Clotting Factor Replacement Research Articles

Hepatectomy in patients with inherited blood coagulation disorders can be safely performed with adequate coagulation factor replacement.

Haemophilia and von Willebrand disease (VWD) are common inherited bleeding disorders. Although patients with haemophilia or VWD have a high risk of hepatitis virus infection and hepatocellular carcinoma (HCC), little is known about the safety of liver resection in these patients. From 2006 to 2016, there were seven hepatectomies with haemophilia A and three hepatectomies with VWD for malignant liver tumours at tertiary care hospitals in Japan and Switzerland. To evaluate the safety of hepatectomy in the blood coagulation disorder group (BD group), short-term outcomes in these patients were compared with 20 hepatectomies (non-BD group) for HCC, matched to a 2:1, operative procedure, period and background liver. Ten liver resections were performed in patients with haemophilia or VWD with administration of recombinant FVIII or VWF concentrate. Comparison of the BD vs non-BD group revealed no significant differences in the operative time (327 vs 407minutes, P=0.359), estimated blood loss (730 vs 820mL, P=0.748), red blood cell transfusion rate (10.0% vs 5.0%, P=0.605), major complication rate (Clavien-Dindo grade III or IV) (10.0% vs 5.0%, P=0.605) or mortality rate (0% vs 0%, P>0.999). Additionally, the length of the postoperative hospital stay was similar between the two groups (13 vs 14days, P=0.296). Liver resection for treatment of HCC in patients with haemophilia or VWD can be safely performed through an appropriate perioperative administration protocol of coagulation factors.

Fibrinogen levels measured by the dry hematology method are lower than those measured by the Clauss method under a high concentration of heparin.

ABSTRACTThe activity of fibrinogen has been reported to decrease soon after the onset of major bleeding and to be an important determinant of the final extent of bleeding and postoperative outcome. A device that measures the perioperative fibrinogen level using the dry hematology (DH) method has recently become available. The aim of this study was to compare perioperative fibrinogen levels measured by the DH method with those measured by the conventional Clauss method and to assess the effects of heparin on these measurements. The study included 206 samples from 36 patients undergoing major surgery who received high-dose heparin (HH group, 23 samples), low-dose heparin (LH group, 57 samples), or no heparin (C group, 126 control samples). Each sample was measured using the DH and Clauss methods. After excluding samples outside the effective measurement range, the three study groups (HH group, n=23; LH group, n=49; C group, n=115) were compared. The mean fibrinogen level measured by the DH method in the HH group (87.9 ± 3.1%) was significantly lower than that measured by the Clauss method. There were no significant differences between the fibrinogen measurements obtained by the two methods between the LH and C groups. In patients on high-dose heparin, the mean fibrinogen level measured by the DH method was significantly lower than that measured by the Clauss method. When hemorrhage requires emergency treatment, a method that can measure the fibrinogen level rapidly is important. The DH method may be useful for decision-making with regard to perioperative coagulation factor replacement.

Severe traumatic brain injury is associated with a unique coagulopathy phenotype.

Traumatic brain injury (TBI) patients present on a spectrum from hypocoagulability to hypercoagulability, depending on the injury complexity, severity, and time since injury. Prior studies have found a unique coagulopathy associated with TBI using conventional coagulation assays such as INR; however, few studies have assessed the association of TBI and coagulopathy using viscoelastic assays that comprehensively evaluate the coagulation in whole blood. This study aims to reevaluate the TBI-specific trauma-induced coagulopathy using arrival thrombelastography. Because brain tissue is high in key procoagulant molecules, we hypothesize that isolated TBI is associated with procoagulant and hypofibrinolytic profiles compared with injuries of the torso, extremities, and polytrauma, including TBI. Data are from the prospective Trauma Activation Protocol study. Activated clotting time (ACT), angle, maximum amplitude (MA), 30-minute percent lysis after MA (LY30), and functional fibrinogen levels (FFLEV) were recorded. Patients were categorized into isolated severe TBI (I-TBI), severe TBI with torso and extremity injuries (TBI + TORSO/EXTREMITIES), and isolated torso and extremity injuries (I-TORSO/EXTREMITIES). Poisson regression was used to adjust for multiple confounders. Overall, 572 patients (48 I-TBI, 45 TBI + TORSO/EXTREMITIES, 479 I-TORSO/EXTREMITIES) were included in this analysis. The groups differed in INR, ACT, angle, MA, and FFLEV but not in 30-minute percent lysis. When compared with I-Torso/Extremities, after adjustment for confounders, severe I-TBI was independently associated with ACT less than 128 seconds (relative risk [RR], 1.5; 95% confidence interval [CI], 1.1-2.2), angle less than 65 degrees (RR, 2.2; 95% CI, 1.4-3.6), FFLEV less than 356 (RR, 1.7; 95% CI, 1.2-2.4) but not MA less than 55 mm, hyperfibrinolysis, fibrinolysis shutdown, or partial thromboplastin time (PTT) greater than 30. Severe I-TBI was independently associated with a distinct coagulopathy with delayed clot formation but did not appear to be associated with fibrinolysis abnormalities. Low fibrinogen and longer ACT values associated with I-TBI suggest that early coagulation factor replacement may be indicated in I-TBI patients over empiric antifibrinolytic therapy. Mechanisms triggering coagulopathy in TBI are unique and warrant further investigation. Retrospective cohort study, prognostic, level III.

