J Pediatr Adolesc Gynecol (2010) 23:S38eS42

Rare Bleeding Disorders in Young Women

Lakshmi Venkateswaran, MD and Donald L. Yee, MD
Department of Pediatrics, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas, USA

Abstract. Rare bleeding disorders can cause signicant bleeding in children and adolescents. These encompass rare clotting factor deciencies, and brinolytic 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.

Key Words. Rare bleeding disorderMenorrhagia Vascular anomalies

Introduction Rare bleeding disorders (RBD) affect between 1 in 500,000 (FVII deciency) to 1 in 2 million or more individuals (e.g., FII, FXIII, and combined factor deciencies such as FVFVIII). 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 deciency). Although some authors de-emphasize the clinical signicance of heterozygous defects and state that fairly minimal plasma levels of coagulation factors (levels above

Address correspondence to: Lakshmi Venkateswaran, MD, Texas Childrens Hospital Clinical Care Center Suite 1510.00, 6621 Fannin St, Houston, TX 77030; E-mail: lxvenkat@txccc.org
The authors have disclosed no conicts of interest.
2010 North American Society for Pediatric and Adolescent Gynecology Published by Elsevier Inc.

20%, equivalent to 0.20 IU/mL) sufce 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 patients 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 deciency and undergo treatment or prophylaxis under certain circumstances as well as genetic counseling, if such interventions benet 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 nonspecic, considerable clinical overlap exists and only directed factor assays can reliably distinguish between specic RBD. For this reason, specic 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 antibrinolytics are primary mainstays of therapy for menorrhagia associated with RBD and such nonspecic 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 factorspecic replacement product, summaries of which are readily accessible and updated regularly.3 Some specic information is summarized for each disorder below, but numerous reviews are available for more detailed background and guidance, 1,4e11 and management of patients with RBD should always occur in close consultation with a hematologist. Third,
1083-3188/$36.00 doi:10.1016/j.jpag.2010.08.011

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this article focuses on congenital RBD; acquired conditions characterized by low factor activity levels (such as acquired factor inhibitors, liver disease, vitamin K deciency, 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. Screening for RBD A fairly parsimonious screening panel for RBD would include a prothrombin time (PT), activated partial thromboplastin time (aPTT), and brinogen. Such a panel does not adequately assess for von Willebrand disease, platelet function abnormalities or hemophilia carriership. We do not identify abnormalities of brinolysis or vascular anomalies as an underlying cause for abnormal bleeding; they are discussed in further detail below. Isolated Prolonged PT A prolonged PT with normal aPTT and brinogen level suggests FVII deciency, the most common of the RBD. As with all factor deciencies, FVII deciency is conrmed only through specic measurement of factor activity. However, along with FXI deciency (see below), FVII deciency is well recognized for particularly poor correlation between measured factor levels and bleeding tendency (e.g., 40% of homozygous individuals are asymptomatic despite severely depressed FVII levels).2 Treatment options for severe bleeding episodes include infusion with plasma-derived or activated recombinant factor VII concentrate.3,12 Fresh frozen plasma (FFP) can also be used if factor concentrate is not available. Current therapeutic challenges include FVIIs short half-life (4e6 hours) and high cost of replacement, especially for the recombinant form. Isolated Prolonged aPTT Besides possible hemophilia carriership (i.e., low FVIII or FIX), an isolated, signicantly prolonged aPTT could suggest FXI deciency in a bleeding patient. FXI deciency confers an increased tendency to bleed, especially in tissues featuring high brinolytic activity such as the genitourinary system; menorrhagia occurs frequently in women affected by this disorder.5 Like FVII deciency, levels are poorly predictive of bleeding risk. For severe bleeding, FXI concentrate can be given but is not approved in all countries.3

