Rare inherited autosomal bleeding disorders in women: sex-related bleeding, pregnancy and delivery. A narrative review.

Inherited bleeding disorders (IBDs) are a heterogeneous group of coagulation diseases, characterized by a wide variability in frequency and severity, with autosomal and X-linked inheritance. Rare autosomal IBDs (RAIBDs) include rare bleeding disorders (RBDs): congenital fibrinogen disorders, congenital deficiency of Factors II, V, VII, X, XI and XIII, combined deficiency of the Factors V and VIII and combined vitamin K-dependent clotting factors deficiency and inherited platelet disorders (IPDs) ( Table I ) 1 . Women affected by RAIBDs must face some additional problems with respect to male patients with the same disorders, such as heavy menstrual bleeding (HMB: a total blood loss volume greater than 80 mL) and post-partum hemorrhage (PPH: a blood loss ≥500 mL with vaginal delivery or ≥1,000 mL with cesarean delivery) 2 – 4 . HMB has a strong impact on women’s quality of life, being able to determine discomfort and iron-deficiency anemia. On the other hand, pregnancy and delivery are important challenges that impose a careful and multidisciplinary approach 5 . Therefore, compared to men, women suffer a delay in diagnosis and a reduced tendency to be treated with hemostatic prophylaxis 6 . RAIBDs in women are, for these reasons, a clinical but also a socioeconomic problem. Since interest has recently grown about sex-specific issues in women affected by RAIBDs, the aim of the present review is to analyze the current evidence about RAIBDs in women, focusing mainly on sex-specific bleeding and on the management of pregnancy and delivery in this subset of patients. The rarity of bleeding disorders is a diagnostic challenge mainly during pregnancy when hemostatic changes occur physiologically ( Table II ) 7 .

Bernard Soulier syndrome (BSS) is due to a complete quantitative deficiency in the GPIb-V-IX complex (vWF receptor); this functional defect of platelet adhesion is associated with thrombocytopenia and a morphological alteration resulting in giant platelets (macrothrombocytopenia) 52 . BSS is caused by GP1BA , GP1BB or GP9 gene variants; while most BSS cases show autosomal recessive inheritance, monoallelic forms have been reported. The incidence of BSS is estimated at 1: 1.000.000 and the syndrome is characterized by a severe hemorrhagic phenotype with mucocutaneous bleeding, including spontaneous bruising and excessive trauma-induced bleeding 53 . Glanzmann thrombasthenia (GT) is a disorder of platelet aggregation due to defects in the platelet fibrinogen receptor GPIIb/IIIa (CD41/CD61), that can be absent (type I), reduced (type II) or dysfunctional (type III). GT is an autosomal recessive disorder caused by gene variants of ITGA2B or ITGB3 . Bleeding symptoms can vary from mild to severe. Patients usually present in the first year of life with mucocutaneous (purpura, epistaxis, gum bleeding, HMB) or post-trauma/procedure bleeding; gastrointestinal bleeding is present in 10–20%, intracranial hemorrhage in 1–2% 54 . The diagnosis of IPDs is often challenging. First, physical examination and collection of family and personal history are needed. The ISTH-BAT (International Society of Thrombosis and Haemostasis Bleeding Assessment Tool) score is then calculated. This score has been demonstrated to efficiently discriminate IPD subjects, and it has a predictive value for bleeding events at follow-up 55 . Laboratory tests requested for IPD diagnosis are summarized in Table IV . The bleeding tendency in patients suffering from IPDs can be of variable intensity, usually presenting with mucocutaneous bleeding including nosebleeds, ecchymoses, oral bleeding, HMB but also bleeding from minor wounds or following surgery or childbirth. Muscle hematomas, CNS hemorrhages, hematuria and gastrointestinal bleeding may also occur 56 . Moreover, like any other inherited hemorrhagic syndromes, women are more frequently diagnosed with IPD because of menstruation, childbirth, uterine fibroids, endometrial hyperplasia and polyps 57 . Furthermore, even in the mildest forms, IPD can be associated with significant morbidity, especially due to the complications of HMB, such as iron-deficiency anemia, which is significantly associated with a reduction in quality of life 57 . HBM has a reported prevalence of 51% in BSS, and of 98% in GT 58 . In a study analyzing 232 women of childbearing age studied for HMB, 59% had an abnormality of platelet ATP release 59 . In two studies enrolling adolescents with HMB, abnormalities of platelet aggregation were found in 7% and 31% of patients, respectively 58 , 59 . Initial treatment of HMB involves the use of antifibrinolytics, such as tranexamic acid (TA), started at the beginning of the menstrual flow, with a dosage of 15–25 mg/kg orally three times a day for three days 60 . The second line of therapy consists of the use of Desmopressin (DDAVP), alone or in combination with antifibrinolytics: severe forms of IPD may not respond even with this combined approach 61 . In patients with GT the use of recombinant activated Factor VII has been shown to be effective and safe 60 , 62 . In those situations in which the above-mentioned measures fail to control menstrual bleeding, hormonal therapy (combined oral contraceptives or progestins) or platelet transfusions are indicated 57 . Furthermore, there are other therapeutic options that include uterine tamponade, endometrial ablation, uterine artery embolization and, in extrema ratio , hysterectomy 56 . Regarding pregnancy, there are few data on the frequency of PPH: some authors described a high prevalence of PPH (26 PPH out of 74 pregnancies) in women suffering from GT, while a review analyzing women with BBS reported 18 PPH in 30 deliveries 63 , 64 . A recent retrospective study on 65 pregnancies in 34 women with IPD showed a PPH frequency of 14% in patients with “storage pool disease” and of 50% in patients with GT 63 . In a systematic review, antenatal bleeding and PPH were reported in about 50% and 30% of patients with GT, respectively, and maternal alloimmunization against platelet antigens was reported in a significant number of pregnancies and it was associated with neonatal death 65 . Delivery is very challenging for patients affected by IPDs with a high risk of bleeding, which requires a multidisciplinary approach by a team involving a hematologist with expertise in hemostasis, a gynecologist, an anesthesiologist and a neonatologist in order to set up an individualized program of prophylaxis and, if necessary, treatment of PPH 56 . The latter can complicate both vaginal and cesarean delivery 56 . Furthermore, there is no clear recommendation regarding the choice of one or the other delivery method. The newborn, potentially carrying the platelet defect inherited from the mother, must undergo the least possible traumatic stress, therefore extraction with forceps or ventouse is contraindicated 61 . The use of platelet transfusions has a role in the prevention of PPH that is not yet well understood: two large retrospective studies showed a similar incidence of PPH in women who received and those who did not receive transfusions. However, these data may be affected by a selection bias of patients with higher bleeding risk for platelet transfusions, or by an inappropriate dosage 63 , 66 , 67 . In the PIPA study, PPH was recorded in approximately half of the women with GT who had received prophylactic platelet transfusions 63 . Further treatments are represented by TA and by activated rFactor VII, which has been used in GT both in prophylaxis and in the emergency treatment of PPH 67 . In BSS, delivery has been adequately managed using prophylactic platelet transfusions and PPH has been treated with TA and DDAVP together with platelet transfusions 56 . In patients refractory to platelet transfusions, antifibrinolytics and activated recombinant Factor VII can be effective 68 . Moreover, oxytocin and prostaglandins, used to increase uterine contractility, essential for hemostasis at delivery, are also recommended. In this case, it is suggested to avoid intramuscular administration, due to the risk of hematomas 56 .

