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doi:10.1111/jog.12600
J. Obstet. Gynaecol. Res. 2014
Recurrent pregnancy loss is associated with increased red cell distribution width and platelet distribution width Ozgur Dundar1, Mıne Kanat Pektas2, Serkan Bodur3, Lale Vuslat Bakır4 and Ahmet Cetin4 1 Department of Obstetrics and Gynecology, Haydarpasa Military Education and Research Hospital, GATA, 4Department of Obstetrics and Gynecology, Haseki Education and Research Hospital, Istanbul, 2Depertment of Obstetrics and Gynecology, Kocatepe University School of Medicine, Afyon, and 3Department of Obstetrics and Gynecology and Dispensary of Oran, Beytepe Military Hospital, Ankara, Turkey
Abstract Aim: The present study aims to evaluate how components of complete blood count are altered in women with a history of recurrent pregnancy loss. Material and Methods: This was a retrospective evaluation of 60 women who had a history of recurrent pregnancy loss, 60 healthy women who had a first trimester pregnancy and 60 healthy parous women. Results: When compared with pregnant women and healthy controls, the women with a history of recurrent pregnancy loss had significantly higher red cell distribution width (RDW) and platelet distribution width (PDW) (P = 0.001 for both). Thrombophilia was detected in 31.7% of the women who had a history of recurrent pregnancy loss (19 out of 60). When compared to the women without thrombophilia, the women with thrombophilia had significantly lower body mass index (P = 0.034) but significantly higher RDW, PDW and plateletcrit (respectively, P = 0.043, P = 0.001 and P = 0.002). There were significant and positive correlations between RDW and PDW (r = 0.615, P = 0.001), RDW and plateletcrit (r = 0.343, P = 0.007) and PDW and plateletcrit (r = 0.340, P = 0.008) in women with a history of recurrent pregnancy loss. Conclusion: An elevation in PDW and RDW values was found to be associated with recurrent pregnancy loss. Key words: platelet distribution width, recurrent pregnancy loss, red cell distribution width, thrombophilia.
Introduction Approximately 10–15% of all pregnancies result in an abortion and these spontaneous miscarriages are mostly due to chromosomal abnormalities. Recurrent pregnancy loss commonly refers to the spontaneous loss of three or more consecutive pregnancies. The loss of at least two consecutive pregnancies occurs in up to 5% of women at reproductive age. In fact, recurrent pregnancy loss is one of the most significant causes of female sterility.1
The etiology of recurrent pregnancy loss is multifactorial and includes uterine anomalies, endocrinological disorders, immunological causes, infections, chromosomal abnormalities and maternal autoimmune diseases. However, the underlying cause cannot be clarified in 50–60% of all recurrent miscarriages.2,3 Thrombophilia has been identified as one of the main causes of recurrent pregnancy loss. Different polymorphisms of thrombophilic disorders are diagnosed in up to 40% of women who have experienced recurrent miscarriages. However, this association
Received: February 28 2014. Accepted: August 22 2014. Reprint request to: Dr Serkan Bodur, Department of Obstetrics and Gynecology and Dispensary of Oran, Beytepe Military Hospital, Ankara 06450, Turkey. Email: [email protected]
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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depends on the type of thrombophilic disorder and the gestational age at which fetal loss occurs.4 Thrombophilia is related with several biological markers that reflect either coagulation activation (such as prothrombin fragment and thrombin-antithrombin complex) or platelet activation (such as βthromboglobulin or soluble platelet P-selectin). As the measurements of these markers are both timeconsuming and expensive, they cannot be performed as a part of routine laboratory studies.5,6 Thrombophilia induces platelet activation, which ends up with alterations in platelet morphology. That is why mean platelet volume (MPV), mean platelet component (MPC) and platelet distribution width (PDW) have been investigated as the markers of platelet activation markers and, thus, predictors of thrombophilic disorders.7–10 The present study aims to evaluate how components of complete blood count are altered in women with a history of recurrent pregnancy loss.
Methods The present study was approved by the Institutional Review Board and Ethical Committee of Haydarpasa Research and Education Hospital of Gulhane Military Medicine Academy where it was conducted. This was a retrospective evaluation of 60 women who had a history of recurrent pregnancy loss, 60 healthy women who had a first trimester pregnancy and 60 healthy parous women. All of the reviewed subjects were consecutively recruited from the patients who were admitted to the study center between January 2001 and January 2014. Recurrent miscarriage was defined as three or more consecutive first-trimester (24 weeks) combined with at least one first-trimester miscarriage. Women who had experienced recurrent pregnancy loss due to uterine anomalies and/or endocrinopathies were excluded. Data related with age, gravidity, parity, height, weight, body mass index (BMI), smoking habit, complete blood counts and thrombophilic disorders were acquired from medical records.
Complete blood count One sample of 20 mL venous blood was drawn by standard phlebotomy from all of the participants. This sample was kept for the evaluation of hemoglobin, hematocrit, mean corpuscular volume (MCV), mean
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corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), erythrocyte count, leukocyte count, platelet count, PDW, MPV and plateletcrit by means of an automated commercial counter (Coulter counter, Max Instruments Laboratory). After this venous blood sample was conveyed into a sodium citrate tube, it was transported in a temperature-controlled container and collected in plastic provettes (Falcon blue cap) containing 3 mL of 3.8% sodium citrate dihydrate and 136 mM glucosium. Time between sampling and tube reading was never more than 2 min. The samples were read three times and the final result represented the mean of three readings.