When repeated dosing is required, repletion via either concentrate or FFP can be dosed at fairly convenient intervals due to FXIs plasma half-life of 2e3 days.1 An isolated prolonged aPTT also occurs with deciency of factor XII, pre-kallikrein or high molecular weight kininogen; however none of these is associated with increased bleeding risk. Prolonged PT and aPTT Residing downstream of the intrinsic and extrinsic pathways of the classic coagulation cascade (Fig. 1), common pathway factors (brinogen, see below, FII,9 FV,8 and FX6), when decient, lead to prolongation of the PT and aPTT. Certain rare combined deciency states such as combined deciency of FV and FVIII10 or congenital deciency of vitamin K dependent factors (FII, FVII, FIX, and FX)11 have

Fig. 1. Simplied schematics of the classic coagulation cascade (panel A) and brinolytic system (panel B). A: Factors are listed only as inactive forms of proteases or cofactors (e.g., in reality, FX must be transformed by upstream reactions to its activated form, FXa, to in turn activate FII to FIIa). Cofactors and their actions are depicted as ovals and curved arrows, respectively. Plasma half-lives of each factor are listed in parentheses. This model provides a framework for understanding how specic factor deciencies lead to particular patterns of abnormal results on coagulation screening tests. B: Tissue plasminogen activator converts plasminogen to plasmin, which in turn breaks down clot. PAI-1 and a2-AP (grey boxes) inhibit the action of tissue plasminogen activator and plasmin, respectively (dashed lines). Deciencies of either of these negative regulators of brinolysis can thus lead to increased bleeding symptoms.

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also been described and are characterized by prolongation of both tests. Menorrhagia is a commonly reported symptom in these disorders. Each can be treated with FFP, but specic factor replacement via concentrates is preferred when these are available.1,3 Fibrinogen and FX concentrates are commercially available, although not throughout the world. Prothrombin complex concentrates, which contain high levels of the vitamin K dependent factors, are often used to treat bleeds in patients with FII or FX deciency. 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 brinogen are rare and include quantitative deciency states such as abrinogenemia and hypobrinogenemia, and qualitative defects due to variant protein (dysbrinogenemia). Whereas quantitative deciencies are inherited in an autosomal recessive manner, congenital dysbrinogenemia results from autosomal dominant inheritance. Populations with high occurrence of consanguinity report an increased incidence of inherited disorders of brinogen.4 Abrinogenemia is often associated with a severe phenotype with diagnosis established in the newborn period because of umbilical cord bleeding. Heavy menstrual bleeding has been described in these patients. Other afictions in women with this disorder include spontaneous abortions, antepartum and postpartum hemorrhage, and intra-abdominal bleeding due to rupture of the corpus luteum. Impaired wound healing and wound dehiscence due to brinogen deciency may pose a challenge after episiotomy and C-section. In addition, some patients experience paradoxical arterial and venous thromboembolic events due to co-existing thrombophilic conditions, replacement therapy, or other unexplained causes. Hypobrinogenemia usually has a milder bleeding course. Menorrhagia was reported as the most common manifestation (46%) in a survey of 100 such patients from North America and Europe.13 For dysbrinogenemia, approximately 55% of cases have been reported as asymptomatic, 25% with bleeding, and 20% with thrombosis.14 The bleeding spectrum in females with dysbrinogenemia includes menorrhagia, postpartum bleeding, and bleeding at sites of C-section and regional anesthesia. Spontaneous abortions, stillbirths, poor wound healing, and skin necrosis have also been described. PT, aPTT, thrombin time, and reptilase time, all of which depend on brin formation as the assay end

point are usually prolonged. Quantitative deciencies show comparably low levels of brinogen by both functional and antigenic assays, whereas qualitative deciencies tend to show disproportionately low functional levels with normal or near normal antigenic values. Family studies are helpful to differentiate inherited from acquired causes. Genetic analysis to identify a causative mutation can be undertaken to provide a denitive diagnosis, for carrier identication and prenatal diagnosis. Management decisions in brinogen disorders should be made taking into account both clinical and laboratory information as many brinogen variants may not be associated with risk for bleeding or thrombosis. Replacement is required to treat bleeding episodes and during pregnancy to avoid fetal loss.15 Severe quantitative brinogen deciency disorders are treated with replacement therapy to maintain plasma level of more than 1gm/L. Therapeutic choices include plasma-derived brinogen, recombinant brinogen, cryoprecipitate, and fresh frozen plasma. Since the half-life of brinogen is approximately 4 days, alternate day replacement is generally sufcient in the absence of consumption. Prophylaxis is not routinely recommended due to risk for allergic reactions, infections, inhibitor development, and thromboembolism. As with other RBD, heavy menstrual bleeding can be managed with hormonal contraceptive pills and supplemental therapy with antibrinolytic agents. However, in patients with thrombotic tendency, appropriate choices should be made in consultation with a gynecologist to avoid increasing the risk for thrombosis.

