Rare Bleeding Disorders in Young Women

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Abstract

Rare bleeding disorders can cause significant bleeding in children and adolescents. These encompass rare clotting factor deficiencies, and fibrinolytic pathway defects. Vascular anomalies can cause recurrent and refractory bleeding, and are included in this review of rare causes of abnormal bleeding in children and adolescents. Menorrhagia is often reported as a manifestation of these conditions. Succinct knowledge about these disorders, their clinical presentation, diagnostic work-up, and therapeutic options are crucial to the accurate diagnosis and optimal management of affected patients. This review provides an overview of these infrequently encountered disorders, discusses their recognition based on results of suggested screening tests and offers a general guideline for approach to therapy.

Introduction

Rare bleeding disorders (RBD) affect between 1 in 500,000 (FVII deficiency) to 1 in 2 million or more individuals (e.g., FII, FXIII, and combined factor deficiencies such as FV+FVIII). However, these numbers pertain to severe homozygous or compound heterozygous states. Since RBD are mostly inherited in an autosomal recessive manner, cases of heterozygous gene defects occur much more frequently (∼1 in 350 to 700 individuals). Moreover, such traits are even more common in certain ethnic populations (e.g., Ashkenazi Jews for FXI deficiency). Although some authors de-emphasize the clinical significance of heterozygous defects and state that fairly minimal plasma levels of coagulation factors (levels above 20%, equivalent to 0.20 IU/mL) suffice for normal hemostasis,1 registry data suggest that up to 40% of heterozygous individuals report increased bleeding symptoms.2 Our practice is to carefully consider the patient's overall clinical picture in diagnostic and therapeutic decision-making, so that a symptomatic patient with even a mildly decreased factor level (presumably due to a heterozygous state) may be diagnosed with a mild factor deficiency and undergo treatment or prophylaxis under certain circumstances as well as genetic counseling, if such interventions benefit the patient.

Implicit in this review is consideration of heavy menstrual bleeding as a symptom of an underlying RBD. However, RBD can and frequently do feature other forms of abnormal bleeding (e.g., hemarthrosis, severe epistaxis, bleeding after tooth extraction or other invasive procedures) that should suggest a need for evaluation. Because menorrhagia and other bleeding symptoms are quite nonspecific, considerable clinical overlap exists and only directed factor assays can reliably distinguish between specific RBD. For this reason, specific RBD are grouped and organized below according to expected screening test results typical of each condition.

A few additional introductory comments are warranted. First, it should be emphasized that hormonal options and antifibrinolytics are primary mainstays of therapy for menorrhagia associated with RBD and such nonspecific interventions are often effective and adequate. Second, additional treatment approaches may differ between RBD, particularly for more severe bleeding episodes. In such cases, optimal therapy depends largely on availability of a factor-specific replacement product, summaries of which are readily accessible and updated regularly.3 Some specific information is summarized for each disorder below, but numerous reviews are available for more detailed background and guidance, 1, 4, 5, 6, 7, 8, 9, 10, 11 and management of patients with RBD should always occur in close consultation with a hematologist. Third, this article focuses on congenital RBD; acquired conditions characterized by low factor activity levels (such as acquired factor inhibitors, liver disease, vitamin K deficiency, and consumptive or dilutional coagulopathy) will not be discussed, but should be carefully considered in any patient with bleeding symptoms and abnormal coagulation testing results. Finally, since vascular anomalies can present with menorrhagia and other bleeding symptomatology, sharing similarities with RBD in terms of clinical manifestations and general medical management, this class of disorders will also be included in this review.

Section snippets

Screening for RBD

A fairly parsimonious screening panel for RBD would include a prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen. Such a panel does not adequately assess for von Willebrand disease, platelet function abnormalities or hemophilia carriership. We do not identify abnormalities of fibrinolysis or vascular anomalies as an underlying cause for abnormal bleeding; they are discussed in further detail below.

Low Fibrinogen: Disorders of Fibrinogen

Fibrinogen is a hexameric glycoprotein produced in the liver, with a multi-faceted role in hemostasis, including in clot formation and platelet aggregation. Consequently, a qualitative or quantitative defect of the glycoprotein can cause bleeding, thrombotic tendency, or both.4 Congenital disorders of fibrinogen are rare and include quantitative deficiency states such as afibrinogenemia and hypofibrinogenemia, and qualitative defects due to variant protein (dysfibrinogenemia). Whereas

Conclusions

In summary, a wide variety of rare hemostatic disorders can underlie bleeding symptoms in young women. Many of these disorders are detectable by routine coagulation screening tests that are widely available. Abnormal screening results should lead to careful, directed measurement of specific factor activity assays. When significant bleeding and/or other suggestive findings occur in the absence of screening abnormalities, additional directed testing for common (e.g., platelet function testing)

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    The authors have disclosed no conflicts of interest.

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