Plasma-derived Concentrates Research Articles

Improved prevention of bleeding episodes with emicizumab in 3 patients with concomitant hemophilia A and von Willebrand disease.

The typical phenotype of hemophilia A (HA) is that of frequent bleeding episodes, up to several per month, unless prophylactic factor VIII (FVIII) replacement or alternatives are given. Related bleeding may be heightened in severity or frequency by co-morbid bleeding disorders. Based on the reported prevalence of von Willebrand disease (VWD) of up to 1% of the general population, the co-existence of HA and VWD occurs, but is likely less recognized. Prophylactic FVIII replacement may or may not adequately prevent bleeding in persons with HA and mild VWD, and plasma-derived concentrates containing FVIII and von Willebrand factor (VWF) may be used for more successful bleeding prophylaxis. However, therapy adherence remains problematic for many reasons, one being treatment via intravenous access. Emicizumab is a nonfactor subcutaneous prophylactic therapy for HA that may overcome this concern. We describe three patients, with severe HA and VWD, for whom regular FVIII/VWF prophylaxis was deemed inadequate. FVIII/VWF prophylaxis was replaced with weekly prophylactic injections of the bispecific monoclonal antibody, emicizumab. When the patients were transitioned to emicizumab, all experienced a significant reduction in their annualized bleed rate (ABR). Although the mechanism of action does not directly affect or replace VWF function, emicizumab may be an effective prophylaxis alternative to FVIII/VWF concentrate in patients with concomitant severe HA and VWD.

Prophylaxis and Treatment of Bleeding or Thrombosis with Fibrinogen Concentrate (Fibryga) in Patients with Congenital Hypofibrinogenemia or Dysfibrinogenemia

Congenital fibrinogen disorders (CFDs) are rare and make up approximately 0.6% of all inherited bleeding disorders. Two subtypes include a quantitative deficiency of fibrinogen, congenital afibrinogenemia (CA), congenital hypofibrinogenemia (CH), and qualitative defect of the fibrinogen molecule, congenital dysfibrinogenemia (CD). Patients with CD may have a thrombotic as well as a hemorrhagic disease phenotype. In the past, fresh frozen plasma or cryoprecipitate were the only options available for treatment and prevention of bleeding in patients with CFD. Today in the US, human plasma-derived concentrates (FIBRYGA, Octapharma, Lachlen, Switzerland, and RiaSTAP, CSL, Melbourne, Australia) are available and considered safe and effective treatment options for CD and CH. Guidelines for the treatment and prevention of bleeding is not established for CFDs, and especially for CD. We present eight clinical cases of patients with hypo- or dysfibrinogenemia that were effectively treated with a pooled, plasma-derived fibrinogen concentrate (FIBRYGA) either prophylactically for elective or urgent surgery, or post-traumatic injury. The mean age of patients treated was 34 years (min-max 8-70 years). Three patients were male and five, female. Four patients had CH and four, CD. FIBRYGA was used to prophylactically treat a total of ten surgical procedures and two post-traumatic events in these patients. Dosing of FIBRYGA was based on the goal peak plasma fibrinogen concentration and the manufacturer's prescribing information, but modified to align with local laboratory reference ranges for the functional fibrinogen test. No acute or delayed infusion reactions (nausea, fever, rigors, headache) and no hypersensitivity reactions were noted. One patient developed two adverse events, one thrombotic and one hemorrhagic. This patient underwent left, above the knee amputation (AKA) and had a complicated postoperative period due to her multiple comorbidities including type 2 diabetes, hypertension, and long standing, poorly-controlled, severe peripheral arterial disease. She presented nineteen days after receiving FIBRGYA with a PE and multiple DVTs. Fifty-nine days later she presented with wound dehiscence and underwent an extensive excisional debridement with postoperative bleeding deemed to be secondary to her strap sliding during surgery and acting as a tourniquet for venous blood flow. For the majority (86%) of our patients described here with CH and CD, FIBRYGA was well tolerated and effective in preventing post procedural or post traumatic bleeding complications. The post procedural bleeding noted in one patient may have been due to inadequate fibrinogen concentration or other comorbid conditions. Further clinical studies are needed to determine the role of FIBRGYA and other HFC in the treatment of patients with CFD, especially those with CD.

