Alice D. Ma

Cardiovascular comorbidities are increased in US patients with haemophilia A: a retrospective database analysis

There is conflicting evidence in the literature on whether individuals with haemophilia in the USA have greater, reduced, or similar risks for cardiovascular disease as the general population. This study evaluated the prevalence of cardiovascular comorbidities among USA males with haemophilia A, relative to an unaffected general male population with similar characteristics. Males with haemophilia A and continuous insurance coverage were identified by ICD‐9‐CM code 286.0 (1 January 2007–31 December 2009) using the MarketScan® Commercial and Medicare Research Databases. Individuals with haemophilia A were exact matched 1:3 with males without a diagnosis of haemophilia A. The prevalence of cardiovascular comorbidities identified by ICD‐9‐CM code was determined for matched cohorts. Of the study population, 2506 were grouped in the haemophilia A cohort and 7518 in the general cohort. Proportions of individuals with haemorrhagic stroke (2.0% vs. 0.5%, P < 0.001), ischemic stroke (4.7% vs. 2.7%, P < 0.001), coronary artery disease (10.7% vs. 5.8%, P < 0.001), myocardial infarction (0.8% vs. 0.3%, P = 0.003), hypertension (22.6% vs. 15.5%, P < 0.001), hyperlipidaemia (15.9% vs. 11.9%, P < 0.001), arterial thrombosis (12.1% vs. 5.9%, P < 0.001), and venous thrombosis (4.4% vs. 1.1%, P < 0.001) were significantly greater for the haemophilia A cohort. Results were consistent across most age groups, and comorbidities appeared at an earlier age in those with haemophilia A than in the general population. Among the USA haemophilia A population cardiovascular comorbidities are more prevalent and they appear earlier in life in comparison to the general male population, suggesting the need for earlier, enhanced screening for age‐related comorbidities in the haemophilia community.

Single-center experience with rituximab as first-line immunosuppression for acquired hemophilia

Acquired hemophilia (AH) is a rare, life-threatening bleeding disorder with an estimated incidence of 1.48 patients per million per year and a median age at presentation of 78 years [1]. It is caused by the development of autoantibodies directed against coagulation factor VIII (FVIII), with resultant low FVIII activity levels [2]. AH has a significant mortality rate that has been estimated to be between 8% and 22%, and approximately 90% of patients experience severe bleeding episodes [3,4]. Although the majority of cases of AH are felt to be idiopathic, up to 50% of cases are associated with underlying conditions such as autoimmune disorders, the postpartum state, current or past malignancy, infection, or certain medications [2]. Inhibitors may spontaneously remit or may resolve following treatment of the underlying condition [3,5]. Athough spontaneous remissions may occur in patients with AH, it is generally accepted that patients should be treated with immunosuppression to reduce the length of time for which they are at risk for severe bleeding. The use of corticosteroids has been associated with inhibitor resolution in 30–70% of patients, and when they are added to cyclophosphamide, the remission rate approaches 60–80% [1,6]. Chronic use of corticosteroids is often associated with significant adverse affects. Our experience, as well as that described by Collins et al. [1], suggests that this iatrogenic toxicity in a typically elderly population has previously been underestimated in the literature. This impression led us to consider other, potentially less toxic, immunosuppressive therapies for these patients. Rituximab has been reported in the successful treatment of various non-neoplastic immunologic disorders, including AH, where its use has recently been reviewed [7]. However, in many of these case series, rituximab was used in combination with corticosteroids or as a second or later line of therapy. Since August 2005, we have chosen to use rituximab as a single firstline agent in all patients presenting with AH requiring inhibitor eradication. Steroids are not routinely employed, but additional immunosuppressive agents are added when the FVIII inhibitor titer is not felt to be responding adequately, and are instituted at the treating provider s discretion. This was typically performed if the Bethesda Units (BU) titer did not decline significantly within 4–8 weeks of initiation of rituximab. We identified all patients seen at the University of North Carolina for AH from August 2005 through January 2011. Complete remission (CR) was defined as FVIII:C > 70 IU dL or undetectable FVIII inhibitor titer (< 0.4 BU mL). Rituximab was administered intravenously at a dose of 375 mg m weekly for four consecutive weeks (days 1, 8, 15 and 22) upon laboratory confirmation of AH. If corticosteroid therapy had already been instituted prior to transfer to our facility, it was rapidly tapered once rituximab was initiated. This single-center experience includes data on 22 patients (see Table 1 for patient details, including available outcome data). One patient was lost to follow-up after initial hospitalization. Six additional patients died during their initial hospitalization or were discharged to hospices (see Table 1 for details related to death/hospice transfer); five of the six had been started on immunosuppression. Four of these patients had been started on prednisone prior to transfer, andwere therefore treated with both rituximab and prednisone. None of these patients completed all four infusions of rituximab. There were no statistically significant differences between these groups with regard to baseline FVIII levels or FVIII inhibitor titers. Thus, 15 patients were evaluable for response to an initial immunosuppressive regimen. Of these, 12 received rituximab as a single agent, and three received a combination of rituximab and corticosteroids (initiated prior to referral). Of the 12 individuals who received rituximab alone, seven achieved CR, and one achieved partial remission ( PR) with resolution of bleeding symptoms. The remaining four patients required additional immunosuppressive agents to achieve CR. The following associated conditions were noted: infection (8%), past malignancy (12%), active or suspected malignancy (24%), autoimmune disorder (20%), postpartum (4%), and idiopathic (32%). Those patients who achieved CR or PR on rituximab alone had a median baseline FVIII inhibitor titer of 22 BU mL (range 1–163, interquartile range [IQR] 5–113), whereas those who achieved CR with multiple lines of therapy had a median Correspondence: Alice D. Ma, Harold R. Roberts Comprehensive Hemophilia Treatment Center, Division of Hematology/Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Physicians Office Building 3rd Floor CB# 7305, 170 Manning Drive, Chapel Hill, NC 27599-7305, USA. Tel.: +1 919 843 9779; fax: +1 919 966 6735. E-mail: alice_ma@med.unc.edu

