Background Emicizumab, a bispecific antibody factor VIII mimetic, is approved for prophylaxis in hemophilia, and has different risks and side effects compared to factor VIII products. Objective To better understand the early impact of emicizumab on our patients at the University of Colorado Hemophilia and Thrombosis Center (UCHTC), we evaluated adverse reactions, factor prophylaxis overlap, and bleeding rates after starting emicizumab through a quality improvement project. Patients/Methods A retrospective chart review and structured phone interview were conducted from June to September 2019 for all patients who had started emicizumab at the UCHTC. Data about emicizumab dosing, reactions, bleeding events, and bleeding treatment were collected in 68 children and adults (aged 0.55‐79.8 years, on emicizumab a median 213 days; range, 51‐1229 days) with hemophilia A (35.3% with past or current inhibitor). Results Adverse reactions were primarily skin reactions, with no anaphylactic reactions or thrombosis. Bleeding events, defined as pain or swelling treated with factor or supportive measures, demonstrated wide variability, with 25 of 68 experiencing zero bleeds and 5 of 68 experiencing >8 bleeds per year. The most prevalent bleed type was traumatic musculoskeletal bleeding. Bleeding events occurred more often in the first 10 weeks after starting emicizumab, but no time period was without bleeding events. The majority of patients were prescribed every‐week or every‐2‐week dosing, but some had alternative dosing frequency. Conclusions Real‐world emicizumab use in our center was characterized by variations in prescribing practices and bleeding outcomes and lack of severe adverse reactions.
INTRODUCTION Heavy menstrual bleeding (HMB) is one of the most common disease manifestations of biological females with inherited bleeding disorders and is often accompanied by iron deficient anemia (IDA). The most common bleeding disorders identified in biological females are von Willebrand Disease (VWD)/low von Willebrand Factor levels (low VWF) and heterozygosity for factor VIII genetic defects. Several pre-analytical variables including elevated adrenergic stress and estrogen-states can make it challenging to accurately diagnose these conditions as these variables are known to influence VWF and factor VIII activity levels. We sought to investigate whether an iron depleted state impacts the results of a laboratory assessment for VWD/low VWF or mild hemophilia A. METHODS Subjects were recruited from the Spots and Dots clinic (female-identifying bleeding disorder clinic) through the University of Colorado's Hemophilia and Thrombosis Center. Eligible subjects included biological females of any age who had at least two sets of laboratory assessments for von Willebrand levels (VWF antigen, VWF activity, and factor VIII activity level) and markers for total body iron stores (complete blood count and ferritin). Age at time of first testing, iron prescriptions, and underlying bleeding disorder diagnoses were also recorded. IDA was defined as a ferritin less than 20ng/mL with accompanying anemia (Hb <14.3 g/dL). Descriptive statistics and Fisher's exact tests were used to evaluate the association of factor VIII/VWF activity levels and iron stores. RESULTS Thirty-seven subjects were included in the final analysis. The average age at time of first testing was 21.5 years (range 9-50 years). IDA was present in 22 patients at the time of first assessment and in 20 patients at follow up. Serum ferritin improved overall in 23 patients between assessments. Oral iron was prescribed in 20 patients and intravenous iron was prescribed in three. An improvement in serum ferritin predicted a decrease in factor VIII activity (p = 0.0092) on follow-up assessment but did not predict a significant decrease in VWF activity levels (p = 0.0819) (Figure 1). Retesting factor VIII and VWF activity levels after iron repletion led to a diagnosis of low VWF in 4 cases (10.8%) and VWD in 2 cases (5.4%) that would have otherwise been classified as normal without retesting. CONCLUSIONS IDA is frequent in women with HMB and may be insufficiently managed with oral iron therapy in adolescents and those with an underlying bleeding disorder. The fact that many patients remained iron deficient at the time of follow up testing may have blunted the results of this analysis. Despite this limitation, this study still suggests that iron deficient anemia may be a significant enough biological stressor to increase factor VIII and possibly VWF activity levels to a point that may obscure an underlying diagnosis of VWD, low VWF, or hemophilia A. Further investigations are warranted to confirm if universal retesting of VWF and factor VIII activity levels are diagnostically imperative after correction of IDA. Such a recommendation may have a significant impact on this patient population as discovery of an underlying bleeding disorder diagnosis can not only provide an explanation for a patient's HMB but also can identifying individuals who may be at increased risk for bleeding at other sites or during invasive procedures. Disclosures No relevant conflicts of interest to declare.
The hemostasis system is composed of procoagulant, anticoagulant, and fibrinolytic proteins that interact with endothelial and blood cells and with each other in a complex system of checks and balances to maintain blood flow while preventing both hemorrhage and thrombosis. Pregnancy is a unique physiological state in which biological alterations predispose both mother and fetus to both bleeding and clotting. The placenta is a vascular interface for maternal and fetal blood exchange which predisposes the mother to hemorrhage. Maternal hemostasis presents a compensatory hypercoagulability including elevated factor VIII, von Willebrand factor, fibrinogen and thrombin generation, decreased thrombin regulation with resistance to activated protein C and decreased free protein S, and decreased fibrinolysis with increased plasminogen activator inhibitors. The placental vascular surface is of fetal trophoblastic origin that derives many characteristics of endothelium but differs in that tissue factor is constitutively expressed. Ontogeny of fetal hemostasis is characteristic. Platelets, von Willebrand factor, factor VIII, and fibrinogen are expressed and mature early in gestation, while vitamin K–dependent and contact factors exhibit delayed development. The fetal hemostatic system has a decreased capacity to generate or regulate thrombin, resulting in a fragile balance with little capacity to compensate under stress conditions, particularly in the infant born prematurely. Dysfunction of the maternal/placental/fetal unit gives rise to gestational disorders including preeclampsia, fetal growth restriction, placental abruption, and premature delivery. Knowledge of normal hemostasis levels and function are critical to evaluate bleeding or clotting syndromes in the pregnant woman and her fetus or newborn infant.
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