|Year : 2021 | Volume
| Issue : 1 | Page : 24-29
Platelet function disorder in women with heavy menstrual bleeding in Eastern Uttar Pradesh
Shuchi Jain1, Nisha Rani Agrawal1, Vijai Tilak2, Ekhlak Mohammad3, D Dash3, Madhu Jain1
1 Department of Obstetrics and Gynaecology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
2 Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
3 Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
|Date of Submission||17-Mar-2021|
|Date of Acceptance||17-Apr-2021|
|Date of Web Publication||04-Aug-2021|
Department of Obstetrics and Gynaecology, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: Platelet function disorder (PFD) is turning out to be a major cause of heavy menstrual bleeding (HMB) in women. One should suspect for this entity and should look for it in all girls who have this issue since menarche to impart proper management.
Objectives: This study was carried out to find the incidence of PFD in Patients with HMB referred to our tertiary care teaching hospital.
Materials and Methods: Platelet aggregation in response to ristocetin-induced platelet aggregation (RIPA), Adrenaline, adenosine diphosphate, and Collagen was studied in 50 women with HMB and in the equal number of age-matched healthy women. Bleeding time and Platelet count were also measured.
Results: Glanzmann's thrombasthenia (GT) was detected in 5 and Bernard Soulier Syndrome (BSS) in 2 women with HMB. Macrothrombocytopenia was observed in BSS. RIPA was also significantly reduced in BSS but normal in GT. Coagulopathies should always be doubted in the presence of significant anemia. One should carry out the Platelet function studies when screening parameters like prothrombin time, partial thromboplastin time, von Willebrand factor , and factor VIII activity level are normal. Normal platelet count and morphology in addition suggest functional defects in platelets which can be detected by various aggregation studies, electron microscopy, flow cytometry, and thromboelastography.
Conclusion: The clinicians treating women with HMB should be aware of PFD as an important etiology and the platelet function should be studied in all women with HMB in a phase-wise manner in order not to miss the diagnosis and also to make it more cost-effective.
Keywords: Bernard Soulier syndrome, Glanzman's thrombasthenia, heavy menstrual bleeding, platelet function disorders
|How to cite this article:|
Jain S, Agrawal NR, Tilak V, Mohammad E, Dash D, Jain M. Platelet function disorder in women with heavy menstrual bleeding in Eastern Uttar Pradesh. J Med Soc 2021;35:24-9
|How to cite this URL:|
Jain S, Agrawal NR, Tilak V, Mohammad E, Dash D, Jain M. Platelet function disorder in women with heavy menstrual bleeding in Eastern Uttar Pradesh. J Med Soc [serial online] 2021 [cited 2022 Aug 15];35:24-9. Available from: https://www.jmedsoc.org/text.asp?2021/35/1/24/323162
| Introduction|| |
Heavy menstrual bleeding (HMB) is a significant health issue, particularly in adolescent girls causing psychosocial problems. About 5%–10% of the girls in this age group seek medical attention for this recurring condition. This study was carried out to find the incidence of Platelet function disorder (PFD) in Patients with HMB referred to our tertiary care teaching hospital in Eastern Uttar Pradesh, India.
The alteration in any of the functions of platelets interferes with the formation of the primary hemostatic plug which leads to prolonged bleeding. The dysfunctions in the Platelets can be hereditary as well as acquired. The prevalence of inherited platelet disorders is not exactly known. However, Glanzman's thrombasthenia (GT), and Bernard Soulier Syndrome (BSS) are more frequently seen in clinical practice.
| Materials and Methods|| |
Fifty adolescents and women in the reproductive age group (15–49 years) with a history of HMB (menstrual blood loss >80 ml per cycle or having a duration of >7 days) and normal von Willebrand factor (vWF) and Factor VIII activity were part of the study. The patients with the endocrine disorder such as hypo- or hyperthyroidism, pelvic pathologies such as fibroid uterus and Intrauterine Contraceptive Device (IUCD) were excluded. Those having treatment with anticoagulants within past 2 months, Oral contraceptive pills within one cycle of participation, NSAIDS within 14 days of participation, Platelet impairing medication or herbal medications within 14 days of participation were also excluded. Fifty healthy controls with no menstrual irregularity and in the same age group were taken as control.
Nine milliliters blood was collected in a centrifuge tube with 1 ml of 3.2% sodium citrate as anticoagulant (9:1 ratio). The sample was processed within 2 h of blood collection or stored at the appropriate temperature in the lab. Platelet-rich plasma (PRP) was made by centrifuging the blood at 200 g for 10 min and used for platelet studies. Platelet aggregation was evaluated with adenosine diphosphate (ADP), Adrenaline (Adr) (manually); Collagen, and Ristocetin using Platelet Aggregometer on dual-channel chronolog aggregometer at ristocetin (Sigma) concentration of 1.5 mg/ml. LTA studies of PRP with a count of <1509109/L should be interpreted with caution.
Prolonged BT and defective aggregation with ADP, Adr Collagen, or Ristocetin were the diagnostic criteria for PFD in general.
| Results|| |
Among the fifty patients with HMB evaluated for PFD, PFD could be diagnosed in 7 (14%) out of whom there were only 2 patients (4%) with BSS and 5 (10%) with GT. Among these, 4 (57.14%) were below the age of 20 years, and the remaining 3 (42.85%) between 20 and 44 years age group but none older [Table 1].
|Table 1: Age distribution of platelet function disorder in patients with heavy menstrual bleeding|
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The patients with BSS were grossly anemic. The platelets were significantly larger and fewer in number when compared with the control. The platelet aggregation in response to ADP, Adr, and Collagen was as good as among the controls but very low or absent in response to Ristocetin in patients with BSS [Table 2].
|Table 2: Laboratory parameters in patients of Bernard Soulier syndrome versus control|
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The patients with GT had normal count and platelet aggregation in response to Ristocetin but significantly reduced in response to ADP, Adr, and Collagen [Table 3]. Besides the difference in aggregation studies between BSS and GT, the bleeding time was significantly more prolonged along with significant thrombocytopenia in BSS [Table 4].
|Table 3: Laboratory parameters in patients of Glanzmann's thrombasthenia versus control|
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|Table 4: Laboratory parameters Bernard Soulier Syndrome versus Glanzmann thrombasthenia|
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| Discussion|| |
The glycoprotein receptors present on the surface of platelets help in their binding to the collagen, fibronectin in the exposed endothelial substrate in the event of injury to the vascular endothelium, the process being facilitated by the von Willebrand factor. This process of adhesion is followed by activation of the platelets which happens as a result of the change in the cytoskeleton system due to intracellular calcium. Further, the α-granules of platelets secrete ADP and their other contents in response to the impulses coming in from outside the cell. The released ADP causes structural change in GPIIb/IIIa glycoprotein receptors on the platelet surface. Fibrinogen binds two or more platelets via these altered receptors and thus the process of aggregation takes place resulting ultimately in the formation of platelet plug at the injured site. The changes in phospholipids present on the platelet surface following the process of activation causes activation of some of the clotting factors paving the way for platelet procoagulant activity.,, Thus, the basic functions of platelets are: adhesion, activation, aggregation, and secretion with the formation of the platelet plug.
HMB in women is quite a common health issue with psychosocial repercussions and often remains uninvestigated. As per guidelines of the National Institute of Health and Care Excellence, HMB is defined as “excessive menstrual blood loss which interferes with a woman's physical, social, emotional and/or material quality of life.” The World Health Organisation reports HMB in 18 million women globally. Although, the medical treatment for this hemostatic disorder is initially given, some women in later part of their reproductive life undergo surgical intervention without being evaluated for the underlying hemostatic defect. Therefore, accurate diagnosis of the underlying etiology is very much warranted to optimize the outcome.
Among the various bleeding disorders responsible for HMB, von Willebrand disease (vWD) has been found to be present in 13%–20% of the women in reproductive age. It is quite logical to look for the vWD first because of the high cost involved in carrying out the platelet function studies. The initial steps should be the estimation of mean platelet volume (MPV) and count. MPV has been found to correlate with platelet function and proves to be a good marker of platelet activation and reactivity. However, others are of the opinion that the clinical utility of Platelet Volume Indices is significantly limited by variability in its measurement and lack of definitive cut-off values. The two patients with BSS in our study had MPV of 12.3 fL which is beyond the normal range of 6.5–12 fL.
Fifty women with HMB in our study who had normal vWF and factor VIII activity were evaluated for various platelet aggregation tests in response to ADP, Adr, Collagen, and Ristocetin. Seven of these women (14%) were found to be suffering from PFD, 5 from GT, and 2 from BSS. However, Lowe et al. found PFD in 47% of 185 patients with HMB. They found six distinct categories of the platelet defect such as cyclo-oxygenase deficiency (10%), Gi receptor signaling defect (20%), secretion defect (18%), thrombocytopenia (30%), ADP P2Y12 receptor defect (4%) and “other” defects (18%). They found about half of the women with HMB and not diagnosed as suffering from vWD to suffer from PFD. Theirsuch a high incidence of PFD could be due to their study in the patients who were referred from hemophilia centers only in contrast to our patients who were a mix of referred and nonreferred both but none from the centers designated for Hemophilia. Further, categorization of PFD into various subtypes like them is feasible only in the laboratories earmarked for diagnosis of hemostatic disorders due to high cost and special equipment. Israels (2015) is also of the opinion that Platelet function testing is both complex and labor intensive. He suggests a stepwise approach to the evaluation of patients with suspected platelet disorders to optimize the use of laboratory resources.
Philipp et al. found decreased platelet aggregation with one or more agonists in 35 out of 74 (47.3%) women suffering from HMB. They found reduced aggregation responses to ristocetin in 22 women as the most common platelet function defect followed by that to epinephrine in 16 women. In contrast, we found severely reduced or absent response of platelets to ristocetin and normal aggregation in response to ADP, Collagen, and Adr in two patients (4%) diagnosed as suffering from BSS. In the five patients labeled with GT (10%), aggregatory response to ADP, Collagen and Adr was significantly reduced but to ristocetin induced platelet aggregation, was within the normal range. In another study from Northern India, Kushwaha et al. in a study of 104 patients with HMB, found hemostatic abnormalities in only 23 (22.1%) with vWD topping the list among them with 43.4%, followed by GT in 30.4% and BSS in 4.3%.
The defect in the platelet function could be at different levels. There could be defect in their adhesion to exposed collagen in subendothelium, aggregation and defective clump formation, secretory activity, and in the storage of various secretory products within the platelets. However, the study of aggregation is the one most easily carried out. A study in 43 postmenarche adolescents with menorrhagia revealed platelet function defect in 37 (86%), while another study in 74 women in the age group of 17–55 years with unexplained menorrhagia found decreased platelet ATP release in 43 women (58.1%), 16 abnormal platelet aggregation (21.6%) and 13 both (17.6%). In a study among adolescents with HMB, a platelet function abnormality was detected in nearly one-third of those in whom whole blood platelet aggregometry was performed (19/68; 28%). A study of 14 adolescents with HMB revealed platelet dysfunction in 6 (43%). Vijapurkar et al. from Mumbai, India, in a study of 44 women including adolescents found GT in 38.63% and BSS in 4.5% of them. All these studies emphasize upon the fact that PFD is quite common than expected in young girls with menorrhagia.
Adler et al. reported GT in 7.4% of their patients along with some other platelet function defects (9.7%) which overall surpassed the incidence of vWD (9.1%). Gresele et al. agree that making the diagnosis of PFD is quite cumbersome and that many patients may be missed. Although the diagnosis of PFD is much more elusive in the majority of patients, it is quite easier to detect severe PFD such as GT, or Bernard-Soulier syndrome. Gresele also realized that the diagnostic evaluation of PFD required technically challenging, and time-consuming laboratory assays which might be difficult to interpret. Further, these tests are available in specialized laboratories only.
As compared to the Western countries, the prevalence of hereditary type platelet disorder in India is suspected to be higher due to consanguinity, which is much common in India. Way back in 2008, Ahmad et al. reported vWD in 8.62% and PFD in 27.77% of the patients studied. They found GT in about 2% and BSS in 0.7% of the patients with PFD. Peyvandi et al. 2011 reported the prevalence of menorrhagia in 51% of BSS and up to 98% in women with GT as compared to only 5%–10% in healthy women.
Although Manisha et al. from western India reported the incidence of vWD in more patients (11%) than that of PFD (5%; GT accounted for 84.3% and BSS 12.5%) like us, there are many reports from India and abroad with the incidence of PFD to be higher than that of vWD. Seravalli et al. found the incidence of qualitative platelet defects in 18% and vWD in 14% among the patients referred to them. Saxena et al. from India, evaluated 337 women with menorrhagia and found the incidence of PFD to be around 83%. However,. Sahoo et al. in a retrospective study from a tertiary care hospital in North India found the prevalence of 4% of vWD but 7% of PFD even among the pediatric population. Another study from India reported much higher incidence of PFD (35.8%) out of which isolated PF3 availability defect (48.1%) was most common, followed by unclassified PFD (37.2%).
PFDs although typically present with symptoms of severe mucocutaneous bleeding (MCB) in form of epistaxis or postdental extraction/gum bleeding often in childhood, HMB might be the first clinically significant symptom starting with menarche and it needs proper hemostatic assessment by treating physician/gynecologist. Sahoo et al. reported ecchymosis to be the most common associated symptoms (65.6%) followed by bleeding from the oral cavity or gums (56%) and epistaxis (40.65) in their patients, whereas Kushwaha et al. found epistaxis to be the most common associated symptom besides menorrhagia followed by bleeding from gums, and from minor trauma. We, however, found epistaxis to be present in all the patients with PFD, gum bleed in 71.4% and bleeding from minor trauma in 42.85%.
| Conclusion|| |
The causes of more common, mild, inherited MCB remain unknown. Diagnostic testing is helpful in identifying deficiencies of platelet function or VWF in some, but not all, patients with MCB. Efforts to standardize available testing will help us to optimally interpret these tests. Platelet function testing should be conducted in laboratories with specialized expertise and should be interpreted based on clinical information.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]