Women affected by RAIBDs present some peculiar issues that have important implications: HMB is often the most frequent reported symptom, and often the reason for referral 46 . Delayed identification of this type of bleeding can lead to a delay of diagnosis 69 . HMB often provokes iron deficiency, which can be accompanied by anemia and has an important burden in terms of clinical symptoms and quality of life 46 . The rarity of hemostasis defects poses an insidious challenge in the management of pregnancy and delivery, especially if the bleeding disorder is not diagnosed prior to the physiological changes in hemostasis related to these events, which make the diagnosis more difficult. The Italian health system implements in many regions the systematic use of a pregnancy diary in which diagnostic tests are prescribed according to gestational age. However, given the diagnostic delays that have been mentioned, and the fact that HMB can manifest itself as early as adolescence, it would probably be advisable to study hemostasis in adolescence when a suspected hemostasis disorder, in a hemorrhagic phenotype, can be observed. The hemorrhagic phenotype can be systematically quantified with questionnaires such as the ISTH-BAT score 70 . Currently, there is only limited evidence about how to manage patients affected by RAIBDs during pregnancy and delivery, therefore the current clinical practice is often based on local policy. In our opinion, specific open issues that need further studies are: 1) the possible usage of plasma-derived FVII concentrate instead of rFVIIa in the setting of pregnancy 18 (because of its reduced thrombotic risk); 2) the appropriateness of platelet transfusion in IPDs (in particular in GT) due to the risk of alloimmunization and its possible relationship with adverse fetal outcome 65 . In conclusion, women suffering from RAIBDs form a particular population, with great clinical and socioeconomic resonance. Further studies including women in RAIBDs registries and clinical trials are necessary to develop guidelines able to guide the physician to treat this subset of patients. Management of women with RAIBDs might be coordinated by a dedicated Hemostasis and Thrombosis specialist embedded within the hospital’s Patient Blood Management program; this expert brings unique clinical and laboratory insights to guide individualized hemostatic treatments and ensure judicious use of blood products. Integration of this role fosters multidisciplinary collaboration among hematologists, gynecologists, and anesthesiologists.