Thrombophilia testing Thrombophilia testing included factor V Leiden mutation, prothrombin G20210A mutation, protein C deficiency ( 40 GPL or homozygosity for factor V Leiden.11,12 Statistical analysis Collected data were analyzed by spss 18.0. Continuous variables were expressed as mean ± standard deviation or median (range: minimum–maximum) whereas categorical variables were denoted as numbers or percentages. The Smirnov–Kolmogorov test was used to test the distribution of data. One-way anova test and the Student’s t-test were used to compare the continuous variables with normal distribution while the χ2-test and Kruskal–Wallis test were used to compare the categorical variables and continuous variables without normal distribution. Bonferroni adjustment was applied for all possible group comparisons, controlling for type I
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Pregnancy loss and complete blood count
Table 1 Demographic characteristics of study cohort
Age (years) Gravidity Parity Height (m) Bodyweight (kg) Body mass index (kg/m2) Systolic blood pressure Diastolic blood pressure Smoking habit Alcohol intake
Pregnant women (n = 60)
Recurrent pregnancy loss (n = 60)
Healthy controls (n = 60)
P
27.1 ± 5.2 (18–41) 2.3 ± 1.2 (1–5) 1.3 ± 1.2 (1–4) 1.61 ± 0.07 (1.48–1.73) 59.2 ± 7.1 (47–80) 23.11 ± 2.65 (21.46–26.76) 99.9 ± 10.3 (70–120) 58.4 ± 9.3 (40–80) 3 (5.0%) 0 (0.0%)
27.0 ± 5.2 (18–39) 4.2 ± 1.1 (2–6) 0.9 ± 0.7 (0–5) 1.62 ± 0.07 (1.50–1.75) 59.6 ± 7.1 (49–81) 22.94 ± 3.39 (21.78–27.68) 102.2 ± 12.5 (90–150) 62.8 ± 10.8 (50–110) 6 (10.0%) 1 (1.7%)
27.6 ± 5.3 (19–40) 2.4 ± 1.8 (1–5) 1.5 ± 1.2 (0–5) 1.62 ± 0.07(1.45–1.70) 58.6 ± 7.0 (48–79) 22.39 ± 3.16 (22.83–27.34) 105.3 ± 12.4 (80–140) 62.7 ± 10.7 (50–90) 2 (3.3%) 1 (1.7%)
0.808 0.001†* 0.001‡* 0.449 0.677 0.405 0.042§* 0.029§* 0.284 0.364
*P < 0.05 was accepted to be statistically significant. †There is a statistically significant difference between pregnant women and women with recurrent pregnancy loss. ‡There is a statistically significant difference between healthy controls and women with recurrent pregnancy loss. §There is a statistically significant difference between pregnant women and healthy controls.
Table 2 Complete blood counts of study cohort
Hemoglobin (g/dL) Hematocrit (%) Mean corpuscular volume (fL) Mean corpuscular hemoglobin (pg) Mean corpuscular hemoglobin concentration (g/dL) Red cell distribution width Erythrocyte count (×106/mm3) Leukocyte count (×103/mm3) Platelet count (×103/mm3) Platelet distribution width (fL) Mean platelet volume (fL) Plateletcrit (%)
Pregnant women (n = 60)
Recurrent pregnancy loss (n = 60)
Healthy controls (n = 60)
P
12.5 ± 1.3 36.9 ± 4.0 86.4 ± 6.7 28.8 ± 4.0 33.8 ± 1.1 14.2 ± 3.1 4323.2 ± 486.2 11.5 ± 4.1 264.6 ± 59.5 16.1 ± 0.9 10.4 ± 1.1 0.22 ± 0.04
11.9 ± 1.3 35.4 ± 3.1 87.3 ± 7.1 29.3 ± 3.0 33.5 ± 1.6 16.3 ± 4.6 4169.7 ± 406.4 10.9 ± 2.5 255.5 ± 56.5 17.5 ± 3.8 10.9 ± 1.1 0.20 ± 0.04
12.1 ± 1.5 36.1 ± 4.0 86.2 ± 6.5 28.8 ± 3.5 33.7 ± 1.4 14.1 ± 2.6 4198.5 ± 466.8 9.7 ± 2.8 263.0 ± 55.4 15.9 ± 0.7 10.5 ± 0.9 0.21 ± 0.04
0.081 0.890 0.632 0.702 0.414 0.001†* 0.148 0.007§* 0.652 0.001‡* 0.002†* 0.051
*P < 0.05 was accepted to be statistically significant. †There is a statistically significant difference between pregnant women and women with recurrent pregnancy loss. ‡There is a statistically significant difference between healthy controls and women with recurrent pregnancy loss. §There is a statistically significant difference between pregnant women and healthy controls.
errors. Pearson correlation test was utilized to detect the correlations between the variables. A P-value less than 0.05 was considered to be statistically significant.
Results Table 1 demonstrates the demographic characteristics of the study cohort. The pregnant women, the women with a history of recurrent pregnancy loss and healthy controls were statistically similar in terms of age, gravidity, parity, height, body weight, BMI, smoking habit and alcohol intake (P > 0.05 for each). As expected, pregnant women had significantly lower systolic and diastolic blood pressures (respectively, P = 0.042 and P = 0.029). Table 2 shows the demographic characteristics of the study cohort. When compared with pregnant women
and healthy controls, the women with a history of recurrent pregnancy loss had significantly higher RDW and PDW (P = 0.001 for both). Thrombophilia was detected in 31.7% of the women who had a history of recurrent pregnancy loss (19 out of 60). Table 3 compares the demographic characteristics of women with a history of recurrent pregnancy loss in terms of thrombophilia existence. The women with thrombophilia and the women without thrombophilia were statistically similar with respect to age, gravidity, parity, height, bodyweight and smoking habit (P > 0.05 for all). However, the women with thrombophilia had significantly lower BMI than the women without thrombophilia (P = 0.034). Table 4 compares the complete blood counts of women with a history recurrent pregnancy loss in terms of thrombophilia presence. The women with thrombophilia had
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Table 3 Demographic characteristics of women with a history of recurrent pregnancy loss
Age (years) Gravidity Parity Height (m) Bodyweight (kg) Body mass index (kg/m2) Systolic blood pressure Diastolic blood pressure Smoking habit Alcohol intake
With thrombophilia (n = 19)
Without thrombophilia (n = 41)
P
27.0 ± 5.5 (18–38) 4.1 ± 1.0 (2–6) 0.6 ± 0.4 (0–5) 1.59 ± 0.07 (1.50–1.70) 61.3 ± 6.7 (49–80) 24.29 ± 3.67 (21.78–27.68) 103.7 ± 16.4 (90–150) 64.2 ± 14.7 (50–110) 3 (15.8%) 0 (0.0%)
27.0 ± 5.1 (19–39) 4.2 ± 1.1 (2–6) 0.8 ± 0.5 (0–5) 1.62 ± 0.07 (1.52–1.75) 58.8 ± 7.2 (50–81) 22.31 ± 3.10 (21.65–26.45) 101.5 ± 10.4 (90–140) 62.2 ± 8.5 (50–90) 3 (7.3%) 1 (2.4%)
0.971 0.522 0.360 0.105 0.198 0.034* 0.527 0.504 0.309 0.537
*P < 0.05 was accepted to be statistically significant.
