Successful Treatment with Emicizumab of Patient with Type 2N Normandy and Severe Hemophilia a

It is unusual to have both Type 2N VWD and severe hemophilia A. Type 2N (Normandy) von Willebrand Disease (VWD) is an uncommon recessive disorder resulting in a defect in the binding site of von Willebrand Factor (VWF) with factor VIII. Factor VIII plasma levels are low due to rapid clearance. Our patient has severe hemophilia A (factor VIII <1%; Inversion 22) with no history of inhibitors and is heterozygous for a known pathogenic mutation (c2560C>T; p. Arg854Trp) Type 2N "Normandy". He benefited from the use of HEMLIBRA® (Emicizumab-kxwh, Genentech) a humanized bispecific monoclonal antibody with a long half-life independent of VWF interaction. The patient was diagnosed at 11 months old with excessive bleeding from his frenulum and began episodic standard factor VIII. He had 10 bleeds including knees, arms and hamstring before starting prophylaxis at 3 yrs. of age. On ADVATE 50 units/kg/dose twice a week he had nose bleeds, soft tissue bleeds, and joint bleeds. At 11 yrs. of age, the nose bleeds increased daily. VWD testing revealed VWF activity 25%, VWF Antigen 42%, Factor VIII <1% and Normal Multimers with Type 2 Normandy genotype. ALPHANATE® (Anti-hemophiliac factor/von Willebrand factor complex (human), Grifols) prophylaxis was started to address mucosal bleeding however the right elbow synovitis progressed to right elbow contracture and bone cyst on MRI. He returned briefly to ADVATE® 50 units/kg MWF to every other day prophylaxis with continued intermittent bleeding in right elbow joint. With the diagnosis of Type 2N, and the availability of VONVENDI ® (Recombinant von Willebrand factor, Takeda), he was placed on ADYNOVATE® (Antihemophilic Factor Recombinant PEGylated, Takeda) daily and VONVENDI® every 3rd day starting at 14 yrs. old. The combination of ADYNOVATE® every 12-24 hours with VONVENDI® daily to every other day improved his acute bleeding episodes including his nose bleeds (Half-life ADONYVATE®+VONVENDI® 9.25 hr. vs. Half-life ADVATE® 5.5 hr.). The patient continued to participate in high-risk activities such as playing on trampoline which contributed to his injuries but his family felt the treatment was better than previous therapies. After considering the treatment burden of 2 types of factors more than 5 times a week and progression of synovitis in right elbow joint, the patient was started on HEMLIBRA® with weekly subcutaneous injections. Four weeks of loading dose (3 mg/kg/dose) was followed by once per week prophylaxis at standard dosing 1.5 mg/kg weekly. The first bleeding episode on HEMLIBRA® was reported after tooth restoration October 2019. After receiving both ADYNOVATE® and VONVENDI® pre-op, he developed swelling with suspected hematoma at the angle of his jaw about 4 days post-op treated successfully with ADYNOVATE® /VONVENDI®. In April 2020, he had right elbow pain stereotypic of a joint bleeding episode after yard work which was treated successfully with ADYNOVATE® /VONVENDI®. No report of severe nosebleeds. To our knowledge this is the first example of successful use of HEMLIBRA® in a patient with Type 2N VWD and severe hemophilia A. It is unclear why the ALPHANATE® was not clinically effective however the combination of VONVENDI® and ADYNOVATE® provided improved hemostasis with frequent infusions and high cost before the start of HEMLIBRA®. HEMLIBRA once a week has significantly reduced the treatment burden and improved bleeding prevention. The genotype of this patient is unusual however this approach may be successful in other types of VWD that result in significant bleeding phenotype. Figure 1 Figure 1. Disclosures Bryant: Novo Nordisk: Consultancy, Honoraria; Bristol Myers Squib: Consultancy, Honoraria; Hema Biologics: Consultancy, Honoraria. Carr: Genentech: Speakers Bureau; Bayer: Speakers Bureau; Medexus: Speakers Bureau.

MORTALITY ASSOCIATED WITH VARICEAL BLEED IN CIRRHOSIS PATIENTS ATTENDING A TERTIARY CARE CENTRE IN SOUTH KERALA.