Emicizumab for non-severe haemophilia A

The treatment and outlook for people with haemophilia has been transformed in the past 50 years through a series of incremental steps that include the introduction of plasma-derived concentrates and their viral inactivation, the introduction of recombinant products of standard and then extended half-life, and the ability of patients to self-infuse at home and use the concentrates prophylactically. With good factor VIII or factor IX (FVIII/FIX) prophylaxis, people with haemophilia have a markedly improved quality of life and a near-normal life expectancy.

Adamts13 Levels in a Plasma-Derived Fviii Concentrate: A Potential Therapeutic Option for Patients with Congenital Thrombotic Thrombocytopenic Purpura

Adamts13 Levels in a Plasma-Derived Fviii Concentrate: A Potential Therapeutic Option for Patients with Congenital Thrombotic Thrombocytopenic Purpura

Hemophilia: The Past, the Present, and the Future.

Hemophilia: The Past, the Present, and the Future.

Obstacles to Early Diagnosis and Treatment of Inherited von Willebrand Disease: Current Perspectives.

Von Willebrand disease (VWD), the most common inherited bleeding disorder, is highly heterogeneous, and its early diagnosis may be difficult, especially for mild cases and in qualitative von Willebrand factor (VWF) defects. Appropriate VWD diagnosis requires the combination of personal and/or family history of bleeding and abnormal VWF laboratory testing. The use of bleeding assessment tools has been helpful in standardizing bleeding history collection and quantification of bleeding symptoms to select patients who may benefit of further hemostatic testing. Type 1 and 3 VWD which represent quantitative VWD variants are relatively easy to diagnose. The diagnosis of type 2 VWD requires multiple assessments to evaluate the effects induced by the responsible abnormality on the heterogeneous functions of VWF. Sensitive and reproducible tests are needed to evaluate different VWF activities, starting from measuring VWF-platelet interaction. In the recent years, several increasingly sensitive, rapid and automated assays have been developed, but they are not widely available so far. Genetic testing for VWD diagnosis is not a common practice because VWF gene is very large and highly polymorphic and therefore it is used only in specific cases. It is evident that the early and correct VWD diagnosis allows optimal management of bleeding and situations at risk. Tranexamic acid, desmopressin, replacement therapy with plasma-derived concentrates with a variable content of VWF and FVIII, or the new recombinant VWF are the different therapeutic options available. Careful VWD classification guides treatment because desmopressin is widely used in type 1 while replacement therapy is the cornerstone of treatment for type 2 and 3 variants.

A Multicenter Study of Recombinant Factor VIII (Recombinate): Safety, Efficacy, and Inhibitor Risk in Previously Untreated Patients With Hemophilia A

AbstractIn July 1990, the Recombinate Study Group initiated a prospective, open-labeled investigation of recombinant factor VIII (r-FVIII) to assess its safety and efficacy and to characterize the natural history of inhibitor development in previously untreated patients (PUPs) with hemophilia A. All study subjects have severe FVIII deficiency (baseline FVIII level ≤2% of normal) and no history of blood product exposure before study entry. Following the first r-FVIII infusion, plasma was screened for inhibitors once every 3 months, and plasma recovery of r-FVIII at 30 minutes and 24 hours postinfusion was assayed at least once every 6 months. As of May 1993, 73 of 79 patients originally enrolled in the trial continue to participate. The median number of r-FVIII exposure-days for the 71 subjects who have received at least one r-FVIII infusion is 11. A total of 1,785 infusions have been administered to treat 810 bleeding events. Ninety-two percent of bleeding events responded as anticipated to one or two infusions. Two, nonrecurring, acute adverse reactions occurred coincident with r-FVIII infusion, one of which was unrelated and the other, possibly related to the infusion. Seventeen (23.9%) subjects have developed inhibitors: five with peak titers more than 10 Bethesda units (BU) and 12 with peak titers ≤10 BU (range, 0.5 to 10). Survival analysis showed that the probability of remaining inhibitor-free in this group of patients with severe hemophilia A is 88.4% after 8, 73.6% after 10, and 61.6% after 25 r-FVIII exposure-days. Inhibitors disappeared in five (29.4%) subjects on retesting 2 to 16 months after the last positive inhibitor assay. r-FVIII is safe and effective in the treatment of hemophilia A-related bleeding. To date, the inhibitor risk associated with its use is comparable to that in patients treated with plasma-derived concentrates. The majority of inhibitors identified are low in titer and do not preclude continued on-demand therapy with r-FVIII.