Clinical features and management of haemophilic pseudotumours: a single US centre experience over a 30-year period

Given the rarity of haemophilic pseudotumours, consensus on management is lacking. We describe the clinical features and management of haemophilic pseudotumours by retrospectively reviewing the medical records of haemophilia patients with a diagnosis of pseudotumour seen at our Hemophilia Center from 1981 to 2011. We recorded the following data: type and severity of haemophilia, documented aetiological antecedent, localization of the pseudotumour, presenting symptoms, management and outcome. We identified 12 pseudotumours in 11 patients over a 30‐year period. Six patients had known inhibitors or a history of inhibitor. An aetiological antecedent leading to the development of pseudotumour was reported in nine cases. Localization of the pseudotumour was confined to soft tissue (n = 3) and bone (n = 8). Six of the 12 pseudotumours (50%) were not diagnosed at the time of initial presentation, with a delay ranging from 6 weeks to 6 years. In eight cases, surgical intervention (surgical drainage, n = 2; excision, n = 4; limb amputation, n = 2) was the initial treatment choice, with complete resolution in six cases. Conservative management with close monitoring occurred in three cases, with one case subsequently requiring surgical resection. We conclude that haemophilic pseudotumours still occur sporadically, and the diagnosis is frequently delayed. Surgical intervention is generally a safe and effective treatment, although conservative management may be appropriate in selected cases.

US experience with recombinant factor VIIa for surgery and other invasive procedures in acquired haemophilia: analysis from the Hemostasis and Thrombosis Research Society Registry.

Acquired haemophilia (AH) is a rare disorder caused by autoantibodies against factor VIII.

Assessment of acquired hemophilia patient demographics in the United States: the Hemostasis and Thrombosis Research Society Registry

The Hemostasis and Thrombosis Research Society (HTRS) Registry was used to monitor the postapproval use of recombinant factor VIIa. The objective of this manuscript is to provide key insights on the demographics of patients with acquired hemophilia in the HTRS Registry. Acquired hemophilia patient registration in HTRS captured age; sex; comorbidities and predisposing conditions; first bleeding location; laboratory parameters; exposure to blood products, factor, and bypassing agents; and initiation of immune suppression/tolerance therapy. Overall, 166 patients with acquired hemophilia were registered in HTRS (83 women, 73 men, median age 70 years); the majority were non-Hispanic whites (61.4%). The most common comorbidities were autoimmune disease (28.4%) and malignancy (14.5%). The most common first site of bleeding was subcutaneous (27.1%); this was more common in whites (29.1%) than blacks (12.5%) and in non-Hispanics (26.4%) than Hispanics (11.8%). Blood product exposure was reported for 33.1% of patients; the most commonly reported product was packed red blood cells (28%). Of the 57 patients with outcome data available for immune tolerance therapy, 26 patients (46%) reported successful treatment, 13 reported unsuccessful treatment (23%), and 18 (32%) were receiving active treatment at the time of registration. The HTRS Registry final analysis provides the only current comprehensive look at acquired hemophilia in the US population, including details on underlying autoimmune diseases and malignancies. Pertinent to recognition and diagnosis of the disease, subcutaneous bleeding as a presenting bleeding symptom was more common in white and non-Hispanic individuals.