Table 4 Complete blood counts of women with a history of recurrent pregnancy loss
Hemoglobin (g/dL) Hematocrit (%) Mean corpuscular volume (fL) Mean corpuscular hemoglobin (pg) Mean corpuscular hemoglobin concentration (g/dL) Red cell distribution width Erythrocyte count (×106/mm3) Leukocyte count (×103/mm3) Platelet count (×103/mm3) Platelet distribution width (fL) Mean platelet volume (fL) Plateletcrit (%)
With thrombophilia (n = 19)
Without thrombophilia (n = 41)
P
11.9 ± 1.1 35.2 ± 3.1 88.2 ± 5.7 29.6 ± 2.3 33.6 ± 1.4 18.4 ± 5.8 4112.1 ± 442.5 10.9 ± 2.1 264.2 ± 50.7 21.3 ± 4.8 10.8 ± 1.1 0.22 ± 0.03
11.9 ± 1.3 35.5 ± 3.1 86.9 ± 7.7 29.1 ± 3.3 33.4 ± 1.7 15.3 ± 3.6 4196.3 ± 391.4 11.0 ± 2.7 251.5 ± 59.1 15.7 ± 1.0 11.0 ± 0.8 0.19 ± 0.04
0.944 0.765 0.525 0.524 0.691 0.043* 0.460 0.913 0.425 0.001* 0.318 0.002*
*P < 0.05 was accepted to be statistically significant.
significantly higher RDW, PDW and plateletcrit (respectively, P = 0.043, P = 0.001 and P = 0.002). High-risk thrombophilia (positive lupus anticoagulants, anti-thrombin III deficiency, anticardiolipin antibodies > 40 GPL or homozygosity for factor V Leiden) was diagnosed in 10 women while low-risk thrombophilia was detected in nine women. When compared to the women with low-risk thrombophilia, the women with high-risk thrombophilia were found to have significantly higher RDW (23.9 ± 3.3 vs 13.5 ± 0.7, P = 0.001), PDW (25.4 ± 2.5 vs 17.6 ± 3.0, P = 0.001) and plateletcrit (0.23 ± 0.02 vs 0.21 ± 0.02, P = 0.039). As for the subsequent pregnancy outcome, 40 women with thrombophilia (66.7%) delivered healthy term babies whereas 17 women with thrombophilia (28.3%) had miscarriages and three women with thrombophilia were lost to follow-up (5%). The thrombophilic women with subsequent pregnancy loss had significantly higher PDW than the thrombophilic women with subsequent successful obstetric outcome (20.1 ± 5.1 vs 16.7 ± 3.1, P = 0.041).
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As for the women with a history of recurrent pregnancy loss, there were significant and positive correlations between RDW and PDW (r = 0.615, P = 0.001), RDW and plateletcrit (r = 0.343, P = 0.007) and PDW and plateletcrit (r = 0.340, P = 0.008). These women also had significant and negative correlations between plateletcrit and MCH values (r = −0.275, P = 0.034) as well as plateletcrit and MCHC values (r = −0.395, P = 0.002). All correlations are shown in Figure 1.
Discussion Pregnancy causes many alterations in hemostatic balance and, thus, leads to a tendency towards thrombophilia. Such a tendency is considered as a mechanism that compensates for the hemostatic challenge of delivery. The natural inclination towards thrombophilia in pregnancy is due to the increase in several clotting factors, including factor I, factor VII, factor VIII and von Willebrandt factor. Moreover, other
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Pregnancy loss and complete blood count
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Figure 1 There are significant correlations between red cell and platelet distribution widths (r = 0.615, P = 0.001), red cell distribution width and plateletcrit (r = 0.343, P = 0.007), platelet distribution width and plateletcrit (r = 0.340, P = 0.008), mean corpuscular hemoglobin and plateletcrit (r = −0.275, P = 0.034) and mean corpuscular hemoglobin concentration and plateletcrit (r = −0.395, P = 0.002).
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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markers reflecting hypercoagulability (such as Ddimer and/or prothrombin fragment) are increased during pregnancy.13,14 As pregnancy is associated with thrombophilia, episodes of venous thromboembolism can be observed during pregnancy. If a pregnancy is further complicated with an already existing thrombophilic disorder, the risk of thromboembolism is prominently increased. In fact, venous thromboembolism and pulmonary embolism are still the leading causes of maternal morbidity and even mortality during pregnancy or puerperium. Recurrent pregnancy loss, fetal demise, pre-eclampsia and intrauterine growth restriction may also occur in relation with thrombophilic disorders.15,16 Thrombophilia refers to the qualitative failure of the physiological coagulation inhibitors. Either the qualitative or the quantitative impairment of physiological coagulation inhibitors results in pro-coagulatory imbalance, which eventually leads to a condition of compensated coagulopathy. This chronic state of coagulation is associated with an enhancement in platelet activation.10 The enhancement in platelet activation causes the discoid platelets to become more spherical and to acquire pseudopodia. Such an alteration in platelet shape helps the platelets to obtain a larger surface.17 Hematology analyzers based on impedance technology measure platelet volume by the deformation of electrical field, which depends on the vertical platelet diameter. Analyzers with laser optical technology determine platelet volume according to the cross diameter of the platelet. Being independent of the principle of measurement, activated platelets would appear larger.18 Large platelets are metabolically and enzymatically more active than small platelets. That is, large platelets are capable of producing larger amounts of thromboxane A2 and β-thromboglobulin, which have prothrombotic features. An increment in platelet activity is associated with an increase in platelet size, which is further related with increased platelet aggregation and enhanced expression of adhesion molecules.17–19 Both MPV and PDW are parameters of platelet volume that can be determined routinely in nearly all clinical laboratories. The PDW has been implicated as a specific marker of platelet activation and MPV is usually utilized to assess platelet size. However, the combination of MPV and PDW could predict activation of coagulation more efficiently.17,18 As a body of evidence, MPV and PDW are found to be increased in patients who are more prone to venous thromboembolism. These patients include the individuals affected by
