February 2022: Women's Heart Health

by Donna Castellone, MS, MT (ASCP) SH • February 09, 2022



The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.


February reminds us to take care of our heart both emotionally and physically. February 4th is National Wear Red Day. This is a day to help raise awareness of women's number 1 killer cardiovascular disease (CAD). This was previously thought to be a disease that impacted mostly men. We know that there are distinct differences between men and women- just read "Men are from Mars, Women are from Venus", but what about how their coagulation profile impacts their cardiovascular health?

 

Women vs. Men:

Estrogen is present in women throughout their lives, however during menopause this level begins to drop and relaxes the arterial wall which causes a decrease in flexibility and a higher risk of heart disease. Women outlive men, but they catch up in mortality and end up with a slightly higher risk of dying of heart disease just because they live longer. The average age a man has his first heart attack is 65, while for a woman it is 72, but women tend to be more severe and tend to reoccur within two years. Women's symptoms tend to be vaguer and delay an ED visit for a median time of 54 hours versus a visit time of16 hours for men.1

 

Coronary Artery Disease (CAD)

Evidence has shown that circulating levels of coagulation factors may predict CAD risk. A study looked at men versus women who were admitted for coronary angiography. Levels of FVIII (134% versus 117%) and fibrinogen (3.4 g/l versus 3.2 g/l) were statistically significantly higher in women versus men. In female patients with significant atheroma also presented with statistically significant higher levels of PAI-1 (25.0 ng/ml vs 13.4 ng/ml) and vWF (1.25 IU/ml vs 1.06 IU/ml). These elevated factors may contribute to an adverse cardiovascular risk factor profile and poorer prognosis in females than male patients with proven coronary artery disease.2

When evaluating recurrent coronary events post MI a study looked at gender related differences for predicting cardiac events by measuring levels of coagulation factors two months following an event. Male and female levels were compared for fibrinogen, von Willebrand factor, factor VII and VIIa, plasminogen activator inhibitor, D-dimer, cholesterol, apolipoprotein A-1, apolipoprotein B, lipoprotein(a), triglycerides, and high-density lipoprotein cholesterol. After adjustment for clinical covariates, levels of apolipoprotein A, high-density lipoprotein cholesterol, fibrinogen, and factor VIIa were significantly higher in postinfarction women than men. After a 26 month follow up, there were 67 cardiac events 8.5% in men and 5.5% women. Elevated levels of FVII were a significant predictor of cardiac events in women, but not in men. The D-dimer however had prognostic value in men but was not significant in women, making it a better predictor in men.3

Global coagulation profiles using the calibrated automated thrombography assay to assess thrombin generation and the overall hemostatic potential (OHP) assay to assess fibrin generation were evaluated in both male and female patients in the BioHEART-CT study. This study showed that sex is associated with differences in global coagulation assays, but there are no significant differences in global coagulation profiles with the presence or absence of coronary artery disease but a moderately strong associated with the coronary artery calcium score.4

Sex‐segregated analysis demonstrated baseline hypercoagulable profiles in the calibrated automated thrombography assay in women but no differences in the OHP assay. Hypercoagulable OHP profiles were associated with obesity in men and hyperlipidemia in women, and OHP measures were found to correlate with coronary artery disease severity scores in men but not women. The addition of the OHP assay to basic risk models improved the ability of the model to improve prediction of disease severity in men but not in women.4

 

Stroke

The leading cause of adult disability in the US is stroke and women are disproportionately affected, it is the third leading cause of death for women and the fifth leading cause for men. There are 26% more female stroke survivors than male and will increase as the aging population continues to expand. Sex differences contribute to differential ischemic sensitivity including platelets, vascular reactivity and coagulation. An ischemic stroke is a result of the formation of a thrombosis from either a vessel or the heart.5

An increased risk of ischemic events has been associated with inflammation, endothelial damage, and atherosclerosis. Vascular reactivity is characterized as the ability of the cerebral arterioles to improve blood flow. The impairment of this function can be affected by hormones in particular estrogen which stimulates the production of nitric oxide (NO) and the release of NO in response to acetylcholine is higher in females than in males and contribute to vascular function between sexes.6 Estrogens play an important role in the regulation of vascular reactivity resulting in better tissue perfusion in females during and after occlusion of cerebral arteries which in turn may contribute to reduced stroke volumes.