Budget impact analysis of extended half-life recombinant factor IX (rFIXFc) in the treatment of haemophilia B.

Prophylaxis with factor IX (FIX) concentrates, produced by recombinant DNA technology (rFIX) or human plasma-derived concentrates, is the treatment of choice for haemophilia B (HB); rFIX covalently fused to the Fc domain of human immunoglobulin G1 (rFIXFc) allows for prophylaxis/treatment with one infusion every 7-14 days. The purpose of this study is to quantify the financial impact of prophylaxis with rFIXFc vs. other approved rFIX and reimbursed for treatment of HB in Italy. The number of patients was estimated according to Italian epidemiological data and use of rFIX. Dose and frequency of administration used for weekly prophylaxis were those recommended in the Summary of Product Characteristics (SPC), while clinical trials and literature data were used to calculate bleeding rates and management. Drug costs were calculated using regional ex-factory net prices. In the model, a reference scenario (Reference) vs. an alternative scenario (Alternative) were created to account for introduction of rFIXFc, estimating an increasing trend of the market share of rFIXFc in a 3-year timeframe. The analysis was developed in the perspective of the National Health Service and included healthcare costs related to rFIX for prophylaxis and resolution of bleeding events. The model estimated an overall cumulative expenditure (years 1-3) of €209,453,646 for the Reference and €207,465,568 for Alternative scenarios, with calculated cumulative savings of €1,988,068. The increasing use of rFIXFc as a substitute for other rFIX concentrates in the treatment of HB can represent a financially viable choice for the Italian National Health Service while ensuring effective control of bleeding.

Hemophilia therapy: the future has begun

The success story of hemophilia care first began in the 1970s, when the availability of plasma-derived concentrates of coagulation factor VIII (FVIII) and factor IX (FIX) provided efficacious treatment of bleeding in patients with hemophilia A and B. This positive scenario was consolidated in terms of greater safety and availability in the 1990s, when the first recombinant coagulation factors were produced. This meant that, instead of only treating episodic bleeding events, prophylaxis regimens could be implemented as a preventive measure. Following the demonstration of its superiority in the frame of two randomized clinical trials, prophylaxis became evidence-based standard of care. In high-income countries, these achievements have led to a patients’ life expectancy being extended to close to that of the general male population. Alongside this, the last decade has witnessed further spectacular therapeutic progress, such as the availability of coagulation factors with a longer plasma half-life that allow for wider intervals between treatment. Moreover, new therapeutic products based on new mechanisms other than the replacement of the deficient factor, have become available (emicizumab) or are at an advanced stage of development. This review celebrates the success story of hemophilia care, while also discussing current limitations, issues and as yet unmet needs. The prospects of cure by means of gene therapy are also outlined.