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vascular diseases, diabetes mellitus and acute myocardial infarction and hypercholesterolemia.20 The RDW is a measure of anisocytosis, which can be defined as the variation or heterogeneity in erythrocyte size. As a regular component of routine hematology laboratory tests, RDW is commonly used for the classification of anemia. Increased RDW is traditionally linked to anemia and low-grade systemic inflammation.21 Additionally, this parameter has been associated with several demographic and clinical characteristics, including age, waist circumference, BMI, smoking, high alcohol consumption, blood pressure, diabetes mellitus, leukocyte count, and being unmarried.22,23 As erythrocytes participate in the formation of in vivo clots and thrombi, it is possible that anisocytosis could increase the thrombotic predisposition of red blood cells.24 Recently published studies have shown that RDW is associated with increased mortality in a number of cardiovascular disorders, such as coronary artery disease, stroke, peripheral artery disease, heart failure, pulmonary embolism, and pulmonary arterial hypertension.25 It is, however, unclear whether anisocytosis is the underlying cause, or a simple epiphenomenon due to pre-existing conditions, such as inflammation, impaired kidney function, malnutrition, or oxidative damage.24,25 Two studies evaluated RDW in patients with pulmonary embolism and found that a high RDW value (i.e. anisocytosis) was an independent predictor of pulmonary-embolism-related early mortality.26,27 In a study by Zöller et al., RDW was found to be associated with long-term incidence of first event of venous thromboembolism among middle-aged patients.28 Plateletcrit is an effective screening tool for detecting platelet quantitative abnormalities and the value of plateletcrit increases in parallel with the number of platelets. The significant positive correlation between plateletcrit and PDW, the significant positive correlation between plateletcrit and RDW and the significant positive correlation between PDW and RDW may be attributed to the existence of anisocytosis. That is, an increment in the number of platelets and red blood cells with relatively bigger size may lead to a simultaneous increase in PDW, RDW and plateletcrit values. Anisocytosis may occur as erythrocytes and thrombocytes undergo consumption due to underlying inflammation and thromboembolism. On the other hand, the degradation of erythrocytes may cause the MCH and MCHC values to decrease and, thus, a significant negative correlation can be detected between the aforementioned values and plateletcrit.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Pregnancy loss and complete blood count
To the best of our knowledge, this is the first study to demonstrate an association between recurrent pregnancy loss and increased values of MPV, PDW and RDW. The clinical relevance of such an association is that an elevation in these three hematological parameters may implicate an underlying thrombophilic disorder. In other words, MPV, PDW and RDW might be regarded as biological markers that would reflect moderate hypercoagulability. A body of evidence for this hypothesis is the significant increase in PDW, RDW and plateletcrit values of women with high-risk thrombophilia. However, such a prominent increase is observed in only PDW values of thrombophilic women who experienced subsequent miscarriages. The absence of statistically significant differences in MPV, RDW and plateletcrit values of thrombophilic women with respect to subsequent pregnancy outcome may be due to relatively small cohort size. The power of the present study is limited by several factors. First of all, the size of the cohort is inadequate to specify whether the association between recurrent pregnancy loss and elevated MPV, PDW and RDW values is causal or not. Second, the determination of a significant correlation between PDW and RDW may interfere with the probable correlation of these parameters with recurrent pregnancy loss. Third, the association between recurrent pregnancy loss and elevated MPV, PDW and RDW values has been attributed to the underlying thrombophilic disorder despite the fact that thrombophilia has been detected in only 32% of the reviewed subjects. Another major limitation is the lack of information on thromboembolism-precipitating risk factors, such as immobilization, surgery or trauma. Further research is required to clarify the role of MPV, PDW and RDW in the pathogenesis of recurrent pregnancy loss.
Disclosure The authors report no conflicts of interest.
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4. D’Uva M, Di Micco P, Strina I, De Placido G. Recurrent pregnancy loss and thrombophilia. J Clin Med Res 2010; 2: 18–22. 5. Gaussem P. Assessment of platelet function in man. Therapie 2006; 61: 395–400. 6. Joly B, Barbay V, Borg JY, Le Cam-Duchez V. Comparison of markers of coagulation activation and thrombin generation test in uncomplicated pregnancies. Thromb Res 2013; 132: 386– 391. 7. Colkesen Y, Muderrisoglu H. The role of mean platelet volume in predicting thrombotic events. Clin Chem Lab Med 2012; 50: 631–634. 8. Sharma G, Berger JS. Platelet activity and cardiovascular risk in apparently healthy individuals: A review of the data. J Thromb Thrombolysis 2011; 32: 201–208. 9. Lowe G. Can haemostatic factors predict atherothrombosis? Intern Emerg Med 2011; 6: 497–501. 10. Vagdatli E, Gounari E, Lazaridou E, Katsibourlia E, Tsikopoulou F, Labrianou I. Platelet distribution width: A simple, practical and specific marker of activation of coagulation. Hippokratia 2010; 14: 28–32. 11. Makris M. Thrombophilia: Grading the risk. Blood 2009; 113: 5038–5039. 12. Bleker SM, Coppens M, Middeldorp S. Sex, thrombosis and inherited thrombophilia. Blood Rev 2014; 28: 123–133. 13. Colman-Brochu S. Deep vein thrombosis in pregnancy. MCN Am J Matern Child Nurs 2004; 29: 186–192. 14. Robertson L, Wu O, Langhorne P et al. Thrombophilia in pregnancy: A systematic review. Br J Haematol 2006; 132: 171– 196. 15. Jagroop IA, Clatworthy I, Lewin J, Mikhailidis DP. Shape change in human platelets: Measurement with a channelyzer and visualisation by electron microscopy. Platelets 2000; 11: 28–32. 16. Park Y, Schoene N, Harris W. Mean platelet volume as an indicator of platelet activation: Methodological issues. Platelets 2002; 13: 301–306. 17. Ntaios G, Gurer O, Faouzi M, Aubert C, Michel P. Hypertension is an independent predictor of mean platelet volume in patients with acute ischemic stroke. Intern Med J 2011; 41: 691–695. 18. Chu SG, Becker RC, Berger PB et al. Mean platelet volume as a predictor of cardiovascular risk: A systematic review and meta-analysis. J Thromb Haemost 2010; 8: 148–156. 