Background : Acute variceal bleeding is a most common complication of portal hypertension. Despite advancement in management of variceal bleeding still carries a very high morbidity and mortality. The present study was undertaken to study mortality associated with variceal bleed in cirrhotic patients attending a tertiary care hospital. Method : This prospective study was conducted between June 2016 to may 2018. Total 60 patients included in the study who admitted with acute variceal bleeding episode with underlying cirrhosis. Results : Majority of patients were male ( 76 %). The mean age of patients was 54 +/- 13.7. Most common etiology of cirrhosis was Alcohol related liver disease (51.7% ). Most common presenting symptom was hematemesis with melena(41.7%). Majority of patients presented with recurrent bleeding episodes (61.7% ). 18.3% Patients had rebleeding episode within 5 days of admission. Total 21 (35 % ) patients died during study period. Univariate analysis showed advance age, presence of ascites, Encephalopathy, high creatinine, bilirubin and INR were important predictors of mortality. In multivariate analysis only signicant predictors was serum creatinine (OR 43.1 (CL3.05 to 608.64)). Conclusion: Patients with cirrhosis are always at risk of variceal bleeding. The survival after a bleeding episode was inuenced by age, comorbidities, in hospital complications, ascites, high CTPand MELD score , beta blocker therapy

512 A CASE OF AN IDIOPATHIC ACQUIRED HEMOPHILIA A IN AN ELDERLY WOMAN

Introduction Acquired Hemophilia is a bleeding diathesis caused by autoantibodies that interfere with factor VIII (FVIII). Reasons for autoantibodies production are not clear but may be related to gene polymorphisms and/or CD4+ T lymphocytes. 1.3 to 1.5 cases per million population per year are reported in the UK. Half of the cases are secondary to malignancy, pregnancy related conditions, connective tissue disorders or drug reactions while the rest are idiopathic. Case Report We report a case of an acquired hemophilia A in an 86-year-old lady with underlying type 2 diabetes, hypertension, and cognitive impairment, being treated as the left lower limb cellulitis with antibiotics. She was found to have a sudden hemoglobin drop and her CT (Abdomen) confirmed a spontaneous intra-abdominal hematoma. Clotting profile showed prolonged APTT to 168.5 seconds, being not corrected at mixing study, with normal PT and INR. The FVIII assay was reduced to 18.4 iU/dL with FVIII inhibitor concentration of 0.7 Bu. Viral and autoimmune screenings were negative. The idiopathic acquired hemophilia A was diagnosed. Red blood cell transfusions, bypassing agents (FEIBA) and oral tranexamic acid were given for acute bleeding episode. Concomitantly, oral prednisolone was used to reduce the inhibitor levels. Repeated FVIII assay showed 121 iU/dL and 199iU/dL on day 6 and 12, respectively. Steroid was continued for the next 4 weeks and then gradually tapered. No further bleeding episode was noted. Conclusion The diagnosis of acquired hemophilia should be considered in any elderly patient with prolonged APTT. Mixing study is to measure the presence of inhibitors of coagulation or to detect coagulation factor deficiency. Quantitative coagulation factor assays and Bethesda Assays are performed for definitive diagnosis. Immunosuppressive regimens are the mainstay treatment. However, premorbid conditions and co-morbidities should be taken into consideration before initiating the aggressive immunosuppressive therapy in the elderly patients.

Crossed brainstem syndrome revealing bleeding brainstem cavernous malformation: an illustrative case

Background Since the nineteenth century, a great variety of crossed brainstem syndromes (CBS) have been described in the medical literature. A CBS typically combines ipsilateral cranial nerves deficits to contralateral long tracts involvement such as hemiparesis or hemianesthesia. Classical CBS seem in fact not to be so clear-cut entities with up to 20% of patients showing different or unnamed combinations of crossed symptoms. In terms of etiologies, acute brainstem infarction predominates but CBS secondary to hemorrhage, neoplasm, abscess, and demyelination have been described. The aim of this study was to assess the proportion of CBS caused by a bleeding episode arising from a brainstem cavernous malformation (BCM) reported in the literature. Case presentation We present the case of a typical Foville syndrome in a 65-year-old man that was caused by a pontine BCM with extralesional bleeding. Following the first bleeding episode, a conservative management was decided but the patient had eventually to be operated on soon after the second bleeding event. Discussion A literature review was conducted focusing on the five most common CBS (Benedikt, Weber, Foville, Millard-Gubler, Wallenberg) on Medline database from inception to 2020. According to the literature, hemorrhagic BCM account for approximately 7 % of CBS. Microsurgical excision may be indicated after the second bleeding episode but needs to be carefully weighted up against the risks of the surgical procedure and openly discussed with the patient. Conclusions In the setting of a CBS, neuroimaging work-up may not infrequently reveal a BCM requiring complex multidisciplinary team management including neurosurgical advice.