Immune Tolerance Induction (ITI) with a Plasma-Derived Factor VIII for Patients with Hemophilia a and Inhibitors: A Retrospective Study

Introduction: A serious complication in hemophilia A is the formation of inhibitors to clotting factors. The primary means for eradicating inhibitors is immune tolerance induction (ITI) therapy. Antihemophilic factor (human) (Koate®-DVI) is a purified dried concentrate indicated for the treatment of hemophilia A with insufficient activity of Factor VIII (FVIII). Although other plasma-derived concentrates containing von Willebrand factor have been utilized successfully for ITI, studies evaluating this product for ITI therapy have not been published. An evaluation of patient- and treatment-related factors associated with outcomes following primary or rescue ITI with antihemophilic factor (human) in patients with hemophilia A and inhibitors was conducted in this retrospective multicenter chart review project. Methods: An evaluation of medical records of 13 inhibitor patients treated with antihemophilic factor (human) for primary or rescue ITI therapy between January 1, 2012, and July 31, 2017, was conducted in five US hemophilia treatment centers. To be eligible for inclusion, patients were required to have a diagnosis of hemophilia A of any severity level, inhibitor to FVIII at the time of treatment initiation with antihemophilic factor (human), and ongoing treatment with antihemophilic factor (human) for primary or rescue ITI. Data were de-identified and analyzed descriptively. Outcome measures were defined, per the International Immune Tolerance consensus recommendations, as "complete success" (inhibitor titer <0.6 Bethesda Units [BU] at 33 months of ITI, FVIII recovery ≥66% and half-life ≥6 hours), "partial success" (a reduction in inhibitor titer to <5 BU mL with FVIII recovery <66% and/or FVIII half-life <6 hours associated with clinical response to FVIII therapy not followed by a treatment-limiting anamnestic rise in inhibitors to >5 BU mL), or "failure" (neither complete nor partial success). Results: All (N=13) patients who met the inclusion criteria were males with severe hemophilia, with the exception of one with moderate hemophilia. Six patients were African American, four were Hispanic, two Caucasian, and one was Asian. They were diagnosed with inhibitors between the ages of 8 months and 39 years and were 5 to 53 years old upon ITI with antihemophilic factor (human). Ten of 13 patients (76.9%) had successful ITI; seven with complete success and three with partial success (Table). Three patients failed ITI. As primary therapy, complete success was obtained with all but one of the six patients treated with antihemophilic factor (human). These six patients were all older than 7 at the initiation of ITI, a risk factor for poor ITI. Seven of the 13 total patients had a combined previous 12 attempts at ITI with other products (plasma derived and/or recombinant). Of these seven rescue patients, ITI with antihemophilic factor (human) was completely successful in two and partially successful in three. Adverse events reported once in separate patients during treatment with antihemophilic factor (human) included catheter infection, portal infection, bacteremia, peritonitis due to a ruptured appendix, and complications in treatment. One patient had several adverse events, including cellulitis at the port site, abdominal wall hematoma, right thumb fracture and hematoma, and left shoulder hemarthrosis. Conclusions: While retrospective data has limitations, real-world evidence demonstrates that ITI with antihemophilic factor (human) concentrate can be successful or partially successful in diverse populations of moderately complex patients with hemophilia A and inhibitors. The data suggest that antihemophilic factor (human) may be most appropriate for patients when used as primary ITI, as even patients older than 7 years achieved complete success. Additional patients need to be evaluated to make a definitive conclusion regarding the impact of age on success of ITI therapy in addition to other risk factors. Disclosures Escobar: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rajan:Bayer, Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Amega:Kedrion Biopharma: Employment. OffLabel Disclosure: Koate is not approved to treat vWD, nor, cTTP however, based on some published reports using kotae for these indications, we are anticipating those type of off label inquiries. I will clearly disclose to the participants that these are off label indications.

Can the plasmaderived factor VIII still play a role in the treatment of acquired hemophilia A at the time of new drugs?

