Anti-inhibitor Coagulant Complex Research Articles

Economic analysis of the use of drugs for the treatment of hemophilia A, B and Willebrand's disease

Relevance. Therapy of hemophilia A, B and Willebrand's disease is carried out under the program of 14 VZN due to the use of federal budget funds. The use of funding is increasing in line with the growth of the total number of patients. In 2022,85.99 billion rubles were allocated, which corresponds to a 1.5‑fold increase in funding compared to 2018. The aim of the study was to conduct an economic analysis of the use of drugs for the therapy of hemophilia A, B and Willebrand's disease. Methods. The materials for the analysis were the dosing regimen of LPs selected on the basis of clinical recommendations, the availability of LPs in the 14 VZN program, and the prices for LPs from the State Register of maximum selling prices for VED drugs. Costs of on demand prophylaxis and treatment regimens for hemophilia A, B and Willebrand's disease according to clinical recommendations for each INN for all trade names (TN) were assessed. Results. For hemophilia A the number of submitted drugs by INN is 7;IN — 14; of them domestic drugs were submitted — 1. The minimum cost of LPs for prophylaxis is 2 584 764,00 rubles. Coit-DVI (Grifols Therapeutics LLC, USA), and the maximum cost is RUR 9,955,517.21. Advait (Takeda Manufacturing AG, Austria). Forhemophilia B, the number of represented PL — 2 INN; INN — 6; domestic drugs — 2. The minimum cost is RUR 1,559,376.00. Innonafactor (AO Generium, Russia), maximum — 3 079 319,88 rubles for a year course of prophylaxis LP Immunin (TakedaManufacturing, Austria). To stop bleeding in patients with inhibitor form use anti-inhibitor coagulant complex (Feiba, Austria), which is necessary on average 9100 units per 1 patient, and the average cost of application — 430 863,52 rubles or eptacog alpha(activated) (Coagil-VII, Russia) at multiple administration to the patient 6 times a day — maximum cost — 2 739 803,64 rubles or once a day — 293 550,35 rubles. Conclusion. In the structure of drug supply for patients with hemophilia, domestic drugs are represented by 5 names: Octofactor (JSC "Generium", Russia); Agemfil B (FGBU "NMIC Hematology" of the Ministry of Health of Russia, Russia) and Innonafactor (JSC "Generium", Russia); ArioSaven (LLC "PSK Pharma", Russia) and Coagil-VII (JSC "SG Biotech", Russia). There are no domestic drugs available for the therapy of Willebrand's disease.

Laparoscopic appendectomy in a child with hemophilia A with inhibitors receiving prophylactic treatment with emicizumab

Surgeries in patients treated prophylactically with emicizumab (including surgical procedures with a high risk of postoperative bleeding) are not associated with higher risks or technical difficulties compared with operations in patients receiving standard replacement therapy. On the contrary, the presence of emicizumab in the blood and its maintenance of permanent basic hemostasis allow for the reduction of doses and infusion time of bypassing agents. Patients undergoing surgical procedures with a high risk of postoperative bleeding require an additional hemostatic treatment during the first two or three days after the surgery. Then the duration of hemostatic treatment should be determined individually. We recommend the use of recombinant activated factor VII for the prevention/control of postoperative bleeding in patients with hemophilia A with inhibitors who are currently receiving emicizumab or have received it in the past 6 months. If treatment with anti-inhibitor coagulant complex is required, the daily dose should not exceed 100 units/kg. Here we report the first case of laparoscopic appendectomy in an 8-year-old child with hemophilia A with inhibitors receiving prophylactic treatment with emicizumab. The patient's parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

Laparoscopic appendectomy in a child with hemophilia A with inhibitors receiving prophylactic treatment with emicizumab

Surgeries in patients treated prophylactically with emicizumab (including surgical procedures with a high risk of postoperative bleeding) are not associated with higher risks or technical difficulties compared with operations in patients receiving standard replacement therapy. On the contrary, the presence of emicizumab in the blood and its maintenance of permanent basic hemostasis allow for the reduction of doses and infusion time of bypassing agents. Patients undergoing surgical procedures with a high risk of postoperative bleeding require an additional hemostatic treatment during the first two or three days after the surgery. Then the duration of hemostatic treatment should be determined individually. We recommend the use of recombinant activated factor VII for the prevention/control of postoperative bleeding in patients with hemophilia A with inhibitors who are currently receiving emicizumab or have received it in the past 6 months. If treatment with anti-inhibitor coagulant complex is required, the daily dose should not exceed 100 units/kg. Here we report the first case of laparoscopic appendectomy in an 8-year-old child with hemophilia A with inhibitors receiving prophylactic treatment with emicizumab. The patient's parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

Extracorporeal membrane oxygenator as a bridge to heart–liver en bloc transplant in a patient with Fontan circulation

Extracorporeal membrane oxygenator as a bridge to heart–liver en bloc transplant in a patient with Fontan circulation

Analysis of nationwide hemophilia care: A cohort study using two Japanese healthcare claims databases.