19. Colkesen Y, Acil T, Abayli B et al. Mean platelet volume is elevated during paroxysmal atrial fibrillation: A marker of increased platelet activation? Blood Coagul Fibrinolysis 2008; 19: 411–414. 20. Kamisli O, Kamisli S, Kablan Y, Gonullu S, Ozcan C. The prognostic value of an incresaed mean platelet volume and platelet distribution width in the early phase of cerebral venous sinus thrombosis. Clin Appl Thromb Hemost 2013; 19: 29–32. 21. Perlstein TS, Weuve J, Pfeffer MA, Beckman JA. Red blood cell distribution width and mortality risk in a communitybased prospective cohort. Arch Intern Med 2009; 169: 588–594. 22. Borné Y, Smith JG, Melander O, Hedblad B, Engström G. Red cell distribution width and risk for first hospitalization due to heart failure: A population-based cohort study. Eur J Heart Fail 2011; 13: 1355–1361. 23. Fujita B, Strodthoff D, Fritzenwanger M et al. Altered red blood cell distribution width in overweight adolescents and
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its association with markers of inflammation. Pediatr Obes 2013; 8: 385–391. 24. Gersh KC, Nagaswami C, Weisel JW. Fibrin network structure and clot mechanical properties are altered by incorporation of erythrocytes. Thromb Haemost 2009; 102: 1169–1175. 25. Montagnana M, Cervellin G, Meschi T, Lippi G. The role of red blood cell distribution width in cardiovascular and thrombotic disorders. Clin Chem Lab Med 2011; 50: 635–641. 26. Zorlu A, Bektasoglu G, Guven FM et al. Usefulness of admission red cell distribution width as a predictor of early
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mortality in patients with acute pulmonary embolism. Am J Cardiol 2012; 109: 128–134. 27. Ozsu S, Abul Y, Gunaydin S, Orem A, Ozlu T. Prognostic value of red cell distribution width in patients with pulmonary embolism. Clin Appl Thromb Hemost 2014; 20: 365– 370. 28. Zöller B, Melander O, Svensson P, Engström G. Red cell distribution width and risk for venous thromboembolism: A population-based cohort study. Thromb Res 2014; 133: 334– 339.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
doi:10.1111/jog.12600
J. Obstet. Gynaecol. Res. 2014
Recurrent pregnancy loss is associated with increased red cell distribution width and platelet distribution width Ozgur Dundar1, Mıne Kanat Pektas2, Serkan Bodur3, Lale Vuslat Bakır4 and Ahmet Cetin4 1 Department of Obstetrics and Gynecology, Haydarpasa Military Education and Research Hospital, GATA, 4Department of Obstetrics and Gynecology, Haseki Education and Research Hospital, Istanbul, 2Depertment of Obstetrics and Gynecology, Kocatepe University School of Medicine, Afyon, and 3Department of Obstetrics and Gynecology and Dispensary of Oran, Beytepe Military Hospital, Ankara, Turkey
Abstract Aim: The present study aims to evaluate how components of complete blood count are altered in women with a history of recurrent pregnancy loss. Material and Methods: This was a retrospective evaluation of 60 women who had a history of recurrent pregnancy loss, 60 healthy women who had a first trimester pregnancy and 60 healthy parous women. Results: When compared with pregnant women and healthy controls, the women with a history of recurrent pregnancy loss had significantly higher red cell distribution width (RDW) and platelet distribution width (PDW) (P = 0.001 for both). Thrombophilia was detected in 31.7% of the women who had a history of recurrent pregnancy loss (19 out of 60). When compared to the women without thrombophilia, the women with thrombophilia had significantly lower body mass index (P = 0.034) but significantly higher RDW, PDW and plateletcrit (respectively, P = 0.043, P = 0.001 and P = 0.002). There were significant and positive correlations between RDW and PDW (r = 0.615, P = 0.001), RDW and plateletcrit (r = 0.343, P = 0.007) and PDW and plateletcrit (r = 0.340, P = 0.008) in women with a history of recurrent pregnancy loss. Conclusion: An elevation in PDW and RDW values was found to be associated with recurrent pregnancy loss. Key words: platelet distribution width, recurrent pregnancy loss, red cell distribution width, thrombophilia.
Introduction Approximately 10–15% of all pregnancies result in an abortion and these spontaneous miscarriages are mostly due to chromosomal abnormalities. Recurrent pregnancy loss commonly refers to the spontaneous loss of three or more consecutive pregnancies. The loss of at least two consecutive pregnancies occurs in up to 5% of women at reproductive age. In fact, recurrent pregnancy loss is one of the most significant causes of female sterility.1
The etiology of recurrent pregnancy loss is multifactorial and includes uterine anomalies, endocrinological disorders, immunological causes, infections, chromosomal abnormalities and maternal autoimmune diseases. However, the underlying cause cannot be clarified in 50–60% of all recurrent miscarriages.2,3 Thrombophilia has been identified as one of the main causes of recurrent pregnancy loss. Different polymorphisms of thrombophilic disorders are diagnosed in up to 40% of women who have experienced recurrent miscarriages. However, this association
Received: February 28 2014. Accepted: August 22 2014. Reprint request to: Dr Serkan Bodur, Department of Obstetrics and Gynecology and Dispensary of Oran, Beytepe Military Hospital, Ankara 06450, Turkey. Email: [email protected]
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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depends on the type of thrombophilic disorder and the gestational age at which fetal loss occurs.4 Thrombophilia is related with several biological markers that reflect either coagulation activation (such as prothrombin fragment and thrombin-antithrombin complex) or platelet activation (such as βthromboglobulin or soluble platelet P-selectin). As the measurements of these markers are both timeconsuming and expensive, they cannot be performed as a part of routine laboratory studies.5,6 Thrombophilia induces platelet activation, which ends up with alterations in platelet morphology. That is why mean platelet volume (MPV), mean platelet component (MPC) and platelet distribution width (PDW) have been investigated as the markers of platelet activation markers and, thus, predictors of thrombophilic disorders.7–10 The present study aims to evaluate how components of complete blood count are altered in women with a history of recurrent pregnancy loss.
