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Three Part Question

Could a [raised d-dimer level] be the result of [hormonal changes] seen in [normal menstruation]?

Clinical Scenario

A 22 year old student is sent from the Walk-In Centre because she has complained of pleuritic chest pain. In the referral letter the GP asks you to rule out a Pulmonary Embolism. She is low risk, has no abnormal chest signs and has a normal chest X ray. To your great surprise her d-dimer is reported as >10,000. She has a V/Q scan which is reported as low probability for a PE. You wonder whether her raised d-dimer could be caused by menstruation?

Search Strategy

Medline 1946 to March Week 2 2014
Cochrane Reviews
(fibrin degradation products.mp. or exp Fibrin Fibrinogen Degradation Products/) OR (d-dimer.mp.) AND (menstruation.mp. or Menstruation/) OR (menstrual cycle.mp. or exp Menstrual Cycle/) OR (ovarian cycle.mp. or exp Menstrual Cycle/)

Search Outcome

34 papers were found using Medline. Five papers were directly relevant to the question. There was also a Systematic Review, which referred to an additional study. These papers are summarised in Table 1. There were also four cohort studies measuring haemostatic variables in women on hormone treatments, so these were not included. Neither were the studies, which referred to fibrin degradation products but not d-dimer, although they are mentionned in the comments.
There were no Cochrane Reviews relevant to the question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Knol et al. 2012 Holland	Systematic review of haemostatic variables during the normal menstrual cycle. Five studies measured d-dimer levels.	Systematic review	D-dimer	In one study the lowest d-dimers were found on cycle days 10-14, in the other the lowest levels were seen on day 28 (total n=50)	Only two of five (Koh et al. 2005, and Giardina et al. 2004) identified studies documented cyclical changes in d-dimer levels, and they gave quite divergent results. One paper compared d-dimer levels in oral contraceptive users against those taking a placebo.
Chaireti et al. 2013 Sweden	102 healthy women. 86 had previous exposure to COC. Multiple haemostatic parameters (including d-dimer) measured during follicular and luteal phases of normal menstrual cycles (cycle days 3-5 vs 22-25). D-dimer measured using photometric method.	Prospective cohort study	D-dimer	Follicular phase: 0.1 +/- 0.1 mg/L vs luteal 0.07 +/- 0.06 mg/L, p=0.067.	Only 73 subjects had full thrombin generation profiles. Uncertain how many subjects contributed to the d-dimer dataset.
Toth et al. 2007 Germany	27 healthy women with regular menstrual cycles, who had not taken oral contraceptives for at least 6 months. 14 had blood taken during the follicular phase, 13 in the luteal phase. Assessment of microparticles and platelet-derived and endothelial-derived microparticles including d-dimer. D-dimer assayed using a latex amplified immunoassay system. Comparison was made with 18 healthy men.	Prospective case-control study	D-dimer	D-dimer >0.25 mcg/ml in 12 women vs 1 man.	Small numbers of subjects. Single blood sample from each. No report of differences in d-dimer levels in the two phases of the menstrual cycle as there was no within subject testing of the two phases.
Giardina et al. 2004 USA	20 healthy women with a normal menstrual cycle for more than 6 months. Morning blood taken twice weekly during the four weeks of the menstrual cycle (wk 1 early follicular, wk 2 late follicular, wk 3 early luteal, wk 4 late luteal). Haemostatic and fibrinolytic factors assessed. D-dimer measured using an Enzyme-Linked Immunosorbent Assay (ELISA).	Prospective cohort study	D-dimer	Follicular phase 374 +/- 224 ng/ml vs luteal 317 +/- 192 ng/ml, p<0.05	Small numbers but twice weekly blood samples with values averaged. No data presented on the individual weeks.
Feuring et al. 2002 Germany	18 healthy women, not taking oral contraceptives, with regular ovarian cycles. Blood samples taken during the follicular (days 8-11) and luteal phases (days 18-21) of the cycle and assayed for hormones and indices of platelet function. D-dimer measured with "commercially available test kits" - Diagnostica, Germany).	Prospective cohort study	D-dimer	Follicular phase 0.12 +/- 0.09 mcg/ml vs luteal phase 0.14 +/- 0.07 mcg/ml, ns.	Small numbers
Koh et al. 2005 Singapore	30 healthy women not on any medication with menstrual cycles of 28-30 days. Blood sample during one menstrual cycle: menstruation (days 1-3), follicular phase (days 5-9), mid-cycle (days 10-14), and luteal phase (days 21-26).	Prospective cohort study	D-dimer (ng/ml)	Day 1-3: 268 (SD 123) vs day 5-9: 222 (SD 108) vs day 10-14: 182 (SD 72) vs day 21-26: 237 (SD 152), p=0.04.	Measurement only made during one cycle. D-dimer assay not specified except for name of manufacturer.