: Bypassing agents are the first-line therapy in the treatment of acquired hemophilia A (AHA), but not the only one. Other options as recombinant porcine factor VIII or plasmaderived concentrates (pdFVIII) are available to clinicians. Aim of this study was to evaluate whether the pdFVIII can still play a role in the treatment of AHA, and which patients could benefit from this therapy. All patients with AHA, presenting severe cardiovascular comorbidities, and treated with pdFVIII with or without von Willebrand factor (vWF), referred to two different hospitals, were initially considered. Eight patients were studied and divided into two groups: first, patients treated with daily infusion of pdFVIII; second, patients treated with pdFVIII continuous infusion. After 6 months of follow-up, all patients reached complete response. Mean consumption of clotting factor (219 000 vs. 142 000 IU), mean duration of therapy (61.5 vs. 10.5 days), and mean time necessary to disappearance of the inhibitors (INHs) (64 vs. 9 days) were higher in group 1, and the differences between the two groups were statistically significant (P < 0.05). Patients in group 1 also had a mean INH titer of 20.4 BU, higher than that of group 2 patients (8.4 BU), with a lower detectable FVIII level. Our study showed that pdFVIII can be an effective option for patients at high thromboembolic risk, even for those with high-titer INHs, especially if combined with vWF. The immunomodulatory role of vWF should, however, be better investigated in wider trials. The days of treatment with pdFVIII continuous infusion was proven to be similar to those reported with other drugs.

Genetic risk stratification to reduce inhibitor development in the early treatment of hemophilia A: a SIPPET analysis

AbstractA recent randomized trial, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET), showed a higher risk of inhibitor development with recombinant factor VIII (rFVIII) than plasma-derived concentrates (pdFVIII). We investigated whether risk stratification by F8 mutation identifies patients who do not suffer this deleterious effect of rFVIII. Among 235 randomized patients with severe hemophilia A previously untreated with FVIII concentrate, 197 with null mutations were classified as high risk and 38 with non-null mutations were classified as low risk. With pdFVIII, no inhibitors occurred in those with low genetic risk, whereas high-risk patients had a cumulative incidence of 31%. The risk among low- and high-risk patients did not differ much when they were treated with rFVIII (43% and 47%, respectively). This implies that patients with low genetic risk suffer disproportionate harm when treated with rFVIII (risk increment 43%), as also shown by the number needed to harm with rFVIII, which was 6.3 for genetically high-risk patients and only 2.3 for low-risk patients. Risk stratification by F8 mutation does not identify patients who can be safely treated with rFVIII, as relates to immunogenicity. This trial was registered at the European Clinical Trials Database (EudraCT) as #2009-011186-88 and at www.clinicaltrials.gov as #NCT01064284.

Current and Emerging Options for the Management of Inherited von Willebrand Disease.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder with an estimated prevalence of ~1% and clinically relevant bleeding symptoms in approximately 1:10,000 individuals. VWD is caused by a deficiency and/or defect of von Willebrand factor (VWF). The most common symptoms are mucocutaneous bleeding, hematomas, and bleeding after trauma or surgery. For decades, treatment to prevent or treat bleeding has consisted of desmopressin in milder cases and of replacement therapy with plasma-derived concentrates containing VWF and Factor VIII (FVIII) in more severe cases. Both are usually combined with supportive therapy, e.g. antifibrinolytic agents, and maximal hemostatic measures. Several developments such as the first recombinant VWF concentrate, which has been recently licensed for VWD, will make a more “personalized” approach to VWD management possible. As research on new treatment strategies for established therapies, such as population pharmacokinetic-guided dosing of clotting factor concentrates, and novel treatment modalities such as aptamers and gene therapy are ongoing, it is likely that the horizon to tailor therapy to the individual patients’ needs will be extended, thus, further improving the already high standard of care in VWD in most high-resource countries.

Purification of Plasma-Derived Coagulation Factor VIII by Immobilized-Zn2+ and -Co2+ Affinity Chromatography

Coagulation factor VIII (FVIII) is a glycoprotein that plays a crucial role in the clotting cascade. Replacement therapies with recombinant and plasma-derived concentrates of FVIII are used for treatment of hemophilia A. We have previously purified the human plasma FVIII by immobilized metal affinity chromatography (IMAC) using Cu2+ as the metal ligand. In this work we report the purification of FVIII using Zn2+ and Co2+, two metal ions that bind proteins more weakly. Human plasma was directly applied to the anion-exchange ANX Sepharose FF column and the eluate was used as starting material for the studies in IMAC columns. Using imidazole as desorbing agent, FVIII was recovered with 65% activity in the IMAC-Zn2+ column and with 74% activity in the IMAC-Co2+ column. Purification factors were 4 and 9, respectively. Using a pH gradient, FVIII was eluted at pH 5.0 with 17% activity in the IMAC-Zn2+ and 77% activity in the IMAC-Co2+. Vitamin K-dependent proteins, a family of proteins that includes Prothrombin and coagulation factor IX, coeluted with FVIII in the ANX Sepharose FF column and were recovered with the unbound proteins on both IMAC columns. Therefore, Co2+ and Zn2+ columns were as effective as the Cu2+ column in separating FVIII from vitamin K-dependent proteins. Finally, we have shown that FVIII remained complexed with the von Willebrand factor.