Vascular injury causes activation of the coagulation cascade leading to the formation of a fibrin-platelet clot. During an ischemic stroke the activation causes an acute thrombosis. It appears that the inhibition of FXIIa can provide a novel target for the primary prevention of stroke due to the estrogen sensitivity of the F12 gene transcription.7

A retrospective study investigated the levels of FXI, FXII and Plasminogen Activator Inhibitor (PAI1) and their association with the increased incidence of acute ischemic stroke (AIS) in particular in women. Levels were evaluated 24 hours after AIS in patients with no history of coagulation disorders versus 29 controls. FXI levels were higher in control subject and higher in females versus males while PAI1 and FXII levels were not statistically different in men versus women while female controls had higher FXI controls than male AIS patients. Decreased levels of FXI were found to be statistically significant in stroke patients when compared to controls, yet females presented with a higher baseline FXI in both controls and stroke patients.8

Platelets can be activated by circulating factors in the blood or by sub-endothelial collagen exposed endothelial injury. When atherosclerotic plaque ruptures, platelet will adhere to exposed collagen and von Willebrand factor (vWF), bound by thrombin resulting in platelet activation. Secretion of dense granules release adenosine diphosphate and platelet cyclooxygenase-1 converts phospholipid derived arachidonic acid to prostaglandin which is then converted to thromboxane and released resulting in the amplification of platelet activation and induction of platelet aggregation at the site. This then exposes a phospholipid surface on which coagulation factors bind and produce thrombin resulting in the formation of a stable fibrin/platelet clot.7

Platelet reactivity may be influenced by sex and sex hormones since both men and women express estrogen receptors on their platelets, however the relationship seems to be complex. Women appear to have a greater baseline platelet reactivity; estrogen may assist in attenuating this increased activity and may be why when estrogen decreases after menopause the incidence of stroke increases.9

Antiphospholipid antibodies (aPLs) have a strong association with arterial thrombosis by activation of endothelial cells. This results in up regulation of pro-inflammatory cytokine secretion, tissue factor release and initiation of the coagulation cascade. The Framingham Offspring Cohort study showed a sex-specific association between aCL titers and ischemic stroke. There was a positive correlation with advancing age as well as being female for stroke when compared to male counterparts. There was also a trend towards higher risk in pre and peri menopausal women above the aCL threshold than in post-menopausal women. Results indicate that even though estrogen has been shown to be neuroprotective it may also play a role in the induction of aPL and hypercoagulability leading to an increase in stroke risk.7

 

Conclusion:

There are distinct differences in the risk of heart disease and stroke in men and women. It is important to be aware of how coagulation factors may aid in the risk stratification for these disorders. Being aware of how hormone levels may impact different levels of coagulation reactivity plays a role in the diagnosis and treatment of achieving heart health.

 


REFERENCES:

  1. https://www.stlukeshealth.org/resources/women-vs-men-surprising-differences-heart-health, January 21, 2020.
  2. Ossei-Gerning N, Wilson IJ, Grant PJ. Sex differences in coagulation and fibrinolysis in subjects with coronary artery disease. Thromb Haemost. 1998 Apr;79(4):736-40.
  3. Kalaria VG, Zareba W, Moss AJ, Pancio G, Marder VJ, Morrissey JH, Weiss HJ, Sparks CE, Greenberg H, Dwyer E, Goldstein R, Watelet LF. Gender-related differences in thrombogenic factors predicting recurrent cardiac events in patients after acute myocardial infarction. The THROMBO Investigators. Am J Cardiol. 2000 Jun 15;85(12):1401-8.
  4. Kott, KA., Morel, MC., Vernon, ST., Takagi, Y., DiBartolo, BA., Peter, K., Yang, JY., Grieve, SM., Ward, C., Figtree, GA., Association of Global Coagulation Profiles With Cardiovascular Risk Factors and Atherosclerosis: A Sex Disaggregated Analysis From the BioHEART‐CT Study, 8 Oct 2021 Journal of the American Heart Association
  5. Go ASM, Mozaffarian DM, DrPH, FAHA, Roger VLM, MPH, FAHA, et al. Executive Summary: Heart Disease and Stroke Statistics-2013 Update: A Report From the American Heart Association. Circulation. 2013;127(1):143–152.
  6. Weiner CP, Lizasoain I, Baylis SA, Knowles RG, Charles IG, Moncada S. Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci U S A. 1994 May 24;91(11):5212–5216.
  7. Roy-O'Reilly M, McCullough LD. Sex differences in stroke: the contribution of coagulation. Exp Neurol. 2014 Sep;259:16-27.
  8. Chindhuri Selvadurai, Yu-Bo Wang, Meaghan Roy-O'Reilly, James J Grady, and Louise D McCullough, Sex Differences in Coagulation After Stroke: Factor XI Levels Drop After Acute Ischemic Stroke, 16 Feb 2016 Stroke.
  9. Bar J, Lahav J, Hod M, Ben-Rafael Z, Weinberger I, Brosens J. Regulation of platelet aggregation and adenosine triphosphate release in vitro by 17beta-estradiol and medroxyprogesterone acetate in postmenopausal women. Thromb Haemost. 2000 Oct;84(4):695–700