The haemostatic system in polycystic ovarian syndrome

Burchall, G 2018, The haemostatic system in polycystic ovarian syndrome, Doctor of Philosophy (PhD), Health and Biomedical Sciences, RMIT University.

Document type: Thesis
Collection: Theses

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Title The haemostatic system in polycystic ovarian syndrome
Author(s) Burchall, G
Year 2018
Abstract Polycystic ovary syndrome (PCOS), diagnosed based on hyperandrogenism, ovulatory dysfunction and polycystic ovaries, is one of the most common disorders of reproductive aged females affecting up to 18% of women in this age group. The aetiology of PCOS is still unknown but includes both genetic and environmental/lifestyle factors contributing to both insulin resistance and hyperandrogenism. Clinically PCOS has reproductive, psychological and metabolic features, the latter predisposing to cardiovascular disease (CVD). Haemostatic abnormalities have an association with and a demonstrated pathophysiological role in CVD in non-PCOS populations, yet have not been adequately explored in PCOS.

Women with PCOS appear to have altered coagulation and fibrinolysis with a prothrombotic state, with epidemiological evidence of increased venous thromboembolism. In an established case-control cohort of lean, overweight and obese women with (n=107) and without (n=67) PCOS, and existing measures of plasminogen activator inhibitor 1 (PAI-1) and asymmetric dimethylarginine (ADMA), other haemostatic markers were measured in plasma samples including prothrombin fragments 1 and 2 (PF1 & 2), plasminogen, tissue plasminogen activator (tPA) and thrombin generation (TG). Higher levels of ADMA (0.70 vs 0.39 µmol/L, p<0.01), PAI-1 (4.80 vs 3.66 U/mL, p<0.01) and plasminogen (118.39 vs 108.46%, p<0.01) were seen in women with PCOS versus controls, which persisted after adjustment for age and body mass index (BMI). PF1 & 2 was marginally lower (180.0 vs 236.0 pmol/L, p=0.05), while tPA and TG were not different between groups, following adjustment for age and BMI. Significant relationships were observed between hormonal and metabolic factors with ADMA and PAI-1. Impaired fibrinolysis was demonstrated in PCOS. In the context of abnormal endothelial function, known hormonal and metabolic abnormalities, outcomes of this study suggest there is an increased risk of cardiovascular disease and venous thrombosis in women with PCOS.

Women who have PCOS have an increased risk of cardiovascular and venous thromboembolic disease (VTE) related to metabolic and hormonal features, obesity and a hypofibrinolytic state, and current PCOS treatments may possibly exacerbate these risks. The haemostatic impacts of common pharmacological treatments administered to women with the syndrome was investigated, and involved a mechanistic sub-study using biobanked samples from a six month randomised comparative trial of pharmacological treatments. Pro- and anti-thrombotic markers and overall haemostatic activity were measured. Overweight women (mean BMI of 36.5±7.0 kg/m2) of mean age 33.9±6.7 years with PCOS (n=60) were randomised to either: (1) metformin, (2) higher-dose oral contraceptive pill (OCP) or (3) low-dose OCP+spironolactone (OCP+S). The main outcome measures included changes over the six month investigation period in PAI-1, ADMA, PF1 & 2, plasminogen, tPA, thrombin activatable fibrinolysis inhibitor (TAFI) and TG as well as relevant hormonal and metabolic markers. PAI-1 activity fell in all groups (p<0.015), ADMA decreased with higher-dose OCP (p=0.0125), PF1 & 2 increased with metformin and higher-dose OCP (p<0.044), TG increased(p<0.009) and tPA decreased in both OCP groups (p<0.013), plasminogen increased in all (p<0.038) and TAFI increased after higher-dose OCP (p=0.0004). Endothelial function (marker of the primary haemostatic response) improved with higher-dose with some improvement with low-dose OCP+S and metformin. Both OCPs however increased coagulation and induced a hypofibrinolytic state in the higher-dose form, with a subsequent increased risk of thrombosis. Metformin did not show (net) negative effects on overall coagulation. The results suggest an additional dimension of treatment (haemostatic system effects) that favours metformin over that of OCPs in PCOS.

The fibrinolytic system and relevant inhibitors play a number of roles, apart from their function in blood haemostasis and thrombosis, namely in ovulation processes. Plasminogen is converted to plasmin at the time of follicular rupture through a decrease in PAI-1 and an increase in plasminogen activators. Only active plasmin is involved in follicular wall breakdown. PCOS is the leading cause of anovulatory infertility with oligo-/anovulation and ovarian follicle arrest as key characteristics. The presence and distribution of fibrinolytic/proteolytic markers plasminogen, plasminogen/plasmin, tPA and uPA and inhibitor PAI-1 in the ovaries of control and PCOS mice were examined using an existing PCOS mouse model with dihydrotestosterone treated mice that display extensive ovarian, endocrine and metabolic features of humans affected by the syndrome. The expression of PAI-1, tPA, uPA, plasmin/plasminogen and plasminogen on six PCOS and six control ovaries were examined by immunohistochemistry using the appropriate antibodies and quantitative comparisons using digital image analysis were completed. There was a difference in the ovarian distribution of PAI-1 that was localised throughout the PCOS ovary unlike a peripheral distribution seen in control ovaries and plasminogen that was observed in small follicles only in PCOS and not in small follicles of control ovaries. While no differences were noted in the overall expression (mean total percentage and mean colour intensity) of ovarian staining of markers assessed, these findings showed a potential role for the plasminogen system in both the physiological mouse ovary and in the pathological PCOS state. Further studies evaluating these markers at different time-points of ovulation will help to further clarify both physiological and potential pathological roles these markers play in ovulation processes distorted in PCOS.

Collectively these related studies enhance our understanding of the haemostatic and fibrinolytic/proteolytic systems in women with PCOS. As a hypofibrinolytic state was demonstrated in the first study, this serves as a potential further CVD and VTE risk factor in a group of women already at high-risk. Additionally, use of the commonly prescribed OCPs in the management of women with PCOS has also demonstrated potential further risk factor/s for thrombosis following observations of increased coagulation and a hypofibrinolytic state with use of the higher-dose form. Metformin however did not show any net negative coagulation outcomes and was noted to be the treatment of choice over the use of both OCPs in the management of women with this syndrome. While at a systemic level a hypofibrinolytic state may increase venous thrombotic risks, the third study showed that at a local ovarian level fibrinolytic system changes are also observed in the PCOS ovary in comparison to normal ovaries and may be associated with the aberrant ovulation frequently noted in women with PCOS. Overall the results from these studies will enhance our understanding of PCOS, help to better inform clinical practice as well as assist with development of improved treatment options.
Degree Doctor of Philosophy (PhD)
Institution RMIT University
School, Department or Centre Health and Biomedical Sciences
Subjects Cardiovascular Medicine and Haematology not elsewhere classified
Keyword(s) Polycystic Ovarian Syndrome
Haemostatic System
Fibrinolytic System
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Created: Thu, 20 Sep 2018, 09:37:38 EST by Adam Rivett
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