Methods The present study was approved by the Institutional Review Board and Ethical Committee of Haydarpasa Research and Education Hospital of Gulhane Military Medicine Academy where it was conducted. This was a retrospective evaluation of 60 women who had a history of recurrent pregnancy loss, 60 healthy women who had a first trimester pregnancy and 60 healthy parous women. All of the reviewed subjects were consecutively recruited from the patients who were admitted to the study center between January 2001 and January 2014. Recurrent miscarriage was defined as three or more consecutive first-trimester (24 weeks) combined with at least one first-trimester miscarriage. Women who had experienced recurrent pregnancy loss due to uterine anomalies and/or endocrinopathies were excluded. Data related with age, gravidity, parity, height, weight, body mass index (BMI), smoking habit, complete blood counts and thrombophilic disorders were acquired from medical records.
Complete blood count One sample of 20 mL venous blood was drawn by standard phlebotomy from all of the participants. This sample was kept for the evaluation of hemoglobin, hematocrit, mean corpuscular volume (MCV), mean
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corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), erythrocyte count, leukocyte count, platelet count, PDW, MPV and plateletcrit by means of an automated commercial counter (Coulter counter, Max Instruments Laboratory). After this venous blood sample was conveyed into a sodium citrate tube, it was transported in a temperature-controlled container and collected in plastic provettes (Falcon blue cap) containing 3 mL of 3.8% sodium citrate dihydrate and 136 mM glucosium. Time between sampling and tube reading was never more than 2 min. The samples were read three times and the final result represented the mean of three readings.
Thrombophilia testing Thrombophilia testing included factor V Leiden mutation, prothrombin G20210A mutation, protein C deficiency ( 40 GPL or homozygosity for factor V Leiden.11,12 Statistical analysis Collected data were analyzed by spss 18.0. Continuous variables were expressed as mean ± standard deviation or median (range: minimum–maximum) whereas categorical variables were denoted as numbers or percentages. The Smirnov–Kolmogorov test was used to test the distribution of data. One-way anova test and the Student’s t-test were used to compare the continuous variables with normal distribution while the χ2-test and Kruskal–Wallis test were used to compare the categorical variables and continuous variables without normal distribution. Bonferroni adjustment was applied for all possible group comparisons, controlling for type I
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Pregnancy loss and complete blood count
Table 1 Demographic characteristics of study cohort
Age (years) Gravidity Parity Height (m) Bodyweight (kg) Body mass index (kg/m2) Systolic blood pressure Diastolic blood pressure Smoking habit Alcohol intake
Pregnant women (n = 60)
Recurrent pregnancy loss (n = 60)
Healthy controls (n = 60)
P
27.1 ± 5.2 (18–41) 2.3 ± 1.2 (1–5) 1.3 ± 1.2 (1–4) 1.61 ± 0.07 (1.48–1.73) 59.2 ± 7.1 (47–80) 23.11 ± 2.65 (21.46–26.76) 99.9 ± 10.3 (70–120) 58.4 ± 9.3 (40–80) 3 (5.0%) 0 (0.0%)
27.0 ± 5.2 (18–39) 4.2 ± 1.1 (2–6) 0.9 ± 0.7 (0–5) 1.62 ± 0.07 (1.50–1.75) 59.6 ± 7.1 (49–81) 22.94 ± 3.39 (21.78–27.68) 102.2 ± 12.5 (90–150) 62.8 ± 10.8 (50–110) 6 (10.0%) 1 (1.7%)
27.6 ± 5.3 (19–40) 2.4 ± 1.8 (1–5) 1.5 ± 1.2 (0–5) 1.62 ± 0.07(1.45–1.70) 58.6 ± 7.0 (48–79) 22.39 ± 3.16 (22.83–27.34) 105.3 ± 12.4 (80–140) 62.7 ± 10.7 (50–90) 2 (3.3%) 1 (1.7%)
0.808 0.001†* 0.001‡* 0.449 0.677 0.405 0.042§* 0.029§* 0.284 0.364
*P < 0.05 was accepted to be statistically significant. †There is a statistically significant difference between pregnant women and women with recurrent pregnancy loss. ‡There is a statistically significant difference between healthy controls and women with recurrent pregnancy loss. §There is a statistically significant difference between pregnant women and healthy controls.
Table 2 Complete blood counts of study cohort
Hemoglobin (g/dL) Hematocrit (%) Mean corpuscular volume (fL) Mean corpuscular hemoglobin (pg) Mean corpuscular hemoglobin concentration (g/dL) Red cell distribution width Erythrocyte count (×106/mm3) Leukocyte count (×103/mm3) Platelet count (×103/mm3) Platelet distribution width (fL) Mean platelet volume (fL) Plateletcrit (%)
Pregnant women (n = 60)
Recurrent pregnancy loss (n = 60)
Healthy controls (n = 60)
P
12.5 ± 1.3 36.9 ± 4.0 86.4 ± 6.7 28.8 ± 4.0 33.8 ± 1.1 14.2 ± 3.1 4323.2 ± 486.2 11.5 ± 4.1 264.6 ± 59.5 16.1 ± 0.9 10.4 ± 1.1 0.22 ± 0.04
11.9 ± 1.3 35.4 ± 3.1 87.3 ± 7.1 29.3 ± 3.0 33.5 ± 1.6 16.3 ± 4.6 4169.7 ± 406.4 10.9 ± 2.5 255.5 ± 56.5 17.5 ± 3.8 10.9 ± 1.1 0.20 ± 0.04
12.1 ± 1.5 36.1 ± 4.0 86.2 ± 6.5 28.8 ± 3.5 33.7 ± 1.4 14.1 ± 2.6 4198.5 ± 466.8 9.7 ± 2.8 263.0 ± 55.4 15.9 ± 0.7 10.5 ± 0.9 0.21 ± 0.04
0.081 0.890 0.632 0.702 0.414 0.001†* 0.148 0.007§* 0.652 0.001‡* 0.002†* 0.051
*P < 0.05 was accepted to be statistically significant. †There is a statistically significant difference between pregnant women and women with recurrent pregnancy loss. ‡There is a statistically significant difference between healthy controls and women with recurrent pregnancy loss. §There is a statistically significant difference between pregnant women and healthy controls.
errors. Pearson correlation test was utilized to detect the correlations between the variables. A P-value less than 0.05 was considered to be statistically significant.