Contribution of Capsule Endoscopy Early in a Bleeding Episode to Treatment of Small Bowel Angioectasia: A Case Report

Background: Recent advances in endoscopic devices such as small bowel capsule endoscopy and balloon-assisted endoscopy have improved the level of medical care for small bowel bleeding. However, treating small bowel angioectasia remains challenging because repeated intermittent bleeding can occur from the multiple minute lesions (about 1 mm in size) that develop in a synchronous and metachronous manner. Here, we report a case of small bowel angioectasia in which capsule endoscopy performed early in a bleeding episode contributed to treatment. Case Summary: A 66-year-old man with suspected small bowel bleeding underwent small bowel capsule endoscopy and balloon-assisted endoscopy with argon plasma coagulation hemostasis for a small intestinal angioectasia. Because small bowel bleeding recurred intermittently after the treatment, small bowel capsule endoscopy and balloon-assisted endoscopy were repeated when there was no bleeding, but no abnormalities were found. Subsequent small bowel capsule endoscopy during a bleeding episode revealed bloody intestinal fluid in the proximal small intestine. Peroral balloon-assisted endoscopy was performed 2 days after SBCE for detailed observation of the small intestinal mucosa at the suspected bleeding site, and there a 1-mm Dieulafoy’s lesion with no active bleeding was identified. We performed argon plasma coagulation, and no bleeding was observed thereafter. Conclusions: Small bowel capsule endoscopy immediately after bleeding onset can identify the bleeding source of multiple minute lesions in small bowel angioectasia.

Dalteparin in Newborn Thrombosis, Time for a New Starting Dose

Background: Neonatal thrombosis is a frequently encountered complication in a neonatal intensive care unit. Dalteparin can be used to treat thrombosis in newborn infants. Objectives: In this study, we evaluate the current recommended starting dose of 129 ± 43 U/kg/24 h, hypothesizing that this dose is too low to reach therapeutic anti-Xa levels. Methods: From 2008 until 2017, all infants treated with dalteparin in the University Medical Centre Utrecht were included in this study. In this retrospective cohort study, the correlation between dose and anti-Xa level was observed. Results: Sixty-six infants were included. The most common thrombus types were catheter-related (29 patients, 44%) and venous sinus thrombosis (28 patients, 43%). The mean dalteparin dose needed for the first adequate anti-Xa level (0.5–1.0 IU/mL) was 297.6 U/kg/12 h. Two infants developed a first bleeding episode under dalteparin therapy; they both had anti-Xa levels in the therapeutic range. Conclusion: The increase of the starting dose of dalteparin will lead to earlier therapeutic levels of anti-Xa in the studied population and appears to be safe. However, this needs to be evaluated in further study.

Six cases of autoimmune acquired coagulation factor VIII deficiency: Single center experience in Japan

We report six cases of autoimmune acquired coagulation factor VIII deficiency, which is a rare bleeding disorder. It is an autoimmune disease, however, there are various causes. We experienced cases with malignancy, co-exist with another autoimmune disease, pregnancy, and unknown epidemiology with repeated bleeding episode. All patients were controlled the acute bleeding phase and they have been under treatment with immunosuppression.

Peak Thrombin and D-Dimer Levels in Subjects with Severe Hemophilia Receiving Acute Treatment for Bleeding Episodes Experienced during Prophylactic Marstacimab Treatment