The History of Clotting Factor Concentrates Pharmacokinetics.

Clotting factor concentrates (CFCs) underwent tremendous modifications during the last forty years. Plasma-derived concentrates made the replacement therapy feasible not only in the hospital but also at patients’ home by on-demand or prophylactic regimen. Virucidal methods, implemented soon after hepatitis and AIDS outbreak, and purification by Mabs made the plasma-derived concentrates safer and purer. CFCs were considered equivalent to the other drugs and general rules and methods of pharmacokinetics (PK) were applied to their study. After the first attempts by graphical methods and calculation of In Vivo Recovery, compartment and non-compartment methods were applied also to the study of PK of CFCs. The bioequivalence of the new concentrates produced by means of recombinant DNA biotechnology was evaluated in head-to-head PK studies. Since the beginning, the large inter-patient variability of dose/response of replacement therapy was realized. PK allowed tailoring haemophilia therapy and PK driven prophylaxis resulted more cost effective. Unfortunately, the need of several blood samples and logistic difficulties made the PK studies very demanding. Recently, population PK (PopPK) has been applied to the prediction of CFCs dosing by Bayesian methodology. By PopPK also sparse data may allow evaluating the appropriateness of replacement therapy.

Recombinant factor VIIa concentrate versus plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors.

In people with haemophilia, therapeutic clotting agents might be recognised as a foreign protein and induce anti-factor VIII antibodies, known as 'inhibitors'. Drugs insensitive to such antibodies, either recombinant or plasma-derived, are called factor VIII 'by-passing' agents and used for treatment of bleeding in people with inhibitors. To determine the clinical effectiveness of recombinant factor VIIa concentrate compared to plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Coagulopathies Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Coagulopathies Trials Register: 23 September 2015. Randomised and quasi-randomised controlled clinical trials comparing recombinant factor VIIa concentrate to human plasma-derived concentrates (high-dose human or recombinant factor VIII or factor IX concentrate; non-activated prothrombin complex concentrates; activated prothrombin complex concentrates) in people with haemophilia. Comparisons with animal-derived products were excluded. Two authors independently assessed the trials (eligibility and risk of bias) and extracted data. No combined meta-analyses were performed due to the unavailability of outcomes and comparisons common to the included trials. A total of 15 trials were identified, two of which (with data for a total of 69 participants) were eligible for analysis. Both trials showed methodological flaws and did not show superiority of one treatment over the other. Both the treatments showed that recombinant factor VIIa and activated prothrombin complex concentrate appeared to have a similar haemostatic effect in both trials, without increasing thromboembolic risk. Based on the separate analysis of the two available randomised trials, recombinant factor VIIa and activated prothrombin complex concentrate were found to be similar in efficacy and safety. However, there is a need for further, well-designed, adequately-powered, randomised controlled trials to assess the relative benefits and risks of using recombinant factor VIIa compared to human plasma-derived concentrates in people with haemophilia with inhibitors. It is advisable that researchers in the field define commonly agreed objective outcome measures in order to enable the pooling of their results, thus increasing the power of comparisons. To date, data could not be combined in a formal meta-analysis. For the same reason reporting concordant and discordant pairs in cross-over trials is recommended.

Maladies hémorragiques congénitales : quel avenir pour les dérivés plasmatiques par rapport aux recombinants et aux produits sanguins labiles ?

Until 1990, congenital hemorrhagic disorders were treated by plasma-derived concentrates. The first recombinant drug, recombinant factor VIII was available after this date and few years later recombinant factor IX could also be proposed to patients. The evolution of market share in France was different between these two drugs: while recombinant factor VIII took a large place in hemophilia A treatment (85%), plasma-derived factor IX represent 50% of the French market. In the next years, the arrival of long-acting antihemophilic factors may lead to the dramatically reduce the amount of plasma-derived antihemophilic factors used to treat hemophilia. For rare bleeding coagulation disorders, plasma-derived concentrates are still widely used, while they are the only concentrates available in most diseases. This situation is unlikely to evolve significantly in the next years.

Treatment of hemophilia in the near future.

Advancements and debacles have characterized hemophilia treatment over the past 50 years. The 1970s saw the availability of plasma-derived concentrates making prophylaxis and home therapy possible. This optimistic perception changed extremely in the early 1980s, when most people with hemophilia were infected with HIV and hepatitis viruses. Then, also in the 1980s, the rapid progress in molecular biology led to the development of recombinant therapeutic products. This important advancement was a huge technological leap fresh off from the earlier 1980s disaster. Now in the 21st century, the newer bioengineering drugs open a new hopeful phase for the management of hemophilia. The current efforts are concentrated on producing novel coagulation factors with prolonged bioavailability, increased potency, and resistance to inactivation and potentially reduced immunogenicity; this phase of evolution is improving very quickly. 2014 is the year of marketing approval by the Food and Drug Administration of the first bioengineered FVIII and FIX long-acting drugs, using Fc-fusion strategy. This represents the first significant advance in the hemophilia therapy that dramatically transforms patient management by substantially reducing the frequency of injections, improving compliance, and simplifying prophylaxis and, in turn, refining the quality of life of hemophilia patients, offering them a nearly normal life expectancy, particularly to newborns with hemophilia B.

Real-life evidence in evaluating effectiveness of treatment in Haemophilia A with a recombinant FVIII concentrate: a non-interventional study in emerging countries.

Some progress has been made regarding availability of recombinant factor VIII concentrates and prophylaxis for haemophilia A in emerging countries, where plasma-derived concentrates were used in the vast majority. Clinical studies to document their introduction and effectiveness are so far not widely available in literature. This non-interventional study evaluates the real-life effectiveness and safety of prophylactic and on-demand treatment with recombinant factor VIII formulated with sucrose (rFVIII-FS) for bleed control and preservation of joints in emerging countries from Eastern Europe, North Africa and Middle East area. One hundred and eighty-six patients from 11 countries were enrolled, mean±SD age 12.8±12.7years. At enrolment, majority (79.6%) had severe haemophilia A (<2%IUmL(-1) ), 47.8% had a target joint, 15% had an inhibitor history and one patient was on immune tolerance induction. During the 24-month observation period, 58.1% of the patients were prescribed prophylaxis at every visit, 31.7% were on an on-demand regimen. Patients with severe haemophilia A on prophylaxis (n=82) had a mean annual rate of treated bleeds of 2.8±4.4, whereas it was 19.1±32.0 for the on-demand group (n=31), and a mean total Gilbert Score of 9.9±10.3 at baseline and 4.1±6.7 at study end; vs. 15.2±17.3 and 13.7±17.1 for on-demand respectively. The majority of the bleeds (91.1%) were treated with one or two infusions. Four patients without inhibitor history had a first positive inhibitor test during the study. This study demonstrates the effective use of rFVIII-FS in emerging countries and adds to the established safety profile of rFVIII-FS.

Plasma-Derived C1 Inhibitor Concentrate Did Not Increase the Risk of Thromboembolism in Patients with Hereditary Angioedema Due to C1-Inhibitor Deficiency – a Long-Term Survey

Plasma-Derived C1 Inhibitor Concentrate Did Not Increase the Risk of Thromboembolism in Patients with Hereditary Angioedema Due to C1-Inhibitor Deficiency – a Long-Term Survey