Use of recombinant activated factor VII for acute bleeding episodes in acquired hemophilia: final analysis from the Hemostasis and Thrombosis Research Society Registry acquired hemophilia study.

The Hemostasis and Thrombosis Research Society Registry was used to monitor the postapproval use and safety of recombinant activated factor VII (rFVIIa). The objective of this article is to evaluate the data from the Hemostasis and Thrombosis Research Society Registry related to rFVIIa-treated bleeding episodes in patients with acquired hemophilia. For each rFVIIa-treated bleeding episode, the initial dose, total dose, average infused dose, number of doses, and treatment duration were calculated. Efficacy was assessed on a three-point scale. Out of the 166 registered patients with acquired hemophilia, 110 patients were treated for 237 bleeding episodes (139 rFVIIa treated); the majority (70%) were in patients older than 60 years. The most frequently reported bleeding locations were subcutaneous (40%) and mucosal (32%). Subcutaneous bleeding episodes were more commonly reported in women (55% vs. 40% men) and white patients (44 vs. 27% black). Of the 139 rFVIIa-treated bleeding episodes, rFVIIa was used as first-line treatment in 127 bleeding episodes. The median initial dose was 90 &mgr;g/kg; the median total dose per episode was 333.5 &mgr;g/kg. Physician-rated efficacy of rFVIIa for each bleeding episode was reported as ‘bleeding stopped’ in 85% of bleeding episodes, ‘bleeding slowed’ in 11% of bleeding episodes, ‘no improvement’ in 4% of bleeding episodes, and was not documented in 1 bleeding episode. One thromboembolic event was reported; transient neurologic symptoms were reported in a 31-year-old postpartum patient after 110 doses of rFVIIa. Adequate hemostasis was provided for most rFVIIa-treated bleeding episodes at doses largely conforming to the package insert. No major safety concerns were reported.

Safety of human plasma-derived clotting factor products and their role in haemostasis in patients with haemophilia: meeting report.

In September 2006, an international group of haemo philia experts met in Chicago, Illinois, USA, to discuss issues surrounding the safety of humanderived factor concentrates and the role of these products in achieving and maintaining haemostasis, primarily in patients with haemophilia. Moderator Louis Aledort, MD, prefaced the presentations by noting that in the early 1970s, when factor VIII (FVIII) and factor IX concentrates first became widely used, the median age of patients with haemophilia was 16 years. [Correction added after online publication 14 June 2007: in the preceding sentence, the term FIX was corrected to factor IX.] Approximately a decade later, the haemophilia community was ravaged by HIV and the hepatitis C virus infections, transmitted by infusions of the clotting factor concentrates that had so recently revolutionized bleed management. Now, the outlook has changed dramatically for the better, with the youngest generation of haemophilia patients enjoying freedom from infusion-associated infection with most known viral pathogens. These patients also have the expectation of excellent joint health, provided they do not develop inhibitors that cannot be eradicated.

Lower doses of recombinant porcine factor VIII maintain excellent haemostatic efficacy.