Results Table 1 demonstrates the demographic characteristics of the study cohort. The pregnant women, the women with a history of recurrent pregnancy loss and healthy controls were statistically similar in terms of age, gravidity, parity, height, body weight, BMI, smoking habit and alcohol intake (P > 0.05 for each). As expected, pregnant women had significantly lower systolic and diastolic blood pressures (respectively, P = 0.042 and P = 0.029). Table 2 shows the demographic characteristics of the study cohort. When compared with pregnant women
and healthy controls, the women with a history of recurrent pregnancy loss had significantly higher RDW and PDW (P = 0.001 for both). Thrombophilia was detected in 31.7% of the women who had a history of recurrent pregnancy loss (19 out of 60). Table 3 compares the demographic characteristics of women with a history of recurrent pregnancy loss in terms of thrombophilia existence. The women with thrombophilia and the women without thrombophilia were statistically similar with respect to age, gravidity, parity, height, bodyweight and smoking habit (P > 0.05 for all). However, the women with thrombophilia had significantly lower BMI than the women without thrombophilia (P = 0.034). Table 4 compares the complete blood counts of women with a history recurrent pregnancy loss in terms of thrombophilia presence. The women with thrombophilia had
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Table 3 Demographic characteristics of women with a history of recurrent pregnancy loss
Age (years) Gravidity Parity Height (m) Bodyweight (kg) Body mass index (kg/m2) Systolic blood pressure Diastolic blood pressure Smoking habit Alcohol intake
With thrombophilia (n = 19)
Without thrombophilia (n = 41)
P
27.0 ± 5.5 (18–38) 4.1 ± 1.0 (2–6) 0.6 ± 0.4 (0–5) 1.59 ± 0.07 (1.50–1.70) 61.3 ± 6.7 (49–80) 24.29 ± 3.67 (21.78–27.68) 103.7 ± 16.4 (90–150) 64.2 ± 14.7 (50–110) 3 (15.8%) 0 (0.0%)
27.0 ± 5.1 (19–39) 4.2 ± 1.1 (2–6) 0.8 ± 0.5 (0–5) 1.62 ± 0.07 (1.52–1.75) 58.8 ± 7.2 (50–81) 22.31 ± 3.10 (21.65–26.45) 101.5 ± 10.4 (90–140) 62.2 ± 8.5 (50–90) 3 (7.3%) 1 (2.4%)
0.971 0.522 0.360 0.105 0.198 0.034* 0.527 0.504 0.309 0.537
*P < 0.05 was accepted to be statistically significant.
Table 4 Complete blood counts of women with a history of recurrent pregnancy loss
Hemoglobin (g/dL) Hematocrit (%) Mean corpuscular volume (fL) Mean corpuscular hemoglobin (pg) Mean corpuscular hemoglobin concentration (g/dL) Red cell distribution width Erythrocyte count (×106/mm3) Leukocyte count (×103/mm3) Platelet count (×103/mm3) Platelet distribution width (fL) Mean platelet volume (fL) Plateletcrit (%)
With thrombophilia (n = 19)
Without thrombophilia (n = 41)
P
11.9 ± 1.1 35.2 ± 3.1 88.2 ± 5.7 29.6 ± 2.3 33.6 ± 1.4 18.4 ± 5.8 4112.1 ± 442.5 10.9 ± 2.1 264.2 ± 50.7 21.3 ± 4.8 10.8 ± 1.1 0.22 ± 0.03
11.9 ± 1.3 35.5 ± 3.1 86.9 ± 7.7 29.1 ± 3.3 33.4 ± 1.7 15.3 ± 3.6 4196.3 ± 391.4 11.0 ± 2.7 251.5 ± 59.1 15.7 ± 1.0 11.0 ± 0.8 0.19 ± 0.04
0.944 0.765 0.525 0.524 0.691 0.043* 0.460 0.913 0.425 0.001* 0.318 0.002*
*P < 0.05 was accepted to be statistically significant.
significantly higher RDW, PDW and plateletcrit (respectively, P = 0.043, P = 0.001 and P = 0.002). High-risk thrombophilia (positive lupus anticoagulants, anti-thrombin III deficiency, anticardiolipin antibodies > 40 GPL or homozygosity for factor V Leiden) was diagnosed in 10 women while low-risk thrombophilia was detected in nine women. When compared to the women with low-risk thrombophilia, the women with high-risk thrombophilia were found to have significantly higher RDW (23.9 ± 3.3 vs 13.5 ± 0.7, P = 0.001), PDW (25.4 ± 2.5 vs 17.6 ± 3.0, P = 0.001) and plateletcrit (0.23 ± 0.02 vs 0.21 ± 0.02, P = 0.039). As for the subsequent pregnancy outcome, 40 women with thrombophilia (66.7%) delivered healthy term babies whereas 17 women with thrombophilia (28.3%) had miscarriages and three women with thrombophilia were lost to follow-up (5%). The thrombophilic women with subsequent pregnancy loss had significantly higher PDW than the thrombophilic women with subsequent successful obstetric outcome (20.1 ± 5.1 vs 16.7 ± 3.1, P = 0.041).
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As for the women with a history of recurrent pregnancy loss, there were significant and positive correlations between RDW and PDW (r = 0.615, P = 0.001), RDW and plateletcrit (r = 0.343, P = 0.007) and PDW and plateletcrit (r = 0.340, P = 0.008). These women also had significant and negative correlations between plateletcrit and MCH values (r = −0.275, P = 0.034) as well as plateletcrit and MCHC values (r = −0.395, P = 0.002). All correlations are shown in Figure 1.
