p<0.001) and C-reactive protein (CRP)(p<0.0001). Eight pro-coagulation proteins were elevated in PCOS: plasminogen activator inhibitor-1 (PAI-1)(p<0.0001), fibrinogen (p<0.01), fibrinogen gamma chain (p<0.0001), fibronectin (p<0.01), von Willebrand factor (p<0.05), D-dimer (p<0.0001), P-selectin (p<0.05), and plasma kallikrein (p<0.001). However, two anticoagulant proteins, vitamin K-dependent protein-S (p<0.0001) and heparin cofactor-II (p<0.001) were elevated and prothrombin was decreased (p<0.05). CRP, as a marker of inflammation, and insulin resistance (HOMA-IR) correlated with 11 and 6 of the clotting proteins, respectively (p<0.05). When matched for BMI<25 (16 PCOS, 53 controls) HOMA-IR remained elevated (p<0.05) and heparin cofactor-II was increased (p<0.05). In a multivariate analysis accounting for inflammation, insulin resistance and BMI, there was no correlation of PCOS with any of the coagulation proteins.Conclusion: The hypercoagulable State in PCOS can be fully accounted for by BMI, inflammation and insulin resistance suggesting that only obese PCOS women would be predisposed to an enhanced risk for severe COVID-19-related disease.

Recombinant dermatan sulfate is a potent activator of heparin cofactor II-dependent inhibition of thrombin

The glycosaminoglycan dermatan sulfate (DS) is a well-known activator of heparin cofactor II-dependent inactivation of thrombin. In contrast to heparin, dermatan sulfate has never been prepared recombinantly from material of non-animal origin. Here we report on the enzymatic synthesis of structurally well-defined DS with high anticoagulant activity. Using a microbial K4 polysaccharide and the recombinant enzymes DS-epimerase 1, dermatan 4-O-sulfotransferase 1, uronyl 2-O-sulfotransferase and N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase, several new glycostructures have been prepared, such as a homogenously sulfated IdoA-GalNAc-4S polymer and its 2-O-, 6-O- and 2,6-O-sulfated derivatives. Importantly, the recombinant highly 2,4-O-sulfated DS inhibits thrombin via heparin cofactor II, approximately 20 times better than heparin, enabling manipulation of vascular and extravascular coagulation. The potential of this method can be extended to preparation of specific structures that are of importance for binding and activation of cytokines, and control of inflammation and metastasis, involving extravasation and migration.