Tranexamic Acid - Major Antifibrinolytic Agent Used to Achieve Hemostasis in Hemophilic Patients with Anti-Factor VIII Anti-Bodies Who Must Undergo Total Joint Replecement

Hemophilia is a congenital coagulopathy characterized by a deficiency of coagulation factor VIII or IX. The main complication of this hemopathy is represented by the hemorrhagiparous phenomena that affect mainly the musculoskeletal system. Of the various chronic complications of this condition, hemarthrosis is responsible for the onset of chronic arthropathy, which is a disabling condition. In addition to hematologist-prescribed coagulation factor replacement therapy, acute hemarthrosis and chronic arthropathy management requires close collaboration with both orthopedic surgeons and physiotherapists. This multidisciplinary collaboration is essential both to prevent the onset of hemarthroses and to manage acute bleeding episodes, to assess joint function and to effectively treat hemophilic chronic arthropathy. Hemophilic arthropathy causes significant joint instability and reduced mobility or even total ankylosis, which may lead to permanent disability and hence to a decrease in the patient�s quality of life. From an orthopedic point of view, disabling hemophilic arthropathy may be treated by surgery. Achieving effective hemostasis is vital in order to be able to perform these extremely difficult surgical procedures, due to the high risk of bleeding. This paper aims at highlighting the hemostatic efficacy of tranexamic acid in orthopedic surgery in hemophilic patients who must undergo total joint replacement.

Joint Bleeding Tendencies in Adult Patients With Hemophilia: It’s Not All Pharmacokinetics

Hemophilic arthropathy from joint bleeding remains a complication with major morbidity in the increasingly aging patients with hemophilia. Prophylactic clotting factor infusions, based on pharmacokinetic dosing to reduce bleeding rates, are being explored more and more. However, there is little evidence on the benefits of pharmacokinetic dosing in direct association with bleeding events. Here, we prospectively followed a cohort of adult patients with hemophilia A and B (n = 26) and arthropathic joints on various clotting factor products over a period of 2 years with clinical and radiographic joint health assessments, frequent joint ultrasound, and pharmacokinetic studies. Joint bleeds and synovitis with synovial vascularity changes were objectively diagnosed by musculoskeletal ultrasound and power Doppler and analyzed in relation to pharmacokinetic, joint- and patient-specific parameters. Results revealed that, contrary to common beliefs, bleeding episodes were not readily explained by pharmacokinetic features, as they were not associated with more time spent below certain clotting factor thresholds. Joint bleeding was found to be associated with prominent vascularity changes, suggesting that vascular remodeling and leakiness may contribute to joint bleeding that cannot be prevented by clotting factor replacement alone.

Emicizumab, a bispecific antibody mimicking factor VIII: a novel alternative therapy for hemophilia A with inhibitors

Regular prophylaxis using factor (F) VIII products to prevent bleeding in patients with hemophilia A (PWHAs) results in markedly suppressed onset of arthropathy and greatly contributes to improved quality of life. However, some issues remain with the use of clotting factor replacement therapy. The need for multiple intravenous infusions is associated with substantial mental and physical burden, and the inhibitor development results in difficulty of hemostatic management. To overcome these unmet needs, a recombinant humanized anti-FIXa/FX bispecific antibody mimicking FVIIIa function (emicizumab) was created. In phase 1/2 clinical studies, Japanese patients with PWHAs were treated with once-weekly subcutaneous administration of emicizumab. The annual bleeding rates were markedly reduced, irrespective of inhibitor use. A phase 3 global study for PWHA with inhibitor demonstrated a statistically significant efficacy, whereas thrombotic microangiopathy and thromboembolism were reported in 5 patients treated with emicizumab concomitantly with multiple infusions of activated prothrombin complex concentrates. In Japan, emicizumab (HEMLIBRA®) was approved for treatment of PWHAs with inhibitor on March 2018. In conclusion, emicizumab has promising features. Its subcutaneous bioavailability and long half-life (T1/2; approximately 30 days) enable effective bleeding prophylactic treatment at inhibitor status. Additional studies are warranted to establish clinical data on its safety and to define suitable assays for hemostatic monitoring.