Discussion Pregnancy causes many alterations in hemostatic balance and, thus, leads to a tendency towards thrombophilia. Such a tendency is considered as a mechanism that compensates for the hemostatic challenge of delivery. The natural inclination towards thrombophilia in pregnancy is due to the increase in several clotting factors, including factor I, factor VII, factor VIII and von Willebrandt factor. Moreover, other
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Figure 1 There are significant correlations between red cell and platelet distribution widths (r = 0.615, P = 0.001), red cell distribution width and plateletcrit (r = 0.343, P = 0.007), platelet distribution width and plateletcrit (r = 0.340, P = 0.008), mean corpuscular hemoglobin and plateletcrit (r = −0.275, P = 0.034) and mean corpuscular hemoglobin concentration and plateletcrit (r = −0.395, P = 0.002).
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markers reflecting hypercoagulability (such as Ddimer and/or prothrombin fragment) are increased during pregnancy.13,14 As pregnancy is associated with thrombophilia, episodes of venous thromboembolism can be observed during pregnancy. If a pregnancy is further complicated with an already existing thrombophilic disorder, the risk of thromboembolism is prominently increased. In fact, venous thromboembolism and pulmonary embolism are still the leading causes of maternal morbidity and even mortality during pregnancy or puerperium. Recurrent pregnancy loss, fetal demise, pre-eclampsia and intrauterine growth restriction may also occur in relation with thrombophilic disorders.15,16 Thrombophilia refers to the qualitative failure of the physiological coagulation inhibitors. Either the qualitative or the quantitative impairment of physiological coagulation inhibitors results in pro-coagulatory imbalance, which eventually leads to a condition of compensated coagulopathy. This chronic state of coagulation is associated with an enhancement in platelet activation.10 The enhancement in platelet activation causes the discoid platelets to become more spherical and to acquire pseudopodia. Such an alteration in platelet shape helps the platelets to obtain a larger surface.17 Hematology analyzers based on impedance technology measure platelet volume by the deformation of electrical field, which depends on the vertical platelet diameter. Analyzers with laser optical technology determine platelet volume according to the cross diameter of the platelet. Being independent of the principle of measurement, activated platelets would appear larger.18 Large platelets are metabolically and enzymatically more active than small platelets. That is, large platelets are capable of producing larger amounts of thromboxane A2 and β-thromboglobulin, which have prothrombotic features. An increment in platelet activity is associated with an increase in platelet size, which is further related with increased platelet aggregation and enhanced expression of adhesion molecules.17–19 Both MPV and PDW are parameters of platelet volume that can be determined routinely in nearly all clinical laboratories. The PDW has been implicated as a specific marker of platelet activation and MPV is usually utilized to assess platelet size. However, the combination of MPV and PDW could predict activation of coagulation more efficiently.17,18 As a body of evidence, MPV and PDW are found to be increased in patients who are more prone to venous thromboembolism. These patients include the individuals affected by
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vascular diseases, diabetes mellitus and acute myocardial infarction and hypercholesterolemia.20 The RDW is a measure of anisocytosis, which can be defined as the variation or heterogeneity in erythrocyte size. As a regular component of routine hematology laboratory tests, RDW is commonly used for the classification of anemia. Increased RDW is traditionally linked to anemia and low-grade systemic inflammation.21 Additionally, this parameter has been associated with several demographic and clinical characteristics, including age, waist circumference, BMI, smoking, high alcohol consumption, blood pressure, diabetes mellitus, leukocyte count, and being unmarried.22,23 As erythrocytes participate in the formation of in vivo clots and thrombi, it is possible that anisocytosis could increase the thrombotic predisposition of red blood cells.24 Recently published studies have shown that RDW is associated with increased mortality in a number of cardiovascular disorders, such as coronary artery disease, stroke, peripheral artery disease, heart failure, pulmonary embolism, and pulmonary arterial hypertension.25 It is, however, unclear whether anisocytosis is the underlying cause, or a simple epiphenomenon due to pre-existing conditions, such as inflammation, impaired kidney function, malnutrition, or oxidative damage.24,25 Two studies evaluated RDW in patients with pulmonary embolism and found that a high RDW value (i.e. anisocytosis) was an independent predictor of pulmonary-embolism-related early mortality.26,27 In a study by Zöller et al., RDW was found to be associated with long-term incidence of first event of venous thromboembolism among middle-aged patients.28 Plateletcrit is an effective screening tool for detecting platelet quantitative abnormalities and the value of plateletcrit increases in parallel with the number of platelets. The significant positive correlation between plateletcrit and PDW, the significant positive correlation between plateletcrit and RDW and the significant positive correlation between PDW and RDW may be attributed to the existence of anisocytosis. That is, an increment in the number of platelets and red blood cells with relatively bigger size may lead to a simultaneous increase in PDW, RDW and plateletcrit values. Anisocytosis may occur as erythrocytes and thrombocytes undergo consumption due to underlying inflammation and thromboembolism. On the other hand, the degradation of erythrocytes may cause the MCH and MCHC values to decrease and, thus, a significant negative correlation can be detected between the aforementioned values and plateletcrit.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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To the best of our knowledge, this is the first study to demonstrate an association between recurrent pregnancy loss and increased values of MPV, PDW and RDW. The clinical relevance of such an association is that an elevation in these three hematological parameters may implicate an underlying thrombophilic disorder. In other words, MPV, PDW and RDW might be regarded as biological markers that would reflect moderate hypercoagulability. A body of evidence for this hypothesis is the significant increase in PDW, RDW and plateletcrit values of women with high-risk thrombophilia. However, such a prominent increase is observed in only PDW values of thrombophilic women who experienced subsequent miscarriages. The absence of statistically significant differences in MPV, RDW and plateletcrit values of thrombophilic women with respect to subsequent pregnancy outcome may be due to relatively small cohort size. The power of the present study is limited by several factors. First of all, the size of the cohort is inadequate to specify whether the association between recurrent pregnancy loss and elevated MPV, PDW and RDW values is causal or not. Second, the determination of a significant correlation between PDW and RDW may interfere with the probable correlation of these parameters with recurrent pregnancy loss. Third, the association between recurrent pregnancy loss and elevated MPV, PDW and RDW values has been attributed to the underlying thrombophilic disorder despite the fact that thrombophilia has been detected in only 32% of the reviewed subjects. Another major limitation is the lack of information on thromboembolism-precipitating risk factors, such as immobilization, surgery or trauma. Further research is required to clarify the role of MPV, PDW and RDW in the pathogenesis of recurrent pregnancy loss.
Disclosure The authors report no conflicts of interest.
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