Acquired haemophilia A (AHA) is a rare disorder in which an acquired autoantibody inhibits the activity of coagulation factor VIII. It affects an estimated 1 per million population annually [1] and can cause bleeding that may be life-threatening. Mortality rates are estimated to be between 7% and 27% [1,2], which may be influenced by the advanced age and comorbidities of the typical patients with acquired haemophilia. The management of acquired factor VIII inhibitors is aimed at controlling active bleeding and eradicating the autoantibody. Traditionally, agents that bypass factor VIII – namely, anti-inhibitor coagulant complex (activated PCC, aPCC) and recombinant factor VIIa (rFVIIa) – have been used to manage bleeding complications. These agents, however, inconsistently achieve haemostasis in patients with inhibitors in AHA and congenital haemophilia A, [2–6] and cannot be monitored by standard coagulation assays, complicating management [7]. A plasma-derived porcine FVIII product (Hyate:C) was shown to be effective in treating patients with AHA, however, safety concerns over porcine parvovirus led to its withdrawal from the market in 2004. An advantage of porcine FVIII (pFVIII) is that the domains to which inhibitory antibodies to human FVIII (hFVIII) are most commonly made, A2 and C2, differ between hFVIII and pFVIII (84% and 76% homology respectively), leading to less cross-reactivity between anti-hFVIII and anti-pFVIII inhibitors. Porcine FVIII is therefore used to avoid inhibition by anti-hFVIII antibodies, resulting in effective control of bleeding and the ability to monitor clinically using FVIII activity levels. In 2014, a recombinant porcine FVIII product – B-domaindeleted, antihaemophilic factor (recombinant) porcine sequence (rpFVIII) – was approved by the FDA for the treatment of AHA [8]. A prospective phase II/III clinical trial of 28 patients with serious bleeding due to AHA demonstrated clinical efficacy of rpFVIII, with control of bleeding ultimately achieved in 24 of the 28 subjects [7]. The initial dose used in the prospective trial was 200 Units (U) kg , followed by maintenance dosing titrated according to bleeding control and trough FVIII:c levels. The most common adverse event that occurred in the phase II/III trial was the development of inhibitors to porcine FVIII (antipFVIII), which occurred in 5/28 (17.9%) of patients who did not have detectable anti-pFVIII at baseline [7]. Data on rpFVIII use outside the setting of a clinical trial have not been reported. Since its approval, we have treated four patients with AHA with rpFVIII for 13 bleeding episodes. Herein, we present this experience in which we used rpFVIII at lower than recommended doses with successful haemostatic outcomes. Our management strategy for dosing rpFVIII in the setting of bleeding due to AHA is as follows. We administer an initial dose of 100 U kg , as opposed to the recommended loading dose of 200 U kg . We chose this initial dose because of the supraphysiologic FVIII:c levels that were reported in the pivotal trial [7]. We then aim to measure peak FVIII:c 30 min after dosing and trough FVIII:c after approximately 4 h (immediately prior to the subsequent dose of rpFVIII). We target a peak FVIII:c of 80–100% and a trough of 30– 50%. If either the preceding peak or trough level is below target, the ensuing dose of rpFVIII is again 100 U kg . If, however, both are within the target range, the ensuing dose of rpFVIII is 50 U kg . We continue to administer rpFVIII every 4 h, and titrate the dose and interval based on peak and trough levels. Broadly, subsequent doses are reduced if peak FVIII:c level is above goal, and frequency of dosing is reduced if FVIII:c trough is above goal. We continue to titrate doses until clinical improvement in bleeding occurs. Figure 1 demonstrates our dosing strategy for a selected bleeding event. Patients who received rpFVIII (Table 1) ranged in age from 54 to 78 years, with a median of 67.5 years. Half of the patients were men. Weight ranged from 76.2 to 133.9 kg, with a median of 92.5 kg. One patient received rpFVIII while on haemodialysis. Anti h-FVIII inhibitor titres at diagnosis ranged from 54 to 225 BU mL . Three patients were treated with rFVIIa upon initial diagnosis of AHA, for between 3 and 9 days (median 7 days), but were switched to rpFVIII when acceptable haemostasis was not achieved. The fourth patient did not receive bypassing Correspondence: Alice Ma, MD, Department of Medicine, Division of Hematology Oncology, University of North Carolina, 101 Manning Drive, Campus Box 7305, Chapel Hill, NC 27599, USA. Tel.: +919 966 1996; fax: 919-966-6735; e-mail: alice_ma@med.unc.edu

Rituximab as first-line treatment for the management of adult patients with non-severe hemophilia A and inhibitors

The role of immunosuppression in the management of patients with congenital hemophilia and inhibitors is uncertain. The use of rituximab has been limited to case reports and case series. In most reports, rituximab was used as second‐line or third‐line treatment following failure of conventional immune tolerance induction therapy, and more commonly in pediatric patients.