Introduction: Marstacimab is a fully humanized monoclonal immunoglobulin G1 that targets the shared K2 domains of tissue factor pathway inhibitor (TFPI)α and (TFPI)β and is currently in phase 3 development. The intended indication is routine prophylaxis treatment to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B (with or without inhibitors). Factor replacement or bypass treatment for bleeding events may lead to increased levels of peak thrombin and D-dimer associated with an increased risk of thrombosis . In this post hoc analysis of data from a phase 2 study in patients with hemophilia with and without bleeding episodes, receiving prophylactic marstacimab treatment, peak thrombin and D-dimer levels were investigated to assess the changes in these biomarker levels observed after bleeding episodes. Methods: Individual subject data from the phase 2 study (clinicaltrials.gov identifier: NCT02974855)were used for this analysis. Biomarker data for healthy volunteers who received single doses of marstacimab in a phase 1 dose escalation study (clinicaltrials.gov identifier: NCT02531815) were used as control data, as these subjects represent an intact and uncompromised coagulation system. Study subjects in the phase 2 study received subcutaneous (SC) marstacimab at doses of (1) 150 mg once weekly (QW), with a loading dose of 300 mg, (2) 300 mg QW, and (3) 450 mg QW. All subjects with bleeding episodes were identified, along with on-demand treatment administered for each bleeding episode. Treatments permitted for bleeding episodes included activated coagulation factor VIIa, factor VIII, or factor IX; use of activated prothrombin complex concentrate was prohibited. D-dimer and peak thrombin data collected within 3 days after each bleeding episode were used for this analysis. Time profiles of peak thrombin and D-dimer levels were analyzed to assess the effect of bleed treatment. Biomarker profiles were compared between subjects with and without bleeding episodes, as well as with the data from healthy volunteers (n=41). Results: A total of 15 bleeding episodes were reported in 8 of 26 subjects during the study (excluding screening and follow-up). No subject participating in the study showed any relevant increases in D-dimer levels after receiving on-demand treatment for a bleeding episode while receiving regular prophylaxis with marstacimab, compared with levels seen in subjects who did not experience a bleeding episode. Based on the peak thrombin data (see Figure), 150 nM was observed as the upper limit for 18 of 26 subjects who did not experience any bleeding episodes, which was approximately 50% of the 300 nM observed in healthy volunteer controls treated with 450 mg intravenous marstacimab. Transient increases in peak thrombin of >150 nM were observed at several time points in 3 of 8 subjects who experienced bleeding episodes. The highest peak thrombin level reported was approximately 211 nM in one subject receiving marstacimab 300 mg SC QW and factor VIII concentrate on demand during the study. Conclusions: No transient increases in D-dimer could be attributed to the administration of bleeding episode treatment. The transient increases in peak thrombin levels following on-demand treatment for bleeding episodes did not exceed peak thrombin levels seen in subjects without bleeding events or the levels seen in healthy volunteer controls receiving single doses of marstacimab. Based on peak thrombin and D-dimer levels observed in this post hoc analysis, there does not appear to be any indication of an increased risk of thrombosis post administration of acute on-demand bleeding episode treatment while on prophylactic marstacimab therapy at the doses studied. Disclosures Nayak: Pfizer Inc.: Current Employment, Other. Raje:Pfizer Inc.: Current Employment, Other. Teeter:Pfizer Inc.: Current Employment. Harnisch:Pfizer Inc.: Current Employment, Other. Arkin:Pfizer: Current Employment, Current equity holder in publicly-traded company, Other: own stock/options in the company.

Potential Usefulness of D-Dimers Assay in Treated Patients with FVIII Deficiency to Detect a Prothrombotic State

Introduction The D-dimer (DD) assay represents a major biological test for the diagnosis and monitoring of thrombotic conditions. DD testing is usually not performed as part of the routine laboratory management of patients with hemophilia (PWH). There is an increasing concern about the risk of thrombotic complications in PWH, whether related to age, the presence of cardiovascular risk factors, invasive thrombogenic procedures, over-correction of FVIII or FIX, or the administration of new therapeutic agents in particular rebalancing agents such as TFPI-inhibiting molecules or Fitusiran. Arterial and venous thrombotic events have indeed recently been reported in PWH treated with these agents. It is therefore important to have simple, easily accessible biological tests available to detect and monitor the development of any prothrombotic condition in PWH with these agents and at increased risk of thrombosis. Baseline DD concentrations in PWH have not been extensively studied yet. Patients and methods We prospectively measured over a 18 months period the DD level in all consecutive PWH with hemophilia A (PWHA) in routine clinics outside bleeding episode, invasive procedure or acute medical or surgical problems. A total of 65 adult PWHA (17-76 yr) with severe (58) to moderate (n=7) disease without inhibitor on replacement therapy with FVIII were included. CRP, fibrinogen, FVIII and VWF levels were also measured at time of DD assay. Results Thirty-three patients had not measurable DD (< 250 ng/ml), 15 had levels below 500 ng/ml, 10 had levels between 500-1000 ng/ml and 7 > 1000 ng/ml. Age>70 (3), smoking (7), arterial vascular disease (2), liver cancer (2) could explain DD > 500 ng/ml in 15/17 patients. Conclusions Most PWHA on replacement therapy with FVIII had low or unmeasurable DD levels. The reasons for high DD level in PWHA do not differ from the general population. In most PWAH, the DD assay could be a useful tool to detect prothrombotic state, potentially related to hemophilia therapies. Disclosures Hermans: Bayer:Consultancy, Research Funding, Speakers Bureau;Pfizer:Consultancy, Research Funding, Speakers Bureau;Shire, a Takeda company:Consultancy, Research Funding, Speakers Bureau;Sobi:Consultancy, Research Funding, Speakers Bureau;Biogen:Consultancy, Speakers Bureau;CAF-DCF:Consultancy, Speakers Bureau;CSL Behring:Consultancy, Speakers Bureau;LFB:Consultancy, Speakers Bureau;Novo Nordisk:Consultancy, Speakers Bureau;Roche:Consultancy, Speakers Bureau;Octapharma:Consultancy, Speakers Bureau;Kedrion:Speakers Bureau;EAHAD:Other;WFH:Other.