Comment(s)

In principle menstrual blood loss is an extravascular phenomenon and so the formation of clots and bleeding should not impact on intravascular haemostatic or fibrinolytic factors. However, there is evidence that fibrin degradation product (FDP) concentrations are increased during the menstrual period compared to the intermenstrual weeks (Basu 1970). Basu also found that FDP concentrations were increased in women with menorrhagia compared to those without (as did Bisht et al. 1991 and Hahn et al. 1976, but not Cole and Clarkson 1972). It is also known that increased levels of female sex hormones can have an effect on the coagulation system (Suzuki and Morishita, 1998) and that fibrinogen levels increase during pregnancy (Gatti et al. 1994). There is evidence that d-dimer levels may be raised in pregnancy (Morse 2004). Whether the much smaller changes in female sex hormones seen during the normal ovarian cycle can have an effect on haemostatic variables has been the subject of the studies summarized by Knol et al (2012). There is little evidence about d-dimer levels, and some of that is contradictory. From the little evidence there is it seems unlikely that there is a clear effect of the ovarian cycle on d-dimer levels.

Editor Comment

BAF using

Clinical Bottom Line

There is very little evidence on the effect of the ovarian/menstrual cycle on d-dimer levels in healthy women. An unexpectedly raised d-dimer result should not be attributed to normal menstruation.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.

References

1. Knol HM, Kempermen RFJ, Kluin-Nelemans HC, et al. Haemostatic variables during normal menstrual cycle. Thromb and Haemost 2012:107:22-29.
2. Chaireti R, Gustafsson KM, Bystrom B, et al. Endogenous thrombin potential is higher during the luteal phase than during the follicular phase of a normal menstrual cycle. Human Reproduction 2013;28(7):1846-1852.
3. Toth B, Nikolajek K, Rank A, et al. Gender-specific and menstraul cycle dependent differences in circulating microparticles. Platelets 2007;18(7):515-521.
4. Giardina E-GV, Chen HJ, Sciacca RR, et al. Dynamic variability of hemostatic and fibrinolytic factors in young women. J Clin Endocrinol Metab 2004;89:6179-6184.
5. Feuring M, Christ M, Roell A, et al. Alterations in platelet function during the ovarian cycle. Blood Coagul Fibrinolysis 2002;13:443-447.
6. Koh SCL, Prasad RNV, Fong YF. Hemostatic status and fibrinolytic response potential at different phases of the menstrual cycle. Clin Appl Thrombosis Hemostasis 2005;11(3);295-301.
7. Morse M. Establishing a normal range for D-dimer levels through pregnancy to aid in the diagnosis of pulmonary embolism and deep vein thrombosis. J Thromb Haemost 2004;2:1202-1204.
8. Gatti l, Tenconi PM, Guarneri D et al. Hemostatic parameters and platelet activation by flow-cytometry in normal pregnancy: a longitudinal study. Int J Clin Lab Res 1994;24:217-219.
9. Suzuki S, Morishita S. Platelet hemostatic capacity (PHC) and fibrinolytic inhibitors during pregnancy. Semin Thromb Hemost 1998;24:449-451.
10. Basu HK. Fibrin degradation products in sera of women with normal menstruation and menorrhagia BMJ 1970;1:74-75
11. Bisht D, Gupta SC, Kaushik S, et al. Fibrinolysis in idiopathic menorrhagia. Indian Journal of Pathology & Microbiology 1991;34:200-202.
12. Hahn L, Cedeblad G, Rybo G, et al. Blood coagulation, fibrinolysis and plasma proteins in women with normal and with excessive menstrual blood loss. BJOG 1976:83:974-980
13. Cole SK, Clarkson AR. Menstrual blood loss and fibrin degradation products. BMJ 1972;1:78-79.