Women and girls with haemophilia and bleeding tendencies: Outcomes related to menstruation, pregnancy, surgery and other bleeding episodes from a retrospective chart review

Women or girls with haemophilia (WGH) represent a group of female symptomatic carriers who experience bleeding events more frequently than non‐carriers. Bleeding events include spontaneous/traumatic bleeds and prolonged bleeding related to surgery, menstruation, and pregnancy. Challenges for the treatment of WGH include lack of screening, diagnosis, and treatment guidelines.

ACOG Practice Bulletin No. 192: Management of Alloimmunization During Pregnancy

When any fetal blood group factor inherited from the father is not possessed by the mother, antepartum or intrapartum fetal-maternal bleeding may stimulate an immune reaction in the mother. Maternal immune reactions also can occur from blood product transfusion. The formation of maternal antibodies, or "alloimmunization," may lead to various degrees of transplacental passage of these antibodies into the fetal circulation. Depending on the degree of antigenicity and the amount and type of antibodies involved, this transplacental passage may lead to hemolytic disease in the fetus and neonate. Undiagnosed and untreated, alloimmunization can lead to significant perinatal morbidity and mortality. Advances in Doppler ultrasonography have led to the development of noninvasive methods of management of alloimmunization in pregnant women. Together with more established protocols, Doppler ultrasound evaluation may allow for a more thorough and less invasive workup with fewer risks to the mother and fetus. Prevention of alloimmunization is addressed in another Practice Bulletin ().

Abnormal Uterine Bleeding in Young Women with Blood Disorders

Abnormal uterine bleeding (AUB) is common in adolescents 1. Immaturity of the hypothalamic pituitary ovarian (HPO) axis is the most common cause of AUB in this age group2. Certain aspects of underlying inherited or acquired blood disorders, as discussed in this chapter, exacerbate the “expected” hormonal imbalance at this age, thereby, increasing the morbidity of the underlying problem3,4. Even though blood disorders may induce AUB, uterine structural and/or endocrine abnormalities tend to be overlooked in the presence of a blood disorder5. A multifactorial etiology demands a collaborative approach between hematologists and gynecologists or adolescent medicine physicians6,7. In this chapter, we will discuss management of AUB in adolescents within 4 clinical contexts: AUB while on anticoagulant therapy, and with inherited bleeding disorders, bleeding management with cytopenias, specifically, thrombocytopenia, and in sickle cell disease. Throughout, areas of controversy and opportunities for further research are highlighted.

Inherited Bleeding Disorders in the Obstetric Patient

Inherited bleeding disorders increase the risk of bleeding in the obstetric patient. Randomized controlled trials to compare prophylactic or therapeutic interventions are rare, and guidance documents rely heavily on expert opinion. Here we report the results of a systematic review of the literature for the treatment and prevention of peripartum bleeding in women with an inherited bleeding disorder. The highest-quality evidence is for the use of tranexamic acid in postpartum hemorrhage, which has been shown to decrease bleeding-related mortality in women without bleeding disorders. There is limited evidence for prophylactic use of this agent in women with inherited bleeding disorders. Desmopressin has also been used in observational studies of patients with von Willebrand disease and carriers of hemophilia A with some success, although concerns about the risk of hyponatremia persist. In patients with deficiencies of specific factors, replacement is generally the preferred approach, and concentrates have been studied in deficiencies of VWF and factors VII, VIII, IX, XI, and XIII as well as in patients with fibrinogen deficiency. Because of the small size of these studies, neither safety nor efficacy is well established, although the literature suggests that bleeding history may be more predictive of outcomes than factor levels in many cases. Goal factor levels have not been studied or systematically established in any of these diseases, although observational data suggest that achieving normal levels may be inadequate, particularly for VWF and factor VIII, which are physiologically elevated in pregnancy. For factor deficiencies in which no specific concentrate is available, such as factors II (prothrombin) and V, prothrombin complex concentrate or fresh frozen plasma may be used, and for platelet defects or deficiencies, such as Glanzmann thrombasthenia or Bernard-Soulier syndrome, platelet transfusion is generally first line, although use of recombinant FVIIa has been reported in patients with Glanzmann thrombasthenia to avoid development of, or treat patients with, antibodies to platelet glycoprotein IIbIIIa. Ultimately, data are lacking to definitively support an evidence-based approach to management in any of these disorders, and prospective, controlled studies are desperately needed.

