Kommersiellt obunden läkemedelsinformation riktad till läkare och sjukvårdspersonal

Heparin

Classification: C

Drug products: Heparin AB Unimedic, Heparin APL, Heparin LEO, Heparin sodium, Heparin Sodium, Heparin Sodium Hospira, Heparin Utan Konserveringsmedel, Heparin-Natrium-5000-ratiopharm

ATC code: B01AB01

Substances: heparin, heparin sodium

Summary

Women might require lower doses of heparin than men to achieve therapeutic APTT-value (activated partial thromboplastin time).

Studies show conflicting results on the risk of bleeding due to heparin. Some studies show a higher risk of bleeding in women.

Overall, women have a higher risk of heparin-induced thrombocytopenia than men when treated with unfractionated heparin. In women treated for deep venous thrombosis, unfractionated heparin has a higher risk of inducing thrombocytopenia than low molecular heparins.

Women tend to develop resistance to unfractionated heparin to a higher extent than men.

Additional information

Pharmacokinetics and dosing

When given the same dose of heparin (93 men, 103 women), women had higher concentrations and APTT values (activated partial thromboplastin time) 4-6 hours after bolus and infusion. After adjusting for weight the difference remained in older women [1].

Effects

Clinical trials have shown that female sex is associated with increased APTT. After administration of standardized doses of unfractionated heparin, women had higher heparin levels and greater prolongation of the APTT than men. Therefore, women might require a lower dose of heparin to achieve therapeutic APTT value [1, 2]. Similarly, low-molecular-weight heparin given in the same dose resulted in higher anti-factor Xa levels in women, even after compensating for age, body weight and smoking [3].

Adverse effects

In general, female sex is associated with an increased bleeding risk with thrombolytics, unfractionated heparin and low-molecular-weight heparin [4, 5].  The original manufacturer reports that a higher incidence of bleeding has been reported in patients over 60 years of age, especially women. Therefore, it has been suggested that lower doses of heparin may be indicated in these patients [6].

A randomized clinical trial (93 men, 105 women) found that women compared to men had different pharmacokinetics of unfractionated heparin, but the rates of bleedings were similar in men and women [1]. Similarly, a subgroup analysis from a randomized trial comparing unfractionated heparin with bivalirudin found no sex difference in bleeding (411 men, 391 women) [7].

An analysis of register data, a clinical trial and systematic reviews showed that women more than men are at higher risk for heparin-induced thrombocytopenia (HIT). The overall increased risk for HIT in women was 2.37 (95%CI, 1.37-4.09). The increased risk was observed mostly in patients treated with unfractionated heparin [8].

A large international cohort study (in total 24 401 patients) observed that treatment of venous thromboembolism (VTE) with unfractionated heparin increased the risk of thrombocytopenia in women but not in men, when compared to treatment with low molecular weight heparin (HR 4.90 (95%CI 2.58-9.31) in women vs. 1.60 (0.64-3.97) in men) [9].

Heparin resistance occurs early in the heparin therapy and may put patients at risk of progression of the underlying thrombotic process. Close monitoring of the APTT (activated partial thromboplastin time) and heparin dose adjustment is recommended to reduce the risk. A prospective observation study (99 men, 47 women) found that women were more resistant to heparin than men. The higher rate of resistance to heparin in women extended for up to 48 h. A possible explanation may be the higher level of endogenous factor VIII in women probably because of higher levels of estrogen [10].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Updated: 2019-06-12

Date of litterature search: 2019-01-24

References

  1. Campbell NR, Hull RD, Brant R, Hogan DB, Pineo GF, Raskob GE. Different effects of heparin in males and females. Clin Invest Med. 1998;21:71-8. PubMed
  2. Granger CB, Hirsch J, Califf RM, Col J, White HD, Betriu A et al. Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction: results from the GUSTO-I trial. Circulation. 1996;93:870-8. PubMed
  3. Toss H, Wallentin L, Siegbahn A. Influences of sex and smoking habits on anticoagulant activity in low-molecular-weight heparin treatment of unstable coronary artery disease. Am Heart J. 1999;137:72-8. PubMed
  4. Lansky AJ, Mehran R, Cristea E, Parise H, Feit F, Ohman EM et al. Impact of gender and antithrombin strategy on early and late clinical outcomes in patients with non-ST-elevation acute coronary syndromes (from the ACUITY trial). Am J Cardiol. 2009;103:1196-203. PubMed
  5. Alexander KP, Chen AY, Roe MT, Newby LK, Gibson CM, Allen-LaPointe NM et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA. 2005;294:3108-16. PubMed
  6. HEPARIN SODIUM injection (heparin sodium). DailyMed [www]. US National Library of Medicine. [updated 2018-08-01, cited 2019-02-19]. länk
  7. Asgar A, Chandrasekhar J, Mikhail G, Webb J, Lefèvre T, Tamburino C et al. Sex-based differences in outcomes with bivalirudin or unfractionated heparin for transcatheter aortic valve replacement: Results from the BRAVO-3 randomized trial. Catheter Cardiovasc Interv. 2017;89(1):144-153. PubMed
  8. Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood. 2006;108:2937-41. PubMed
  9. Falvo N, Bonithon-Kopp C, Rivron Guillot K, Todoli JA, Jiménez-Gil M, Di Micco P et al. Heparin-associated thrombocytopenia in 24,401 patients with venous thromboembolism: findings from the RIETE Registry. J Thromb Haemost. 2011;9:1761-8. PubMed
  10. Alsayegh F, Al-Rasheed M, Al-Muhaini A, Al-Humoud E, Al-Ostaz M, Mousa SA. Heparin anticoagulation responsiveness in a coronary care unit: a prospective observational study. Cardiovasc Ther. 2009;27:77-82. PubMed
  11. Concise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2019-03-14.] länk

Authors: Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson