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Revista chilena de pediatría

versión impresa ISSN 0370-4106

Rev. chil. pediatr. vol.91 no.3 Santiago jun. 2020

http://dx.doi.org/10.32641/rchped.v91i3.1571 

ORIGINAL ARTICLE

Inherited bleeding disorders in adolescents with excessive menstrual bleeding. Should we evaluate the fibrinolytic pathway?

N. Aguirre1 

J. Pereira2 

F. Barriga1 

MA. Wietstruck1 

O. Panes3 

P. Sepúlveda4 

A. Salgado1 

P. Zúñiga1 

1 Pediatric hematologist and oncologist. Department of Pediatrics and Hematology Oncology, Pontificia Universidad Católica de Chile, Chile.

2 Hematologist. Department of Hematology, Pontificia Universidad Católica de Chile, Chile.

3 Biochemical. Hemostasis Laboratory. Pontificia Universidad Católica de Chile, Chile.

4 Pediatric hematologist and oncologist. Department of Oncology. Talca, Chile.

Abstract:

Introduction:

Heavy Menstrual Bleeding (EMB) is a frequent problem in adolescence. The prevalence of inherited bleeding disorders (IBD) as a cause of EMB is not well established and the involvement of fibri nolytic pathway defects has been poorly explored.

Objective:

To determine the prevalence of IBD and fibrinolysis defects in adolescents with EMBs.

Patients and Method:

93 adolescents (11 to 18 years old) were included. Personal and family history of bleeding were obtained through a standard ized questionnaire. The following lab tests were performed: prothrombin time (PT), activated partial thromboplastin time (aPTT), von Willebrand factor quantification, and platelet count and function. Those patients who were not diagnosed with IBD were further evaluated with clot lysis time assay.

Results:

41 patients (44%) were diagnosed as IBD (Von Willebrand disease n = 28, platelet func tion defects n=8, mild hemophilia n = 5. Decreased clot lysis time was found in 31 patients. 54% of patients diagnosed with IBD had EMB as the first hemorrhagic manifestation.

Conclusion:

These results support the need to evaluate the coagulation process, including the fibrinolytic pathway in the study of adolescents with EMB.

Keywords: excessive menstrual bleeding; adolescents; fibrinolysis; BUC; abnormal uterine bleeding; inherited bleeding disorders; heavy menstrual bleeding

What do we know about the subject matter of this study?

Heavy menstrual bleeding (HMB) affects 40% of teenage girls and, in many cases, it may be the first symptom, making it a diagnostic opportunity. Hereditary coagulation disorders (HCD) are the most common secondary cause in this age group.

What does this study contribute to what is already known?

This study gives us an insight into the prevalence of hereditary coa gulation disorders in Chilean female adolescents with HMB and explores the possible involvement of an alteration in fibrinolysis.

Introduction

HMB is defined as prolonged bleeding > 7 days and/or blood loss flows higher than 80 ml1,2,3,4,5,6. Recently in the United Kingdom, the National Institute for Health and Care Excellence (NICE) has defined it as excessive menstrual blood loss that affects women’s physical, emotional, social, and material quality of life, addressing the problem more comprehensively7,8.

It affects approximately 40% of adolescent girls1,9 causing morbidity and, in some cases, mortality, in addition to affecting daily life activities, impairing the quality of life4,10,11,12. Good HMB diagnosis allows for the establishment of active measures promptly to reduce the risk of transfusions, chronic anemia, poor school attendance, and improve quality of life13,14,15,16.

Since 2006, the American Academy of Pediatrics and the American College of Obstetrics and Gynecolo gy have recommended, in order to improve the HMB diagnosis, considering the menstruation characteris tics as a ‘vital sign’ in the medical evaluation of girls and adolescents17,18,19.

The most frequent cause of abnormal uterine blee ding after the menarche period is the hypothalamic- pituitary-gonadal axis immaturity, which leads to ano vulatory cycles2,20,21,22. Published studies show variations in the prevalence of HCB, especially in the vWD ran ging between 5% and 36%, and the PD between 3% and 68% of patients with HMB23,24,25.

Although HCDs have as their manifestation HMB, they are diagnosed before menarche and, in most ca ses, have multidisciplinary management, from early stages of life.

The biggest diagnostic challenge is mild bleeding disorders (MBD) since they may present mild or unapparent symptoms, until a hemostatic challenge occurs, such as trauma or surgery, or menstruation as in this case.

So-called mild coagulopathies or MBDs include von Willebrand disease, mild platelet dysfunctions, and mild clotting factors deficiencies.

There has been a discussion on the laboratory diag nosis of MBD26, and recently diagnostic criteria have been standardized for primary hemostasis diseases, in cluding von Willebrand disease and platelet function disorders. Our laboratory has participated in this work and its recommendations have been adopted14,26.

The symptoms of MBD are mostly mucocutaneous or disproportionate bleeding according to their ori gin, in case of hemostatic challenges such as trauma or surgery. In order to objectify these symptoms, ques tionnaires such as the ISTH-SSC Bleeding Assessment Tool (BAT) have been created which is validated for the diagnosis of vWD and PD27. This questionnaire consists of several items to evaluate different bleeding symptoms, including HMB. This questionnaire is po sitive in children when the score is higher or equal to 3 points, which, for example, applies to those patients with HMB who have required the use of antifibrino lytics, hormonal treatment, hospitalization, or transfusions27.

In this regard, it has been described that 92% of pa tients with HCD present HMB28, therefore, we consi der that menarche may be a diagnostic opportunity for these patients, allowing better management, not only for their HMB but also for future interventions such as major and minor surgery and during pregnancy and childbirth.

The role of fibrinolysis in the pathogenesis of HMB is not entirely clear, although most guidelines recom mend antifibrinolytics in its management. Our labora tory has developed a global technique for the evalua tion of fibrinolysis called clot lysis time, which we have incorporated into the evaluation of patients with mu cocutaneous bleeding, especially those with bleeding of unknown cause (BUC). The objective of this study was to determine the prevalence of HCD and acceleration of clot lysis time in patients referred due to HMB to polyclinic hematology.

Patients and Method

Between April 2016 and September 2017, a descrip tive and transversal study was designed that included patients aged between 11 and 18 years who consulted due to HMB at the Pediatric Hematology Polyclinic of the Pontifical Catholic University of Chile. Those pa tients receiving anticoagulation therapy and diagnosed with an HCD were excluded.

All patients completed the ISTH-SSC BAT ques tionnaire reporting personal bleeding symptoms and family history of bleeding disorders A score of > or = 3 was considered positive.

General coagulation tests including activated par tial thromboplastin time (aPTT), prothrombin time (PT), and complete blood count were applied at the first visit. We requested the vWD study which includes blood-clotting factor FVIII, vWF antigen, ristoce tin cofactor, collagen-binding test, and evaluation of platelet function with platelet aggregation test. The pa tients were strongly requested not to present intercu rrent infectious conditions and not to have used non steroidal anti-inflammatory drugs for at least 15 days before the sample collection.

Those patients with abnormal PT-aPTT and those who had a family history of hereditary disorders were studied with clotting factors and those with abnormal platelet aggregation were also studied with platelet se cretion.

If all these results were normal, the study was supplemented with the clot lysis time test to evaluate fibrinolysis. Our laboratory uses platelet-rich plasma stimulated with ristocetin or thrombin receptor ago nist peptide-6 and platelet-poor plasma, evaluating the defects of the fibrinolytic system in a single technique28.

Through statistical analysis performed with IBM SPSS Statistics 20.0.1 software, we were able to observe that those patients with positive ISTH-BAT scores and those with a family history of bleeding, correlated with diagnoses of coagulation disorders (vWD, blood clot ting factor defects, PD and fibrinolysis defects.

This study was approved by the ethics committee of the Pontifical Catholic University of Chile, using in formed consent.

Results

We included 93 patients, the median age was 14 years ranging from 11 to 18 years, 72 patients had a po sitive BAT questionnaire score, and, out of these, 54% had no bleeding symptoms before their menarche. 55 patients presented family history of bleeding disorders.

Regarding initial examinations, 80 patients (90%) had normal PT and aPPT, and 35 (38%) patients had anemia which was severe in 6 cases (hemoglobin < 7 g/dL).

28 patients were diagnosed with vWD, 8 presented platelet function defects, 5 with clotting factor defi ciency (3 patients with factor VIII deficiency, one with factor IX deficiency, and one with factor XI deficien cy), and 1 patient with primary immune thrombocyto penia. (Table 1).

Table 1 Study results. 

In the 51 patients who presented a normal coagula tion study, fibrinolysis analyses were performed where 31 of them showed an accelerated clot lysis time, which is compatible with hyperfibrinolysis. When combining patients with HCD and fibrinolysis defects, 72 patients (77%) presented some kind of bleeding disorder. In 15 patients (75%) diagnosed with vWD, HMB was the first symptom of the disease.

There where no correlation between positive BAT score or family history and the presence of an HCD, including fibrinolysis defects.

Discussion

While this is a selected group, since it has been re ferred due to suspected coagulopathy or anemia, the prevalence of HCD proved to be high. This supports what is described in the literature and reinforces the idea that the possibility of an HCD should be conside red when evaluating an adolescent with HMB.

Although evaluating the causes of referral was not the objective of this study, we believe that it is impor tant for the pediatrician and adolescent health care staff to include menstrual characteristics in the evaluation and assume an active role in the diagnosis, treatment, follow-up, and referral of adolescents with HMB to a specialist, if necessary.

It is important to note that almost 90% of the pa tients studied had normal results in the studies most often requested to rule out bleeding disorder (PT- aPTT) which reinforces that these normal tests do not exclude the presence of coagulopathy and, if there are other mucocutaneous bleeds, family history or poor response to treatment, the patient should be referred for HCD study.

The prevalence of vWD in the general population is low (< 1%). There is an incidence between 5 and 36% in adolescents with HMB26. In our study, the vWD was diagnosed in 30% of patients, and in most of them, HMB was the first symptom of the disease, therefore HMB study could be a diagnostic opportunity for these adolescents.

The reported incidence of platelet function defects in HMB patients also shows a wide variation, ranging from 3% to 68%9,24,30. In our series, 9% of patients pre sented platelet function defects, however, not all had platelet secretion studies, which may have added pa tients who have only secretion defects28.

According to a study by Quiroga et al. in the Chi lean population28, 59.6% of patients presented BUC, which is consistent with the 54% of patients that have no HCD. We believe that these patients should be monitored, both to assess secondary repercussions of HMB and to see their behavior when facing future he mostatic challenges28.

In our study, out of the patients initially classified as BUC, 60% showed a shortening of the clot lysis time which represents 33% of the total group. This suggests that the overall defects of fibrinolysis may play a role in HMB.

There is evidence that fibrinolysis is involved in the endometrial cycle. Levels of plasminogen activators, especially tissue-type plasminogen activator (t- PA) and plasminogen activator inhibitor-1 (PAI-1), increase significantly in the late secretory phase of the endometrial cycle.

There are reports of increased fibrinolytic activity in menstrual flow in patients with abnormal uterine bleeding, in contrast, women receiving hormone the rapy show a decreased one31,32. S. Wiewel-Verschueren et al. published a study in adult patients with HMB that measured quantitatively fibrinolytic activators and in hibitors and found no evident alterations33. However, we think that a global test such as the one we use in our patients can better describe the interactions of the fibrinolytic system and its outcome.

Conclusion

The group studied presented a high prevalence of HCD. The HMB was the first symptom in a significant group of patients with vWD, which reinforces the idea that HMB is a good diagnostic opportunity for HCD, even in patients with little or no other bleeding symp toms.

We believe that the high incidence of shortened clot lysis time found in this study suggests that eva luation of the fibrinolytic pathway in adolescents with EMS is necessary.

Ethical Responsibilities

Human Beings and animals protection: Disclosure the authors state that the procedures were followed ac cording to the Declaration of Helsinki and the World Medical Association regarding human experimenta tion developed for the medical community.

Data confidentiality: The authors state that they have followed the protocols of their Center and Local regu lations on the publication of patient data.

Rights to privacy and informed consent: The authors have obtained the informed consent of the patients and/or subjects referred to in the article. This document is in the possession of the correspondence author.

Conflicts of Interest: Authors declare no conflict of interest regarding the present study.

Financial Disclosure: Authors state that no economic support has been asso ciated with the present study.

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Received: December 26, 2019; Accepted: April 05, 2020

Correspondence: P. Zúñiga. E-mail: pzuniga@med.puc.cl.

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