Background and aimsIn many developed countries, hemophilia care is provided by specialized centers which can offer standardized high‐quality care for patients and collect data for patient registries. However, in countries with less centralized provision of hemophilia care, registry data lacks accuracy and medical care is inconsistent among providers. Claims databases can be an alternative for obtaining nationwide data on hemophilia care, and we applied this approach to evaluate inequalities in hemophilia care in Japan.MethodsMedical records of hemophilia A patients were collected by a combination of ICD‐10 code (D66) and prescribed coagulation factors from two major Japanese claims databases (JMDC and Medical Data Vision [MDV]). Patient records with an anti‐inhibitor coagulant complex were excluded.Based on the annual number of hemophilia A patients, medical facilities were categorized into specialized facilities (SP, ≥5 patients) and nonspecialized facilities (N‐SP, <5 patients). Patient age, comorbidities, diagnostic testing, prescribed drugs and their dosages were compared between facility types.ResultsThe JMDC and MDV databases included 274 and 1266 hemophilia A patients, respectively. In the MDV database, SP facilities prescribed extended half‐life factor VIII (FVIII) products for more patients (31.8% vs 24.3%) than N‐SP. The mean annual FVIII consumption per patient was higher in SP facilities (240 333 IU [international units] vs 210 334 IU), and the mean FVIII dosage was higher in SP facilities for all types of FVIII products. The proportion of patients who received diagnostic blood tests was higher in SP (75.7% vs 56.2%).ConclusionThe MDV database revealed disparities in hemophilia A care between SP and N‐SP facilities in types of FVIII products prescribed, FVIII consumption, and frequency of the relevant management such as blood tests. Claims databases can be an alternative for the assessment of nationwide hemophilia care patterns in countries without a well‐established registry.

Outcomes of activated prothrombin complex concentrate for direct Xa inhibitor bleeding

Bleeding due to oral anticoagulant therapy is recognized as a high priority drug safety problem [ [1] FDA Adverse Events Reporting System (FAERS)Latest Quarterly Data Files (2017) Food and Drug Administration Web Site. 2021 Google Scholar ]. As the use of direct Xa inhibitors continues to expand, the management of bleeding is an important issue. Andexanet, a modified human factor Xa decoy reversal agent for apixaban or rivaroxaban associated bleeding, is available in some countries however concerns with its use have been expressed [ [2] Peled H. Dau N.Q. Lau H. Key points to consider when evaluating andexxa for formulary addition. Neurocrit. Care. 2020; 33: 20-24 Crossref PubMed Scopus (7) Google Scholar ]. Four factor prothrombin complex concentrate (4FPCC) is an alternative reversal agent which has been used off-label for direct Xa inhibitor bleeding [ 3 Steffel J. et al. The 2018 european heart rhythm association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur. Heart J. 2018; 39: 1330-1393 Crossref PubMed Scopus (1060) Google Scholar , 4 Witt D.M. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018; 2: 3257-3291 Crossref PubMed Scopus (188) Google Scholar ]. Four factor PCC is available either as an activated or non-activated product. Limited clinical data exist evaluating activated 4FPCC, FEIBA [anti-inhibitor coagulant complex®, Baxalta US Inc., Lexington MA, USA] as a reversal agent [ 5 Engelbart J.M. et al. Safety and effectiveness of factor eight inhibitor bypassing activity for direct oral anticoagulant-related hemorrhage reversal. Am. J. Emerg. Med. 2019; 37: 214-219 Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar , 6 Mao G. et al. Factor eight inhibitor bypassing agent (FEIBA) for reversal of target-specific oral anticoagulants in life-threatening intracranial bleeding. J. Emerg. Med. 2017; 52: 731-737 Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar ]. As andexanet is not on formulary, the reversal protocol at our institution recommended the use of activated 4FPCC 25–50 IU/kg for direct Xa inhibitor bleeding for situations where reversal is desired. Our goal was to assess the patient characteristics, management and outcomes of activated 4FPCC for reversal of apixaban or rivaroxaban acute bleeding events.

Use of Factor VIIa and Anti-inhibitor Coagulant Complex in Pediatric Cardiac Surgery Patients

Postoperative bleeding is a common cause of morbidity and mortality in cardiac patients who undergo cardiopulmonary bypass (CPB). Pediatric patients are especially at risk for adverse effects of surgery and CPB on the coagulation system. This can result in bleeding, transfusions, and poor outcomes. Excessive bleeding unresponsive to blood products can warrant the off-label use of recombinant activated clotting factor VIIa (rFVIIa) and/or anti-inhibitor coagulant complex (FEIBA). Several studies have shown the utility in these agents off-label in patients who have undergone cardiac bypass surgery with acute bleeding episodes that are refractory to blood products. However, data regarding use of these agents in pediatrics are sparse. The purpose of this study is to report the use of rFVIIa and FEIBA in pediatric cardiac surgery patients in our institution. This was a retrospective chart review of pediatric cardiothoracic surgery patients who received rFVIIa or FEIBA at Children's Healthcare of Atlanta during the study period. Thirty-three patients received rFVIIa and 9 patients received FEIBA either intraoperatively or postoperatively for bleeding related to the cardiac procedure. Approximately 13% of rFVIIa patients and 55% of FEIBA patients required repeat doses. There were decreases for all blood products administered after rFVIIa and FEIBA were given. However, the doses used did not correlate with either positive or negative outcomes. Seventeen percent (n = 7) of rFVIIa patients experienced a thrombus and 22% (n = 2) of FEIBA patients experienced a thrombus. Both rFVIIa and FEIBA reduced blood product usage in pediatric patients following cardiac procedures.

Transfusion Outcomes in Patients Undergoing Unifocalization and Repair of Tetralogy of Fallot With Major Aortopulmonary Collaterals.

Surgical repair of tetralogy of Fallot and major aortopulmonary collaterals (TOF/MAPCAs) involves unifocalization of MAPCAs and reconstruction of the pulmonary arterial circulation. Surgical and cardiopulmonary bypass (CPB) times are long and suture lines are extensive. Maintaining patency of the newly anastomosed vessels while achieving hemostasis is important, and assessment of transfusion practices is critical to successful outcomes. Clinical, surgical, and transfusion data in patients with TOF/MAPCAs repaired at our institution (2013-2018) were reviewed. Types and volumes of blood products used in the perioperative period, in addition to the use of antifibrinolytics and/or procoagulants (factor VIII inhibitor bypassing activity [FEIBA]; anti-inhibitor coagulant complex), were assessed. Outcome measures included days on mechanical ventilation (DOMV), postoperative intensive care unit and hospital length of stay (LoS), and incidence of thrombosis. Perioperative transfusion data from 279 patients were analyzed. Surgical (879 ± 175 minutes vs 684 ± 257 minutes) and CPB times (376 ± 124 minutes vs 234 ± 122 minutes) were longer in patients who received FEIBA than those who did not. Although the indexed volume of packed red blood cells (128.4 ± 82.2 mL/kg) and fresh frozen plasma (64.2 ± 41.1 mL/kg) was similar in patients who did and did not receive FEIBA, the amounts of cryoprecipitate (5.5 ± 5.2 mL/kg vs 5.8 ± 4.8 mL/kg) and platelets (19.5 ± 20.7 mL/kg vs 20.8 ± 13 mL/kg) transfused were more in those who did receive FEIBA. Perioperative transfusion is an important component in the overall surgical and anesthetic management of patients with TOF/MAPCAs. The intraoperative use of FEIBA was not associated with a decrease in the amount of blood products transfused, DOMV, or LoS or with an increase in thrombotic complications.

PRO17 A BUDGET IMPACT ANALYSIS OF ANTI-INHIBITOR COAGULANT COMPLEX USE IN PEDIATRIC HEMOPHILIA A PATIENTS WITH INHIBITORS ACROSS KINGDOM OF SAUDI ARABIA.

Hemophilia is rare genetic disorder affecting blood’s ability to clot due to clotting factor deficiency. Hemophilia A (HA), the most common form of Hemophilia, is due to factor VIII (FVIII) deficiency. HA treatment options include plasma-derived or recombinant-FVIII concentrates. Approximately 30% of HA patients develop inhibitors against FVIII concentrates. Patients with inhibitors are usually managed using bypassing agents, e.g., Anti-Inhibitor Coagulant Complex (ACC) or recombinant human coagulation Factor VIIa. (rFVIIa). In 2016, the Kingdom of Saudi Arabia (KSA) reported 31 pediatric HA inhibitor patients, among whom 26 patients were treated in the ministry of health (MOH) facilities. To assess the budget impact (BI) of switching MOH pediatric HA patients with inhibitors from-rFVIIa to ACC both as prophylaxis and an on-demand therapy. A global BI excel model was adapted from payer’s perspective. Model inputs were retrieved from literature and validated by key experts through face-to-face interviews. The model was adapted for two scenarios: Switching patients from (1) rFVIIa prophylaxis therapy to ACC prophylaxis therapy and (2) rFVIIa on-demand therapy to ACC on-demand therapy. The model considered direct costs such as drug acquisition, drug administration and bleeding episodes management. A sensitivity analysis was performed to assess the robustness of the results. The BI analysis showed that switching patients from rFVIIa prophylaxis to ACC prophylaxis would result in three times (-112 million Saudi Riyal [SAR]) and eight times (-418 million SAR) savings in the annual payers’ budget using rFVIIa standard dose and megadose. Similarly, switching patients from rFVIIa on-demand to ACC on-demand therapy would result in approximately 1.5 times (-15 million SAR) savings in the payers’ budget. Switching pediatric HA patients with inhibitors from rFVIIa to ACC as prophylaxis and on-demand therapies could be cost saving options for KSA payers thereby freeing more resources for other diseases management.

Comparison of extended to standard half-life recombinant factor VIII therapy in patients with hemophilia A on prophylactic therapy

Background: Hemophilia A is a genetic bleeding disorder caused by a deficiency in factor VIII (FVIII). FVIII maintains bleeding homeostasis within the body through its downstream effects on the intrinsic clotting cascade. The extent of the disease – mild, moderate or severe – depends on the amount of available FVIII in the blood. Patients with severe disease (FVIII levels <1%) experience spontaneous bleeds into the joints or muscles causing pain, inflammation and discomfort. Left untreated, this may lead to long-term complications such as joint damage, chronic pain or joint replacements. Treatment of hemophilia A involves replacing FVIII through either on-demand or prophylactic infusion of antihemophilic FVIII products. On-demand treatment involves infusing the FVIII product at the time of a bleed to stop the event. Prophylactic therapy is the routine replacement of FVIII to prevent bleeds from occurring. The Medical and Scientific Advisory Council recommends the use of a prophylactic regimen, particularly in patients with severe disease, to maintain FVIII levels above 1%. This has been shown to reduce bleeds and joint damage over on-demand treatment, and may have the potential to improve health outcomes. Prophylactic treatment with standard half-life (SHL) rFVIII products are typically infused three to four times a week due to an approximate half-life of 8-12 hours. This can have a great impact on patient quality of life, adherence to therapy and treatment outcomes. Improved technology such as PEGylation and fragment-crystallization (Fc) immunoglobulin protein fusion introduced rFVIII products with a half-life of 1.5 to 1.8 times that of standard therapies. These extended half-life (EHL) rFVIII products maintain FVIII levels similar to SHL rFVIII products with an infusion frequency of once to twice weekly. This may present an opportunity for patients to achieve the clinical benefit of prophylactic treatment without the potential limitations and burden of treatment with SHL rFVIII products. EHL rFVIII products have demonstrated efficacy for prophylactic therapy by reducing bleed rates in patients with hemophilia A, particularly in many clinical trials. However, the benefit of using EHL over SHL rFVIII products for prophylactic therapy has not been universally established, and there is no recommendation for one product over the other. A few studies have indirectly compared EHL and SHL rFVIII products or have looked at patient outcomes and bleed rates after switching from SHL to EHL rFVIII products. Limited studies currently exist that directly compare treatment outcomes between EHL and SHL rFVIII products in a real-world patient population. Aims: The primary objective of this study was to compare annualized bleed rates (ABRs) of hemophilia A patients on prophylactic therapy prescribed either EHL or SHL antihemophilic rFVIII products. Secondary objectives were to compare quality of life outcomes (pain, missed school or work, use of mobility accessories, and hospitalizations), monthly factor utilization, cost, monthly insurance coverage amounts and monthly patient copays. Methods: Specialty pharmacy records of patients taking an FDA approved SHL or EHL rFVIII product for the prophylactic treatment of hemophilia A were retrospectively reviewed from 1 January 2017 to 31 December 2018. Data was collected from pharmacy dispensing software, therapy management programs, and chart notes provided from Hemophilia Treatment Centers (HTCs), doctors’ offices and/or home infusion nurses. Data included demographic information, patient reported bleed history, missed work or school, pain, hospitalizations, factor utilization and cost of treatment. Patients were excluded if they were being treated for an inhibitor with immune tolerance therapy (ITT), coagulation factor VIIa (recombinant) (NovoSeven1), anti-inhibitor coagulant complex (Feiba2) or emicizumab-kxwh (Hemlibra3). A secondary analysis was also done to compare the individual EHL rFVIII products to the SHL group. Mann–Whitney and independent t-test statistical data analysis was completed utilizing SPSS software4. Study approval was obtained from the Duquesne University Institutional Review Board. Results: Patients prescribed EHL rFVIII products had a statistically significant lower ABR than those prescribed SHL rFVIII products (p = .005). No statistically significant difference was found in monthly factor utilization (p = .824) or quality of life outcomes between products. EHL rFVIII products were significantly more costly than SHL rFVIII products (p = .035). Monthly insurance coverage amounts and patient copays were similar between the groups. Conclusion: Patients prescribed EHL rFVIII products had a statistically significant lower ABR than those prescribed SHL rFVIII products (p = .005). No statistically significant difference was found in monthly factor utilization (p = .824) or quality of life outcomes between products. EHL rFVIII products were significantly more costly than SHL rFVIII products (p = .035). Monthly insurance coverage amounts and patient copays were similar between the groups.

Unsolved issues of providing medical care to patients with hemophilia with inhibitors in Russia

The implementation of the state program “7 highcost nosologies” and the active work of Russian hematologists have significantly improved the specialized care for children and adults with Hemophilia. Russian hemophilia patient registry as of 10.25.2018 contained information about 7433 patients, of whom with hemophilia A – 6525 people. About 400 people were diagnosed with hemophilia with inhibitors. The inhibitor predominantly appeared at child and young age (up to 20 years). There is a high supply of coagulation factors concentrates for the treatment of hemophilia in the Russian Federation – 8.1 IU of coagulation factor VIII per capita in 2018, which corresponds to the graduation “full integration into society” according to the scale proposed by the World Hemophilia Federation. Due to the sufficient availability of coagulation factors, it is possible to conduct elimination of inhibitors by immune tolerance induction. Treatment with antiinhibitor coagulant complex and eptacog alfa (activated) requires a good venous access and is not always effective. Treatment results remain unsatisfactory in 67 % of adult patients with severe hemophilia with low inhibitor titer due to the number of bleeding per year exceeds 4. Unsatisfactory treatment results are noted in more than 1/ 3 patients with a high inhibitor titer, despite the ongoing prophylaxis with bypassing agents. Currently, clinical studies of fundamentally new drugs for hemophilia treatment, including the inhibitory form, are ongoing. One such drug is emicizumab, which is a bispecific humanized monoclonal antibody that bridges activated factor IX and factor X to restore the function of missing activated factor VIII Emicizumab is not neutralized by inhibitors to FVIII, which allows it to be successfully used in the inhibitory form of hemophilia A. The results of HAVEN 1 and HAVEN 2 studies showed the advantages of using emicizumab in prophylactic regimen in children and adults with the inhibitory form of hemophilia A compared with bypassing agents.

Thromboembolic event rate in patients exposed to anti-inhibitor coagulant complex: a meta-analysis of 40-year published data.

Anti-inhibitor coagulant complex (AICC), an activated prothrombin complex concentrate, has been available for the treatment of patients with inhibitors since 1977, and thromboembolic events (TEEs) have been reported after infusion of AICC in patients with congenital or acquired hemophilia. With the aim of estimating the TEE incidence rate (IR) related to AICC exposure in these patients, a systematic review of the literature was carried out in Medline, according to PRISMA guidelines, from inception date to March 2017. The IR of TEEs was estimated through a meta-analytic approach by using a generalized linear mixed model based on a Poisson distribution. Thirty-nine studies were included (1980-2016). Overall, 46 TEEs were reported; of these, 13 were reported as disseminated intravascular coagulations, 11 as myocardial infarctions, and 3 as thrombotic cerebrovascular accidents. The pooled TEE IR was 2.87 (95% confidence interval [CI], 0.32-25.40) per 100 000 AICC infusions (5.42 in retrospective studies [95% CI, 0.92-31.82]; 1.09 in prospective studies [95% CI, 0.01-238.77]). The TEE rate was 5.09 (95% CI, 0.01-1795.60) per 100 000 AICC infusions administered on demand, whereas no TEEs were reported with prophylaxis. Interestingly, the estimated IR in patients with congenital hemophilia was <0.01 per 100 000 infusions. These findings provide robust evidence of safety of AICC over almost 40 years of published studies.