Normal PT, aPTT, and Fibrinogen Factor XIII Deciency. Besides von Willebrand disease, platelet dysfunction, and disorders of brinolysis (see below), bleeding symptoms in a patient with normal PT, aPTT, and brinogen could suggest FXIII deciency. The activated form of FXIII covalently cross-links brin, thus strengthening newly formed clots (Fig. 1). Its deciency should be considered in patients with severe menorrhagia not associated with coagulation screening abnormalities;16 however, other symptoms have usually surfaced prior to menarche, such as umbilical bleeding or intracranial hemorrhage.7 Impaired wound healing and recurrent miscarriages are other characteristics. Homozygosity or compound heterozygosity appear necessary for clinically relevant bleeding as only minimal levels (5% of normal or greater) are thought to be hemostatically adequate.1 When available, treatment for bleeding consists of FXIII concentrate,3 but cryoprecipitate, which is enriched in FXIII can also be used. For treatment or prophylaxis, dosing of either

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is infrequent, given FXIIIs long plasma half-life (10e14 days). Disorders of Fibrinolysis. The brinolytic system is composed of several proteins that interact to regulate the degradation of brin, the key negative regulators being plasminogen activator inhibitior (PAI)-117 and a2-antiplasmin (Fig. 1). Plasma levels of PAI-1 exhibit diurnal variation, with levels highest in the early morning and lowest in the afternoon. The rst case of qualitative PAI-1 deciency causing a bleeding disorder was reported in 1989. Two years later, the association of quantitative PAI-1 deciency and a bleeding disorder was described. PAI-1 deciency is rare, and its true prevalence is yet to be dened.18 There is no ethnic predilection, and the age at presentation has varied from 4 months to 76 years. Deciency of PAI-1 causes a moderate hemostatic defect with delayed bleeding, associated with increased postsurgical, procedure-related and trauma-induced bleeding, in addition to easy bruisability, epistaxis, oral bleeding, and muscle hematomas. Heavy menstrual bleeding is often reported in young women.19 In the pedigree report of a family of Old Order Amish descent, the proband had menorrhagia since menarche leading to iron deciency anemia.20 Continuous heavy menstrual bleeding lasting as long as 4 months, uncontrolled by hormonal therapy, and severe menorrhagia requiring packed red blood transfusion have been described in patients with PAI-1 deciency. Qualitative deciency of PAI-1 shows normal antigen levels and reduced activity whereas quantitative deciency results in low levels of PAI-1 antigen and activity. In patients with bleeding symptoms, PAI-1 levels !1 U/ml can be considered compatible with the diagnosis of deciency; however, care must be taken to obtain results from a reputable and experienced laboratory. In addition, diurnal variation in PAI-1 levels should be kept in mind while interpreting the results to avoid misdiagnosis. Antibrinolytics are the mainstay of therapy.18 Both tranexamic acid and epsilon aminocaproic acid in the oral and intravenous forms have been used successfully in preventing and treating bleeding in these patients. For effective management of menorrhagia, initiation of therapy a few days before the onset of menstrual cycle may be necessary. Occasional reports describe a2-antiplasmin (a2AP) deciency as a cause of menorrhagia.21 When decient, a2-AP, the primary inhibitor of plasmin(ogen) can cause severe bleeding in homozygous patients, resembling bleeding seen in congenital hemophilia. This rare disorder may cause mild bleeding or no symptoms in heterozygous individuals. It is likely that menorrhagia patients with this disorder are under diagnosed as a2-AP deciency is not detected by

