Gender Difference – Workshop der European Society of Human Reproduction and Embryology

Ein Artikel von mir über Frauen und Blutgerinnung!

Gender differences in hemostasis

Sabine Eichinger, MD

Men and women differ with regard to coagulation factor activity, coagulation inhibitor activity as well as coagulation activation markers (1). In particular, women are subject to specific hormonal changes which may influence factors relevant for thrombosis and hemostasis. During reproductive age the menstrual cycle or pregnancy may alter the pro- and anticoagulant as well the fibrinolytic system, while after menopause age-related aspects contribute to changes in the hemostatic system. At all ages female hormone intake including use of hormone contraceptives or hormone replacement therapy substantially influences on the coagulation system.

During menstrual cycle, most of the studies did not find cyclic variations in VWF, FVIII, FXI, FXIII, fibrinolytic factors and fibrinogen (2). However, in studies where these variables showed any variation, they reached the lowest levels during menstrual and early follicular phase, especially for VWF, FVIII and platelet function tests. Thus, the optimal timing for haemostatic testing during menstrual cycle seems to be menstrual and early follicular phase. Normal pregnancy is associated with alterations of the hemostatic system towards a hypercoagulable state. Elevated markers of coagulation and fibrinolytic system activation, such as D-Dimer, indicate increased thrombin activity and increased fibrinolysis following fibrin formation throughout pregnancy. Overall, during pregnancy the balance between pro- and anticoagulant forces seems to be altered in favour of a prothrombotic state, most likely to decrease the bleeding complications in connection with delivery. This is reflected by various alterations of the hemostatic system which are seen during normal pregnancy. While the levels of factors V, VII, VIII, IX, X, XII and von Willebrand antigen increase, protein S, factor XI and platelets tend to decrease throughout pregnancy (3). In addition, molecular markers of hemostatic system activation increase during pregnancy indicating an increased fibrin generation and an increased fibrinolytic activity. We have demonstrated that even an uncomplicated pregnancy is accompanied by a substantial hemostatic system activation as indicated by increasing markers of coagulation activation, such as prothrombin fragment F1+2 and D-Dimer (4).

Menopause is accompanied by processes of physiological aging which is associated with increased plasma levels of many proteins of blood coagulation, alterations of platelets and fibrinolysis impairment (5). Hormone replacement therapy increases coagulation activity and fibrinolysis (6). Noteworthy, the coagulation activating effects including acquired activated protein C resistance of estrogens are dependent on the route of administration with no or less effects seen with transdermal estrogens (7). Data on potential differential effects of progestagens on the hemostastic system are conflicting.

Hormone contraceptive use is associated with a procoagulant state caused by changes in the levels of coagulation factors, levels of anticoagulant proteins, such as protein S and tissue factor pathway inhibitor as well as fibrinolytic parameters (8). The effects differ between types of hormone contraceptives and are dependent on the dose of estrogen and the progestagen component in the pill.

References:

1. Lowe GD, Rumley A, Woodward M, Morrison CE, Philippou H, Lane DA, Tunstall-Pedoe H. Epidemiology of coagulation factors, inhibitors and activation markers: the Third Glasgow MONICA Survey. I. Illustrative reference ranges by age, sex and hormone use. Br J Haematol 1997;97:775-84.

2. Knol HM, Kemperman RF, Kluin-Nelemans HC, Mulder AB, Meijer K.

Haemostatic variables during normal menstrual cycle. A systematic review. Thromb Haemost 2012;107:22-9.

3. Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin Thromb Hemost 2003;29:125-30.

4. Eichinger S, Weltermann A, Philipp K, et al. Prospective evaluation of hemostatic system activation and thrombin potential in healthy pregnant women with and without factor V Leiden. Thromb Haemost 1999;82:1232-6.

5. Bucciarelli P, Mannucci PM. The hemostatic system through aging and menopause. Climacteric 2009;12 Suppl 1:47-51.

6. Teede HJ, McGrath BP, Smolich JJ, Malan E, Kotsopoulos D, Liang YL, Peverill RE. Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis. Arterioscler Thromb Vasc Biol 2000;20:1404 –1409.

7. Oger E, Alhenc-Gelas M, Lacut K, Blouch MT, Roudaut N, Kerlan V,

Collet M, Abgrall JF, Aiach M, Scarabin PY, Mottier D. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. Arterioscler Thromb Vasc Biol 2003;23:1671–1676.

8. van Hylckama Vlieg A, Middeldorp S. Hormone therapies and venous thromboembolism: where are we now? J Thromb Haemost 2011;9:257-66.