Secondary prophylaxis with anti-inhibitor coagulant complex (AICC) : from anecdote to reality.

Background. Evidence of prophylaxis benefit in patients without inhibitors to reduce hemarthrosis and severe bleeding have not been demonstrate in patients with hemophilia A (HA) and inhibitors, however, we could assume the reduction in bleeding episodes. Several publications have shown good results of secondary prophylaxis with AICC agents to reduce safely the number of bleeding events. We report the results in hemophilia treatment centers of two cities in a developing country, with access difficulties related to the high cost of this therapy to the health system. Objective. To describe the frequency of hemarthrosis and other bleeding episodes in patients with HA and inhibitors under AICC (Feiba®) prophylaxis.

Анализ «влияния на бюджет» применения шунтирующих препаратов антиингибиторный коагулянтный комплекс и эптаког альфа [активированный] при профилактике развития кровотечений у пациентов с ингибиторной формой гемофилии

Анализ «влияния на бюджет» применения шунтирующих препаратов антиингибиторный коагулянтный комплекс и эптаког альфа [активированный] при профилактике развития кровотечений у пациентов с ингибиторной формой гемофилии

Postpartum-acquired hemophilia: A challenging disease to manage

Acquired hemophilia is a severe bleeding diathesis that affects both males and females. It is caused by suddenly appearing autoantibodies that interfere with the coagulation factor VIII activity. This disorder is characterized by spontaneous and post-traumatic subcutaneous bleeds and massive mucosal hemorrhages. We report a case of postpartum-acquired hemophilia with a compartment syndrome of right (Rt.) forearm in a 29-year-old woman. Hemostatic tests indicated a prolonged activated partial thromboplastin time (APTT) to 99 s (normal 30.4–40 s), the prothrombin time was 7.8 s (normal 12–14 s), and the platelet count was 271,000 (normal 155,000–450,000). Further workup demonstrated the presence of autoantibody against factor VIII in a titer of 15 Bethesda Units/ml (BU/ml) and a decreased factor VIII activity to 0.04 IU/ml (normal 0.6–1.5 IU/ml). Immunosuppressive treatment with oral prednisone at 60 mg/24 h was initiated, but she was refractory to steroids; therefore, rituximab was added on a weekly basis for 4 weeks. At the same time, factor eight inhibitor bypassing activity (FEIBA), an anti-inhibitor coagulant complex, has been used as a bypassing agent. Reduction of the factor VIII inhibitor titer to 0 BU/ml and an increase of factor VIII activity to 0.38 were achieved. This led to normalization of hemostatic parameters (APTT 38.9 s, factor VIII activity 0.38).

Co-Administration of Factor XIII with Hemostatic Agents in Hemophilia Promotes Clot Stability and Composition