routine coagulation screening tests (i.e., normal PT, aPTT, and brinogen as are other disorders described in this section). Specic antigen and activity assays characterize qualitative and quantitative deciencies. Antibrinolytics are a primary therapy and FFP may be used as an alternative. Vascular Anomalies Vascular malformations of the uterus are rare, mostly found as case reports in the literature. They are diverse including capillary and cavernous hemangiomas, telangiectasias, and vascular tumors such as angiomyomas and hemangioendotheliomas.22 Specic examples of such uterine lesions associated with systemic disorders include telangiectasis in hereditary hemorrhagic telangiectasia (HHT)23,24 and angiomyolipomas in tuberous sclerosis. Lesions may be present in the serosa, myometrium, and endometrium, separately or in combination. Menstrual irregularities including intermittent spotting, menorrhagia, and menometrorrhagia that may be refractory to conservative management have been reported. Severe complications during pregnancy and delivery have been described, such as lesional rupture leading to hemoperitoneum and fetal demise. Imaging with computerized tomography scan or magnetic resonance angiography can aid in the diagnosis. Evaluation of other clinical features and detection of characteristic genetic mutations will facilitate the diagnosis of systemic disorders such as tuberous sclerosis and HHT. Though hormonal therapy is often attempted as initial therapy in these patients, many of them are refractory, requiring major interventions including endometrial ablation and hysterectomy.22e24 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 specic factor activity assays. When signicant bleeding and/or other suggestive ndings occur in the absence of screening abnormalities, additional directed testing for common (e.g., platelet function testing) and rare disorders (e.g., FXIII level, genetic testing for HHT) needs to be considered. In all cases, specialized diagnostic testing should be performed only in qualied, reliable laboratories with experience in these often challenging testing methods. Consultation with a qualied hematologist is recommended early in the process as this increases the likelihood of timely diagnosis and appropriate treatment of RBD. Although hormonal therapy and antibrinolytics are commonly and effectively used regardless of the

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13. Peyvandi F, Haertel S, Knaub S, et al: Incidence of bleeding symptoms in 100 patients with inherited abrinogenemia or hypobrinogenemia. J Thromb Haemost 2006; 4:1634 14. Hill M, Dolan G: Diagnosis, clinical features and molecular assessment of the dysbrinogenaemias. Haemophilia 2008; 14:889 15. Tziomalos K, Vakalopoulou S, Perifanis V, et al: Treatment of congenital brinogen deciency: overview and recent ndings. Vasc Health Risk Manag 2009; 5:843 16. Ivaskevicius V, Seitz R, Kohler HP, et al: International registry on factor XIII deciency: a basis formed mostly on European data. Thromb Haemost 2007; 97:914 17. Albisetti M: The brinolytic system in children. Semin Thromb Hemost 2003; 29:339 18. Mehta R, Shapiro AD: Plasminogen activator inhibitor type 1 deciency. Haemophilia 2008; 14:1255 19. Repine T, Osswald M: Menorrhagia due to a qualitative deciency of plasminogen activator inhibitor-1: case report and literature review. Clin Appl Thromb Hemost 2004; 10:293 20. Fay WP, Parker AC, Condrey LR, et al: Human plasminogen activator inhibitor-1 (PAI-1) deciency: characterization of a large kindred with a null mutation in the PAI-1 gene. Blood 1997; 90:204 21. Vijapurkar M, Mota L, Shetty S, et al: Menorrhagia and reproductive health in rare bleeding disorders: a study from the Indian subcontinent. Haemophilia 2009; 15:199 22. Johnson C, Reid-Nicholson M, Deligdisch L, et al: Capillary hemangioma of the endometrium: a case report and review of the literature. Arch Pathol Lab Med 2005; 129:1326 23. Berry DL, DeLeon FD: Endometrial ablation for severe menorrhagia in a patient with hereditary hemorrhagic telangiectasia. A case report. J Reprod Med 1996; 41:183 24. Shanberge JN: Hemangioma of the uterus associated with hereditary hemorrhagic telangiectasia. Obstet Gynecol 1994; 84:708

underlying disorder, accurate recognition and diagnosis of RBD is critical for management of severe bleeding episodes that may benet from directed therapies or prophylaxis.

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