Outcomes of Immune Thrombotic Thrombocytopenic Purpura (iTTP) With Upfront Cyclophosphamide vs. Rituximab

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disorder managed with plasma exchange (PLEX) and steroids. Addition of rituximab (RTX) to initial disease treatment has been shown to lower future relapse rates. Information as to whether upfront cyclophosphamide (CTX) treatment is helpful in reducing relapse is not known.

Methods: In a retrospective cohort study, we identified all patients at our institution diagnosed with iTTP between 2010 and 2019. We analyzed outcomes of cumulative incidence of relapse (CIR) and duration of remission.

Results: Thirty Nine patients were studied. Group A (n = 10) included patients who received upfront PLEX and steroids alone, and Group B (n = 28) included those who received either upfront RTX (n = 23) or CTX (n = 5) in addition to PLEX and steroids. The 2-year CIR was 50% in Group A and 27.7% in Group B, with a median duration of remission of 43.6 months vs. 108.3 months, respectively (p = 0.04). Group A was associated with a HR=8.7 (95% CI: 1.27, 59.45), p = 0.027 for duration of remission. There was no significant difference between CTX and RTX in both outcomes of CIR and duration of remission. We observed a potential impact on remission duration based on the presenting absolute neutrophil count (HR = 0.74, 95% CI: 0.58, 0.96) and serum creatinine (HR = 1.42, 95% CI: 1.03, 1.94).

Conclusion: There was no significant difference in iTTP relapse outcomes between upfront RTX and CTX. Absolute neutrophil count and serum creatinine may have a role in predicting relapse. Larger, prospective studies are needed to evaluate these findings.

Post-Transfusion Purpura: Current Perspectives

Post transfusion purpura (PTP) is an uncommonly reported post transfusion adverse event that can present with severe thrombocytopenia; sometimes resulting in significant bleeding and hemorrhage. Its diagnosis can be elusive given its substantial symptomatic overlap with other thrombocytopenic syndromes. Underdiagnosis and underreporting make the true incidence of disease difficult to define. While clinical suspicion is key, laboratory evidence of platelet-targeted antibodies and identification of the antigen(s) they recognize are necessary to confirm the diagnosis. A curious aspect of PTP is paradoxical destruction of both transfused and autologous platelets. Although the first case was reported over 50 years ago, this aspect of PTP pathogenesis is still not fully understood and is widely debated. Several theories exist, but conclusive evidence to support most is lacking. Despite limited understanding of disease incidence and etiology, treatment with IVIG (Intravenous Immunoglobulin) has become standard practice and can be highly effective. Although recurrence is rare, precautions should be taken if patients with a history of PTP require transfusions in the future.

Gynecologic Bleeding Complications in Postmenarchal Female Adolescents Receiving Antithrombotic Medications

Adolescents receiving antithrombotic medications are at risk of developing gynecologic bleeding complications, which can result in anemia, hospitalization, transfusions, or surgery. Provider awareness/screening of HMB as a bleeding complication of antithrombotic medications is less than optimal. Future prospective studies in adolescents receiving antithrombotic medications are needed to better evaluate provider awareness and the prevalence of gynecologic bleeding complications, which can lead to effective management.

A Cross-Sectional Study of Women and Girls with Congenital Bleeding Disorders: The American Thrombosis and Hemostasis Network Cohort

The number of women and girls (WG) with bleeding disorders cared for at hemophilia treatment centers has increased dramatically over the last 30 years, owing to improved recognition of bleeding symptoms specific to WG. However, basic epidemiologic data of this population remain elusive. The ATHNdataset (American Thrombosis and Hemostasis Network) is a surveillance tool for people with bleeding disorders in the United States, providing demographic as well as bleeding symptom and treatment information. The aim of this study was to characterize the female cohort within the ATHNdataset.