Hemophilia A results from the absence, deficiency, or inhibition of factor VIII. Bleeding is treated with use of two broad classes of hemostatic agents; replacement factors (recombinant or plasma-derived human FVIII [FVIII] or factor IX) or bypassing agents (recombinant activated factor VIIa [rFVIIa], plasma-derived anti-inhibitor coagulant complex [FEIBA], or recombinant porcine FVIII [rpFVIII]). Despite treatment with hemostatic agents, some hemophilia patients experience refractory bleeding. Factor XIII-A2B2 (FXIII) is a thrombin-activated protransglutaminase. Activated FXIII (FXIIIa) crosslinks fibrin to stabilize clots and increase red blood cell retention during clot contraction, and therefore, clot weight; these functions have been specifically associated with fibrin alpha-chain crosslinking and production of high molecular weight (HMW) crosslinked fibrin species. Although pilot studies have indicated that in hemophilia co-administration of FXIII with hemostatic agents improves hemostasis, the biochemical mechanisms evoked during co-administration have yet to be elucidated. We hypothesize that co-administration of FXIII with hemostatic agents enhances hemostasis in hemophilia by accelerating FXIII activation, increasing fibrin crosslinking, and improving the composition of contracted clots.We first analyzed in vitrotissue factor-activated coagulation in FVIII-deficient plasmas (n=5) with or without buffer (normal saline with 0.75% bovine serum albumin), plasma-derived FXIII (2 U/mL), and/or recombinant human FVIII (1 U/mL). Reactions were performed at 37°C and quenched with urea/EDTA at varying time points. Clot lysates were separated on 10% Tris-glycine gels, blotted, probed for FXIII(a) and fibrin(ogen), and analyzed by densitometry. Compared to buffer, FXIII, or FVIII-treated hemophilic plasma, FVIII+FXIII co-treatment increased the formation rate and level of FXIIIa. Furthermore, compared to buffer or FXIII-treated hemophilic plasma, both FVIII-treatment and FVIII+FXIII co-treatment increased the formation rate and level of crosslinked fibrin species (gamma chain and HMW species). Notably, compared to FVIII-treatment (alone), FVIII+FXIII co-treatment increased the formation rate and level of HMW crosslinked fibrin species.Next, we analyzed clot formation in whole blood obtained from untreated FVIII-deficient (n=2) or FVIII-inhibitor (n=6) patients. Citrated whole blood was pre-incubated at 37°C for 30 minutes with or without buffer, FXIII (2 U/mL), rFVIIa (25 nM), FEIBA (1 U/mL), or rpFVIII (1 U/mL), alone and in combination with FXIII, and clot formation was triggered with tissue factor and recalcification. In thrombelastography assays, compared to buffer or FXIII-treated hemophilic whole blood, rFVIIa, FEIBA, and rpFVIII treatments alone or with FXIII co-treatment shortened the time to clot formation (clot time [R]). Compared to buffer, FXIII, FEIBA or rpFVIII-treated hemophilic whole blood, rFVIIa-treatment (alone) and co-treatment with rFVIIa+FXIII or FEIBA+FXIIII increased clot stability (area under the elastic curve). In whole blood clot contraction assays, compared to buffer, FXIII, rFVIIa, FEIBA, or rpFVIII-treated hemophilic whole blood, co-treatment with rFVIIa+FXIII, FEIBA+FXIII, or rpFVIII+FXIII significantly increased clot weight.Our data show that in hemophilic plasmas, co-administration of FXIII with hemostatic agents accelerates FXIIIa activation, resulting in accelerated and increased HMW species formation. Furthermore, in hemophilic whole blood, co-administration of FXIII with hemostatic agents improved clot biophysical characteristics and increased clot weight. Collectively, these data suggest co-administration of FXIII with conventional hemostatic agents may promote clot stability and improve the composition of contracted clots by enhancing fibrin alpha-chain crosslinking. DisclosuresNo relevant conflicts of interest to declare.

Should anti-inhibitor coagulant complex and tranexamic acid be used concomitantly?

Inhibitor development in haemophilia patients is challenging especially when undergoing surgical procedures. The development of an inhibitor precludes using factor VIII (FVIII) therapy thereby requiring a bypassing agent (BPA) for surgical bleeding prophylaxis if the FVIII inhibitor titre >5BU. Concomitant use of anti-inhibitor coagulant complex (AICC) and tranexamic acid has been reported in the literature as a beneficial treatment for this population. Anti-inhibitor coagulant complex is known to cause an increase in thrombin generation and tranexamic acid inhibits fibrinolysis. Hence, the combined used of AICC and tranexamic acid has been limited due to safety concerns over possibilities of increased risk of thrombotic events and disseminated intravascular coagulation. However, the rationale for concomitant therapy is to obtain a potential synergistic effect and to increase clot stability. We conducted a literature review of past studies and individual case reports of concomitant use of AICC and tranexamic acid, which was extensively used during dental procedures. Evidence also exists for concomitant use of the combined therapy in orthopaedic procedures, control of gastrointestinal bleeding, epistaxis and cerebral haemorrhages. Some patients who received the combined therapy had failed monotherapy with a single BPA prior to combined therapy. There were no reports of thrombotic complications related to the concomitant therapy and haemostasis was achieved in all cases. Anti-inhibitor coagulant complex and tranexamic acid therapy was found to be safe, well-tolerated and effective therapy in haemophilia patients with inhibitors. Additional randomized controlled studies should be performed to confirm these findings.