A transgender person with haemophilia

Abstract Introduction Transgender people face many obstacles to accessing healthcare but cultural changes are likely to increase provision of sex reassignment surgery in countries with sufficient resources. Haemophilia services traditionally focus on providing factor replacement therapy for males and should therefore understand how the care they provide can be adapted to meet the needs of transgender people. Haemophilia is an X-linked congenital bleeding disorder, caused by deficiency of coagulation factor VIII (haemophilia A) or factor IX (haemophilia B). The condition is passed on through carrier females, the majority of whom have a factor level high enough to allow for normal blood clotting. However, around 10% of carrier females are symptomatic and at risk of abnormal bleeding. Case presentation This case report describes a person with mild haemophilia A who, on first presentation to the haemophilia service, stated he was a transgender person in transition to becoming a male. Haemophilia was diagnosed when heavy bleeding occurred following bilateral mastectomy approximately 25 years previously. He now requested phalloplasty. Management and outcome Phalloplasty was performed at a hospital geographically separate from the haemophilia centre, requiring careful coordination between the two services. A haemophilia specialist nurse provided education and training about haemophilia and its management to the surgical nurses. Twenty-four-hour support was available from the nurse and a specialist doctor. Preparation and administration of clotting factor was the responsibility of the haemophilia nurse until the surgical team was confident in its use. Clotting factor replacement was managed using standard procedures, successfully maintaining factor VIII above a target level of 100% with a twice daily dose. Surgery went well, but wound healing was delayed, in part, due to persistent bleeding. Discussion Close collaboration between the haemophilia and surgical teams provided effective prophylaxis of bleeding during a complex procedure that presented new challenges. Both services now have better understanding of the needs of transgender people.

Effects of Hemostasis Correction on Vascular Remodeling and Synovial Gene Expression Changes in Mice after Induced Hemarthrosis

IntroductionRepeated joint bleeding in patients with hemophilia leads to hemophilic arthropathy (HA), which cannot be entirely prevented by clotting factor replacement. Vascular remodeling and permeability are associated with hemarthrosis and may contribute to HA progression; however, the mechanisms and effects of hemostasis correction are poorly understood. Here, we explored synovial vascular and gene expression changes in FVIII-deficient mice after induced hemarthrosis +/- FVIII replacement, and in wild-type mice with reversible hemostasis suppression.MethodsHemarthrosis was induced in FVIII-deficient mice by sub-patellar needle puncture +/- 100-200 IU/kg recombinant human FVIII (rhFVIII) 2 hours before and 6 hours after injury. Wild-type mice were treated with 10 µg/ml warfarin for 7 days and 0.25 mg/kg anti-FVIII 2 hours before injury (hypoBALB/c). After injury, warfarin was continued for 2 weeks or reversed on day 2 with 100 IU/kg 4-factor prothrombinase complex concentrate (4F-PCC). Vascularity and gene expression were analyzed at baseline and 2 weeks post-injury. Vessel number and remodeling were assessed by histology with Safranin-O-Fast Green and α-smooth muscle actin (αSMA) staining, respectively, and microvascular flow was detected by musculoskeletal ultrasound with Power Doppler. The permeability of synovial vessels was determined by quantification of extravasated albumin-bound Evans blue dye in knee joints. For synovial gene expression studies, libraries were prepared using the NEBNext Ultra II DNA Library Prep Kit and sequenced on an Illumina NextSeq500 (single-end; 75bp reads). The limma-voom method (R BioConductor) was used for differential expression analyses and functional enrichment was performed using Signaling Pathway Impact Analysis.ResultsIn FVIII-deficient mice, knee injury caused profound hemarthrosis that was largely prevented with rhFVIII prophylaxis (day 2 hematocrit: 26.4% and 46.3%). Soft tissue proliferation increased to a similar extent, as did various vascular parameters: microvascular flow (vehicle: 1.8-fold; rhFVIII: 1.5-fold), vessel number (vehicle: 2.3-fold, p=0.0005; rhFVIII: 2.0-fold, p=0.004), vessels with diameter ≥ 20 µm (vehicle: 2.9-fold, p=0.02; rhFVIII: 2.7-fold, p=0.02), and αSMA area per vessel (vehicle: 2.3-fold, p>0.05; rhFVIII: 3.6-fold, p=0.0006). Vascular permeability also increased significantly (1.7-fold, p=0.0007) and was only partially rescued by rhFVIII prophylaxis (1.3-fold, p>0.05). In hypoBALB/c mice (day 2 hematocrit: 29.6%), significant but less pronounced vascular changes occurred regardless of hemostasis correction, and without associated permeability, suggesting this is uniquely associated with FVIII-deficiency. RNA sequencing in FVIII-deficient mice revealed a strong transcriptional response to hemarthrosis (1527 differentially expressed genes (DEG), 13 perturbed pathways) that was only partially dampened with rhFVIII treatment (891 DEG, 20 pathways). Perturbation of extracellular matrix (ECM)-receptor interactions was highly significant in both groups (vehicle: pNDE=7.7x10-10; rhFVIII: pNDE=6.8x10-9). Similarly, numerous genes relating to angiogenesis and ECM remodeling, including collagens and MMPs, were up-regulated and minimally affected by rhFVIII treatment. These transcriptional changes may facilitate the observed vascular remodeling after hemarthrosis.ConclusionsHemarthrosis triggers profound changes in synovial gene expression, notably ECM components, that may drive the associated soft tissue and vascular changes, including vessel remodeling and leakiness. These processes are incompletely mitigated by hemostasis correction and may exacerbate (re-) bleeding tendencies. Therefore, further exploration is needed to identify key molecular pathways that can be targeted to intercept the progression of HA. Disclosuresvon Drygalski:UniQure BV, Bayer, Bioverativ/Sanofi, Pfizer, Novo Nordisk, Biomarin, Shire, CSL Behring: Consultancy.

ASPIRE Final Results Confirm Established Safety and Sustained Efficacy for Up to 4 Years of Treatment With rFVIIIFc in Previously Treated Subjects With Severe Hemophilia A

Introduction: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care in hemophilia A, given its natural mechanism of action, strict homeostatic regulation, and consistent safety profile. Recombinant FVIII Fc fusion protein (rFVIIIFc) is an extended half-life therapy that demonstrated safety and efficacy in previously treated pediatric, adolescent, and adult subjects with severe hemophilia A in the Phase 3 A-LONG and Kids A-LONG trials (NCT01181128 and NCT01458106, respectively) (Young et al, J Thromb Haemostas, 2015; Mahlangu et al, Blood, 2014). Herein, the final results are reported from ASPIRE (NCT01454739), the long-term extension trial of those 2 studies.Methods: This was an open-label, multicenter, long-term trial of previously treated subjects of all ages with severe hemophilia A. Subjects received 1 of the 4 following regimens: individualized prophylaxis (IP; rFVIIIFc 25‒60 IU/kg every 3-5 days, or twice weekly), weekly prophylaxis (WP; rFVIIIFc 65 IU/kg every 7 days), modified prophylaxis (MP; personalized dosing), or episodic treatment (ET; on-demand dosing based on bleeding episodes). Subjects <12 years of age were eligible for only IP or MP. Investigators could switch a subject's treatment group at any time; therefore, each subject may appear in >1 treatment group. The primary endpoint was development of inhibitors. Secondary endpoints included annualized bleeding rates (ABRs), joint ABRs, spontaneous joint ABRs, exposure days (ED), and factor consumption. Descriptive statistics were used for analysis. Analyses were performed separately based on parent study.Results: A total of 211 subjects (150 were from A-LONG and 61 were from Kids A-LONG) enrolled in ASPIRE, and 186 subjects (132 from A-LONG and 54 from Kids A-LONG) completed the study. Subjects from Kids A-LONG had a median (range) age of 6.0 (2-12) years. Of the subjects from the A-LONG study enrolled to ASPIRE, the median (range) age was 31.0 (13-66) years. Most subjects received IP regardless of parent study (Kids A-LONG: IP [n=59], MP [n=3]; A-LONG: IP [n=110], WP [n=27], MP [n=21], ET [n=13]).No inhibitors were observed throughout the study, and the overall safety profile of rFVIIIFc was consistent with the parent studies and prior interim analyses. ABRs remained low throughout the entirety of ASPIRE in subjects prescribed IP (Table 1). For subjects from the Kids A-LONG study, the median (range) number of ED during ASPIRE was 332.0 (18.0-467.0) days. Total median (range) treatment duration was 166.6 (14.4-203.0) weeks. The median (range) number of ED for A-LONG subjects was 267.5 (8.0-660.0) days. Total median treatment duration was 201.4 (5.1-274.6) weeks. Overall, the median (range) duration of treatment with rFVIIIFc was 4.1 (0.4, 5.9) years.From the end of the parent study to the end of ASPIRE, the rFVIIIFc dosing interval increased for 6.6% and 21.1% of subjects from Kids A-LONG and A-LONG, respectively (Table 2). There was no change in median weekly factor consumption from the end of either parent study to the end of ASPIRE. For subjects from Kids A-LONG, the median (IQR) was 0.0 (0.0‒3.2), while the median (IQR) for those from A-LONG was 0.0 (0.0‒0.0).Conclusions: Throughout up to 4 years of treatment with rFVIIIFc in the ASPIRE extension study, no inhibitors were reported, and low ABRs and extended dosing intervals were sustained. These data are consistent with the well-characterized safety profile and durable efficacy of rFVIIIFc prophylaxis in previously treated subjects of all ages with hemophilia A. [Display omitted] DisclosuresNolan:Bayer: Research Funding; CSL Behring: Research Funding; Sobi: Research Funding. Mahlangu:Sanofi: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Alnylam: Consultancy, Research Funding, Speakers Bureau; Bayer: Research Funding; Biogen: Research Funding, Speakers Bureau; Chugai: Consultancy; Catalyst Biosciences: Consultancy, Research Funding; Amgen: Consultancy; Biomarin: Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Young:Bayer: Consultancy; Bioverativ: Consultancy, Honoraria; Kedrion: Consultancy; Novo Nordisk: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Konkle:Sangamo: Research Funding; Gilead: Consultancy; Spark: Consultancy, Research Funding; BioMarin: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy; Bioverativ: Research Funding; Pfizer: Research Funding; Shire: Research Funding. Pasi:Shire: Speakers Bureau; Alnylam: Honoraria, Research Funding; Bayer: Speakers Bureau; Octapharma: Honoraria; Pfizer: Speakers Bureau; Biomarin: Honoraria, Research Funding; Sobi: Honoraria; Bioverativ: Honoraria, Research Funding; NovoNordisk: Speakers Bureau; Catalyst Bio: Honoraria; Apcintex: Honoraria. Oldenburg:Novo Nordisk: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding. Nogami:Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Tripkovic:Sobi: Employment. Rudin:Bioverativ: Employment, Equity Ownership.

Clinical analysis on one patient with hemophilia A complicated with primary immune thrombocytopenia

Objective To investigate the diagnosis, treatment and prognosis of hemophilia A combined with primary immune thrombocytopenia (ITP). Methods The hemophilia A patient with ITP (male, 30 years old)admitted to the Department of Hematology, Xuzhou Medical University Affiliated Hospital on February 21, 2017 was selected as the study subject. During hospitalization, he was repeatedly treated with coagulation factor replacement therapy strategy, as well as symptomatic treatment measures such as hemostasis, platelet transfusion, intravenous infusion of glucocorticoids, and intravenous immunoglobulin (IVIG). By retrospective analysis, his clinical data were collected, and the clinical features, diagnosis and treatment were summarized. This study met the requirements of the Helsinki Declaration of the World Medical Association revised in 2013, and the informed consent of the subjects was obtained, and informed consent was signed with him. Results ① This patient was diagnosed as hemophilia A more than 20 years ago. During that period, the patient achieved a obvious effect by cryoprecipitation and recombinant human FⅧ infusion. About a month ago, without obvious inducement, the patient developed hematuria, epistaxis and oral hemorrhage. His activity of FⅧ was only 21.3%, and the platelet count was just 3×109/L. The patient received phenethylamine, recombinant human FⅧ, methylprednisolone, and intravenous immunoglobulin (IVIG) , but which was not effective for him. ② After admission to our hospital on February 21, 2017, the results of laboratory tests showed that the patient′s platelet count was very low, only for 2×109/L. His activity of FⅧ was 14.3%, and activity of FⅨwas 49.8%. Activated partial thromboplastin time (APTT) prolonged to 50.2 s, APTT was 32.1 s after correction, APTT (incubated at 37 ℃ for 2 h) prolonged to 50.0 s, and APTT (incubated at 37 ℃ for 2 h) was 37.9 s after correction. Morphological examination of bone marrow cells showed that bone marrow cells proliferated actively, granulocytes and erythroid line cells were proliferated, and the morphology was normal, as well as megakaryocyte maturation was accompanied by thrombocytopenia. Abdominal ultrasound results showed that the liver area was dense, the gallbladder wall was rough, and the spleen was not large (about 9.7 cm × 7.0 cm). ③ After admission, combining with previous medical history, results of relevant laboratory examinations and auxiliary examinations, the patient was diagnosed as hemophilia A combined with ITP by excluding other secondary diseases which caused thrombocytopenia. ④ After admission, the patient was repeatedly treated with recombinant human FⅧ. But the patient′s highest activity of FⅧ was only 25.8%, and APTT prolonged to 45.0 s, which suggested that the patient was partially tolerant to treatment. After receiving multiple platelet transfusions, the patient′s platelet count was still low, and did not exceed to 20×109/L, which suggested that the treatment is invalid. On May 5, 2017, the patient started oral eltrombopag (75 mg/d). After 3 months of treatment, the patient′s platelet count was up to 55×109/L, and the evaluation of efficacy was effective. However, after one month of discontinuation of eltrombopag, the patient′s platelet count fell to 10×109/L, which suggested that his disease relapsed. Conclusions Patients with hemophilia A combined with ITP, were clotting factor deficiency and thrombocytopenia, the risk of bleeding of them were high, and the treatment is difficult. In addition to infusion of recombinant human FⅧ, glucocorticoid and other drugs should be given to elevate platelet count, but the prognosis of this patient is not good. Patients with hemophilia A combined with ITP are rare in clinic, and its standard and effective treatment strategy requires a large sample size and multi-center study to further explore. Key words: Hemophilia A; Purpura, thrombocytopenic, idiopathic; Hemorrhage; Drug therapy; Prognosis; Primary immune thrombocytopenia

Continuous infusion of simoctocog alfa in haemophilia A patients undergoing surgeries.

There are two major principles for coagulation factor replacement in the clinical management of surgical procedures in patients with haemophilia, repetitive bolus injections every 6-12hours or administration of coagulation factor concentrates by continuous infusion. The aim was to investigate the efficacy of simoctocog alfa (human-cl rhFVIII) delivered by continuous infusion for bleeding prophylaxis during surgery in patients with haemophilia A. We investigated the use of continuous infusion with simoctocog alfa in haemophilia A patients undergoing major surgical procedures at Oslo University Hospital from September 2015 to March 2018. The objectives were haemostatic outcome, in vivo recovery, stability over time at room temperature (3days) and inhibitor development. Simoctocog alfa demonstrated treatment success in terms of haemostatic efficacy in 100% of major surgeries used as CI: 87% (n=21) excellent; 13% (n=3) good. No erythrocyte transfusions were required in any patient, no adverse events occurred and no inhibitors developed. The product was stable for 3days at room temperature without loss of activity. Mean in vivo recovery was 1.8 (0.3) (IU/mL/IU/kg). Continuous infusion with simoctocog alfa was found to achieve good/excellent haemostatic efficacy in all procedures. No adverse events occurred and no inhibitors developed.

Supply and demand for hemophilia treatments—Systems-based approaches to mitigate the risk

Treatment of hemophilia consists of replacement of the missing coagulation factor, either prophylactically or at the time of injury or bleeding. Because of the high cost of these products, which can present a barrier to care, different procurement strategies have been developed at national and regional levels. The emergence of novel therapeutic agents adds complexity to these strategies. This paper examines the benefits and challenges of these strategies, with primary reference to the Canadian context and a consideration of the concepts of value-based care.

How I approach: Previously untreated patients with severe congenital hemophilia A

Previously untreated patients with severe hemophilia A are a vulnerable population at risk for severe bleeding which is currently managed with exogenous clotting factor replacement. The primary burden of current treatment is high-titer inhibitor development. Evolving data on current treatment products as well as emerging therapeutics may inform treatment decisions to prevent bleeding and inhibitor formation. Considerations for diagnosis, education, and shared decision-making related to product choice and treatment regimen are discussed.

Practical aspects of extended half-life products for the treatment of haemophilia.

Haemophilia A and haemophilia B are congenital X-linked bleeding disorders caused by deficiency of coagulation factor VIII (FVIII) and IX (FIX), respectively. The preferred treatment option for patients with haemophilia is replacement therapy. For patients with severe disease, prophylactic replacement of coagulation factor is the treatment of choice; this has been shown to reduce arthropathy significantly, reduce the frequency of bleeds and improve patients' quality of life. Prophylaxis with standard recombinant factor requires regular intravenous infusion at least two (FIX) to three (FVIII) times a week. Recombinant FVIII and FIX products with an extended half-life are in development, or have been recently licensed. With reported mean half-life extensions of 1.5-1.8 times that of standard products for FVIII and 3-5 times that of standard products for FIX, these products have the potential to address many of the unmet needs of patients currently treated with standard factor concentrates. For example, they may encourage patients to switch from on-demand treatment to prophylaxis and improve the quality of life of patients receiving prophylaxis. Indeed, extended half-life products have the potential to reduce the burden of frequent intravenous injections, reducing the need for central venous lines in children, promote adherence, improve outcomes, potentially allow for more active lifestyles and, depending on the dosing regimen, increase factor trough levels. Members of the Zürich Haemophilia Forum convened for their 19th meeting to discuss the practicalities of incorporating new treatments into the management of people with haemophilia. This review of extended half-life products considers their introduction in haemophilia treatment, including the appropriate dose and schedule of infusions, laboratory monitoring, patient selection, safety considerations, and the economic aspects of care.

Nursing care for patients with hemophilia pseudotumor in coagulation factor replacement therapy during perioperative period

Objective To summarize the nursing methods for patients with hemophilia pseudotumor in coagulation factor replacement therapy during perioperative period. Methods A retrospective analysis was conducted among 25 hemophilia pseudotumor patients who were in the Orthopedic Department of Peking Union Medical College Hospital from June 2010 to September 2016, which were selected by convenience sampling method. All the patients were assessed for psychological status in a standardized method throughout the whole process and given timely intervention. The precise management of preoperative coagulation factor pretest, venous protection, observation and nursing of postoperative wound bleeding, monitoring and nursing of coagulation factor inhibitors were standardized using Coagulation Factor Replacement Treatment Pre-experiment Information Record Table . Results All patients received accurate coagulation factor replacement therapy in perioperative period, which ensured the safety of perioperative period. In addition, all patients were discharged smoothly with an average hospitalization duration of 40.5 days. Conclusions Coagulation factor replacement therapy is the foundation to ensure patient safety, the key of which is accurate nursing. This study provides clinical practice experience for related nursing in China, and lays the foundation for further in-depth research in the future. Key words: Nursing care; Hemophilia; Pseudotumor; Coagulation factors; Replacement therapy

First‐year results of an expanded humanitarian aid programme for haemophilia in resource‐constrained countries

The gaps in haemophilia treatment around the world are enormous; approximately 60% of an estimated 475000 individuals are not identified. Of the 187000 diagnosed, 30% (57000) access clotting factor replacement therapy. Since 1996, humanitarian aid distributed by the World Federation of Hemophilia (WFH) has played a minor, yet vital role providing life-saving clotting factor to countries in emergency situations. Donated amounts have been small and sporadic, often salvaging short-dated products, providing little opportunity to leverage donations with governments. In 2015, a prospective donation programme of 100 million I.U. per year of extended half-life factor VIII and IX over 10years was established, necessitating the development of new logistics and training programmes by WFH. To measure the impact of a greatly expanded haemophilia humanitarian aid program. In 2016, the first full year of the expanded programme, WFH, distributed products to 58 countries with factor VIII usage <1I.U. per capita, a level incompatible with long-term survival and far below the 4I.U. FVIII per capita minimum established in Europe. The scope of the programme and utilization data for 2016 indicate primarily use for acute bleeding, orthopaedic and emergency surgeries. Compared to 2014, 2016 data showed substantial increases in patients served (5.9-fold, from 2119 to 14579), surgeries performed (37-fold) and bleeds treated (6.9-fold). Patients on prophylaxis rose from 0 to 852, including 458 children under 10years old. The expanded humanitarian aid programme impacts an estimated 10% of individuals with haemophilia previously unable to access treatment. This programme represents an unprecedented public-private partnership to deliver medicines to individuals with no access. Further, the programme offers the prospective opportunity to engage governments to take more responsiblity for increasing training, medical management, and product supply in 58 resource constrained countries.

PHARMACOECONOMIC JUSTIFICATION OF A WIDER USE OF PREVENTIVE HEMOPHILIA THERAPY IN THE RUSSIAN FEDERATION

The aim – assess the clinical advantages and economic burden of various treatment strategies in patients with hemophilia A in the Russian Federation and propose the ways of optimizing this area of medical care. Materials and methods . A mathematical model describing the (2017) approach to of hemophilia A in the RF and two additional treatment scenarios are proposed. A partial switch of patients from the “therapy on demand” to the standard and personalized preventive was also simulated. Based on this mathematical model, the treatment outcomes, the costs of outpatient, hospital and social care were evaluated for the treatment of hemophilia A and its complication; a analysis was also performed. Results. Published reports demonstrated a high efficacy of preventive with replacement of coagulation factors VIII in comparison with on demand in the treatment of hemophilia A. Segmentation of the population of patients with hemophilia A in the RF revealed that the on-demand is the most common approach in adult patients (64%), whereas the standard prophylaxis is used in most children (80%). As calculated, under the treatment approach, the total number of bleedings is about 58,710 per year, and the number of potentially targeted joints – 3,409 in adults; the figures for children are 3, 817 and 213, respectively. The application of scenario 1 allows for a significant reduction in negative outcomes: i.e. by 62.1% and 62.4% for the risk of bleedings and targeted joints (respectively) in adults if the prevention strategy is increased to 80%; and by 44.2% and 46.2% in children if the prevention is increased to 100%. Simulated scenario 2 allows for achieving even more significant results – a reduction in the number of bleedings and targeted joints by 62.4 and 62.7% in adults and by 47.9 and 50% in children. Transition to simulated scenarios in most cases requires an increase in the overall budget expenses, and also implies a reshuffle of the expenses between different items. For example, increasing the share of prevention leads to increased expenses for the replacement pharmacotherapy in parallel to a reduction in expenses associated with negative outcomes of the disease (endoprosthetics, disability, etc.). In the next 50 years, in terms of the costs, the difference between scenarios 1 and 2, on the one hand, and the therapy, on the other, is expected to decrease from 26 to 17% and from 26 to 15%, respectively, due to the reduced cost of temporary disability, treatment of bleeding and replacement / re-replacement of joints. According to the cost-effectiveness analysis, the best-fit regimen is scenario 2 (personalized prophylaxis), whereas the current therapy scenario is the least effective. Based on the ICER analysis, the additional expenses associated with a wider use of preventive in scenarios 1 and 2 do not exceed one GDP per capita, and the technologies are cost-effective. Conclusion. In both clinical and economic aspects, the most effective method of treating severe and moderate haemophilia A is preventive with coagulation factor VIII. Expanding this approach will improve the quality of medical care for patients with hemophilia A.

Protocolized warfarin reversal with 4-factor prothrombin complex concentrate versus 3-factor prothrombin complex concentrate with recombinant factor VIIa

IntroductionLife-threatening bleeding can complicate warfarin therapy. Rapid anticoagulant reversal via replacement of vitamin-K dependent clotting factors is essential for hemostasis. We compare two methods of rapid factor replacement for warfarin reversal. MethodsA retrospective cohort study of warfarin-treated patients experiencing life-threatening bleeding who received a reversal protocol comprised of 4F PCC or 3F PCC and rFVIIa was performed. Demographic, clinical and anticoagulant reversal information, and all adverse events attributed to warfarin reversal were recorded. Results195 patients were included in final analysis. While baseline demographics were similar between groups, the 3F-PCC group had a longer ICU LOS and higher in-hospital mortality (p < .01, .01).Pre-reversal INR was similar between both groups, but post-reversal INR was significantly lower in the 3F-PCC group, 0.8 versus 1.3 (p < .01). Significantly more patients experienced thromboembolic complications in the 3F-PCC group than the 4F-PCC group (p < .01). Receipt of rFVIIa was significantly associated with thromboembolic complications. DiscussionA 4F PCC reversal strategy is efficacious in INR reversal and provides lower thromboembolic risk as compared to 3F PCC with rFVIIa.

Management of Hemophilic Cysts and Pseudotumors ofthe Hand in Bleeding Disorders: A Case Series.

Hemophilic cysts and pseudotumors (HCPTs) of the hand are rare and are secondary to bleeding disorders such as hemophilia A and B. This is a report of our experience in the management of this rare condition. Seven male patients with hemophilia A presenting with progressive swelling of the hand were treated between 2004 and 2013 at a tertiary referral hospital. All patients had clotting factor replacement based on our previously reported protocol. The age of the patients ranged from 3 to 49 years (median age, 19 years). Four patients had soft tissue hemophilic cysts and 3 had bony hemophilic pseudotumors. Two patients had traumatic pseudoaneurysm of the ulnar artery in addition to the cysts. The soft tissue cysts required surgical excision in 3 patients under factor cover as per the protocol. The bony lesions were initially managed nonsurgically by factor replacement, but 2 patients failed to respond and required amputation of the fingers. The ulnar artery aneurysm was excised and artery ligated in 1 patient and the artery was vein grafted owing to poor hand perfusion in1. Based on our observations in the management of HCPTs of the hand and the existing literature, we conclude that the soft tissue cysts require surgical excision along with factor replacement and distal bony lesions smaller than 3 cm respond to factor replacement. Larger bony lesions require surgical treatment. Treatment of hemophilic cysts and pseudotumors should be undertaken only in centers with a major hematology backup. Therapeutic V.

A Primary Human Liver Cell Culture Model for Hemorrhagic Fever Viruses.

Viral hemorrhagic fevers affect liver functions such as important metabolic processes and the replacement of new blood cells, coagulation factors, and growth factors. Typically, multi-organ diseases such as viral hemorrhagic fevers are studied in an organism, but it is also possible to derive information about the molecular events involved in disease processes by focusing on liver cell culture. Here we describe a multi-cell culture system that is capable of replicating the arenavirus LCMV-WE, a virus that can cause hemorrhagic fever in primates, as a model for liver infection by a hemorrhagic fever virus.