Factor VIII inhibitory antibody in a patient with combined factor V/factor VIII deficiency

Combined factor V (FV) and FVIII deficiency (F5F8D) is a rare autosomal recessive bleeding disorder that affects approximately 1 in 1 million individuals in the general population. The estimated incidence is as high as 1 in 100 000 in the Middle Eastern Jewish and Iranian populations [1]. F5F8D accounts for approximately 3% of the rare bleeding disorder population worldwide. The disorder results from impaired intracellular transport of FV and FVIII, due to a defect in either the ER-to-Golgi transport protein lectin mannose-binding protein 1 or its cofactor, multiple coagulation factor deficiency 2 (MCFD2) [2]. Circulating levels of FV and FVIII usually range from 5% to 20% in affected individuals. Patients with F5F8D exhibit mild-to-moderate bleeding phenotypes, most often characterized by easy bruising, gum bleeding and epistaxis. While bleeding after surgery, dental extractions, trauma and delivery can also occur, severe spontaneous haemorrhages are uncommon. This report describes a patient with F5F8D who developed severe bleeding complications due to a FVIII inhibitory antibody. To our knowledge, this is the first time such a complication has been described in F5F8D. The patient is a 71-year-old man who exhibits F5F8D due to a donor splice site mutation in the MCFD2 gene (149 + 5 G?A), resulting in complete loss of MCFD2 protein expression [2]. His baseline FV and FVIII levels are 4% and 12% respectively. He did not experience spontaneous bleeding prior to onset of the inhibitor. His past medical history also included coronary artery disease (CAD) necessitating coronary artery bypass grafting, hypertension, hyperlipidaemia and exudative age-related macular degeneration (AMD). He previously suffered an episode of tachycardia and hypotension during plasma exchange, felt to be due to angiotensin-converting enzyme (ACE) inhibitor interaction with the apheresis procedure. He subsequently tolerated re-exposure to plasma without difficulty. In June 2011, the patient fell from a ladder and fractured his distal tibia. He was hospitalized and treated with daily FVIII infusions for 1 week. He underwent open reduction and internal fixation of the distal tibia and afterwards received 1 week of FVIII replacement. In October of 2011, the patient began receiving intra-vitreal injections of bevacizumab to slow progression of vision loss due to AMD. In December 2011 and March 2012, the patient experienced episodic chest pain at rest; in both instances, he underwent percutaneous coronary intervention with placement of a bare metal stent. Recombinant FVIII was administered by continuous infusion immediately prior to and for 5 days after these interventions. He was subsequently treated with prophylactic FVIII infusions three times per week while he remained on a 1-month course of dual antiplatelet medications (aspirin and clopidogrel). During the second hospitalization, a new FVIII inhibitor was noted (0.7 BU mL ). FVIII recovery levels after infusions remained normal, and there was no evidence of excess bleeding. While on clopidogrel, he had intermittent haematuria and the frequency of FVIII infusions was increased to daily. In May 2012, the patient presented with spontaneous right thigh and knee swelling and pain with multiple ecchymoses. Bleeding was initially controlled with a continuous infusion of high-dose FVIII, but approximately 5 days after admission, the inhibitor titre rose rapidly and FVIII activity could no longer be detected despite continued doses of FVIII. The inhibitor titre was found to have risen to 20 BU mL . The patient was treated with intravenous aminocaproic acid and multiple platelet transfusions. Treatment of bleeding with bypassing agents (rFVIIa or FEIBA) was avoided due to repeated episodes of angina, as well as a catheter-associated venous thrombosis that developed during the hospitalization. He experienced multiple complications during the 6-week hospitalization (Table 1). The patient was treated with aggressive immunosuppression (Fig. 1), which resulted in a steady fall in inhibitor titre, restoration of FVIII levels to baseline, and cessation of spontaneous bleeding over a period of several months. He was treated with rituximab 375 mg m 2 for 4-weekly doses, a prednisone taper over 9 months and mycophenolate mofetil for a total of 21 months. Correspondence: Tyler W. Buckner, University of North Carolina, Physicians’ Office Building, CB #7305, Chapel Hill, NC 27599-7305, USA. Tel.: (919)966-3856; fax: (919)966-6735; e-mail: tyler_buckner@med.unc.edu