A Case Series Evaluating the Use of a Von Willebrand Factor/Factor VIII Concentrate (Wilate®) for Immune Tolerance Induction (ITI) in Children with Severe Factor VIII Deficiency

Introduction: Development of circulating anti-factor VIII antibodies (inhbitors) is the most serious and challenging complication in the treatment of hemophilia A. Up to 38% of hemophilia patients develop inhibitors with recombinant FVIII (rFVIII) products (Gouw et al. N Engl J Med. 2013; 368:231-239). The presence of inhibitors leads to an increased risk of bleeding, poor physical functioning and quality of life (Benson et al., Eur. J. Haematol. 2012; 88:371-379). Immune tolerance induction (ITI) is the most common method for eliminating inhibitors, historically performed with high dose, and prolonged treatment with plasma-derived (pd), or recombinant FVIII (rFVIII) concentrates. Although ITI for the eradication of inhibitors has become standard of care for hemophilia patients the therapeutic superiority of a particular product type (rFVIII vs. pd-FVIII) has not yet been conclusively demonstrated. In accordance with its role in stabilizing FVIII, the presence of von Willebrand factor (VWF) in pd-FVIII concentrates has been shown to improve the outcome of ITI. Wilate® (Octapharma) is a high-purity human plasma derived complex containing two proteins (VWF and FVIII) in a 1:1 ratio. The aim of this study was to determine the effectiveness of Wilate for primary ITI therapy for six patients with severe hemophilia A.Patients and Methods: The case history for six pediatric hemophilia A patients prior to and during primary Wilate ITI was reviewed. For 5/6 patients, inhibitors developed during rFVIII factor replacement therapy. For the sixth patient, inhibitors were detected at the time of hemophilia diagnosis. ITI began once patients achieved an inhibitor titer of less than 10 BU/mL. The ITI dosing regimen ranged from 50-60 IU/Kg of Wilate three times per week to 200 IU/Kg once daily. Inhibitor titers were measured regularly, prior to and during ITI using the Nijmegen-Bethesda assay. The number of port-a-cath infections and bleeding episodes were also monitored. ITI success was defined as: an undetectable inhibitor level (<0.6 BU/mL), FVIII plasma recovery ≥ 66% of predicted, and FVIII half-life ≥6 hours.Results: Wilate ITI was well tolerated in all patients, with no product-related adverse events. All patients had a port-a-cath device inserted for Wilate injections. Two port-a-cath infections occurred during ITI. Five of six patients had poor prognostic factors for ITI outcome. These poor prognostic factors included a high-risk FVIII gene mutation, historical peak inhibitor titer greater than 50 BU/mL, age of ITI onset greater than 6 years, and ITI onset more than 12 months from inhibitor development. The frequency of these poor prognostic factors varied amongst the patients: 1 patient had 4, 1 patient had 2, and 3 patients presented with 1 poor prognostic factor. Despite the presence of these high-risk factors, Wilate was successful at reducing the inhibitor titers to undetectable levels in all patients. Furthermore, inhibitor titers have remained low or undetectable without significant spikes for the duration of treatment. Patient plasma recovery and FVIII half-life results have also indicated that patients are progressing towards successful ITI. Importantly, for 6/6 patients (including 3 patients who had previously been treated with Anti-Inhibitor Coagulant Complex (FEIBA) prophylaxis therapy) - Wilate therapy was successful at reducing the number of bleeding episodes allowing for the cessation of FEIBA prophylaxis. Since commencing Wilate ITI, 6/6 patients have not reported any major bleeding episodes. The improved clinical outcome was perceived by the patients as an improved well-being, and quality of life.Conclusion: Wilate ITI was found to be well tolerated, safe, and successful at reducing inhibitor levels to below the detectable range for six severe hemophilia A patients. Patients experienced no treatment related adverse events, had a low rate of port-a-cath infections, and did not present with any major bleeding episodes while on Wilate ITI. In light of the 3-5 fold increase in overall treatment costs of immune tolerance induction, careful consideration should be given to choice of product (rFVIII versus pd-FVIII) – especially for patients at high-risk of failure. (Dimichele et al. Haemophilia 2004: 10 Suppl 4;140-145). The present data suggest that Wilate, a pd-FVIII product, is effective in managing patients with inhibitors. DisclosuresBelletrutti:Baxter Canada: Honoraria, Membership on an entity’s Board of Directors or advisory committees; CSL Behring Canada: Honoraria.

Ferric Carboxymaltose

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, call The Formulary at 800-322-4349. The January 2014 monograph topics are obinutuzumab, anti-inhibitor coagulant complex, macitentan, riociguat, and conjugated estrogens/bazedoxifene. The DUE/MUE is on conjugated estrogens/bazedoxifene.

PSY9 - Pharmacoeconomic Analysis of Anti-Inhibitor Coagulant Complex (AICC) in the Treatment of Inhibitor Hemophilia

PSY9 - Pharmacoeconomic Analysis of Anti-Inhibitor Coagulant Complex (AICC) in the Treatment of Inhibitor Hemophilia