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Transfusion Therapy for Coagulation Factor Deficiencies
This chapter reviews products available to treat deficiencies of plasma coagulation proteins. The development of blood component therapy and subsequently protein concentrates that are enriched in particular coagulation factors and other proteins made possible the effective treatment of bleeding episodes in patients with hemophilia and other diatheses. In the 1940s, a collaborative effort funded by the US government was undertaken among protein scientists with the goal of rapidly developing a method to isolate albumin from human plasma to provide a lyophilized intravascular volume expander for use in the military. As part of this effort, Dr. Edwin Cohn developed an ethanol fractionation procedure that was amenable to large-scale manufacturing. Building on the foundation of the Cohn fractionation procedure (see Chapter 115 ), the first coagulation factor concentrates were developed in the mid-1960s and provided a safer and more effective treatment for patients with the X-linked coagulation deficiencies, hemophilia A and B. Given the limited human plasma resource as a raw material for the production of all but a few coagulation protein concentrates, manufacturers of human plasma–based products attempted to derive the maximum yield from each pool of plasma by deriving more products from these processes.
The development of recombinant products was fueled by infectious disease transmission through derived products. Currently licensed products are produced in mammalian cell culture to optimize necessary posttranslational modifications required for biologic activity. These recombinant expression processes are complicated and expensive. Transgenic recombinant technology has been explored as a way to decrease or eliminate reliance on the human plasma resource.
Recently, recombinant technology has made substantial progress in the development of long-acting factor VIII and IX preparations, which are effective in preventing as well as treating bleeding episodes; however, the advances have been more significant in the extension of the factor IX half-life, rather than factor VIII. By multiple mechanisms the half-lives of these coagulation proteins have been extended, profoundly impacting the daily life of patients with hemophilia who use factor concentrate as prophylaxis, as prolonged half-life factors have reduced the number of infusions to maintain factor efficacy.
During the last decade, several non-factor concentrates, novel agents with preferred routes of administration and improved dosing schedules have become available for patients with hemophilia with and without inhibitors. In addition, results from gene therapy for both factor VIII and IX deficiencies are promising and may lead to a dramatic shift in the future paradigm treatment for these patients. Viral vectors enable the liver cells to make a functional copy of the missing factor, eliminating the need for routine prophylactic therapy and reducing the number of spontaneous or trauma-related bleeding episodes.
Hemophilia A and B
The hemophilias are X-linked disorders caused by deficiencies of either factor VIII (hemophilia A, or classic hemophilia) or factor IX (hemophilia B, or Christmas disease). The genes for these coagulation factors are located in close proximity to the long arm of the X chromosome. Whereas hemophilia A affects 1:5000 males, hemophilia B affects 1:30,000. This difference in incidence is roughly correlated with the size of the genes, and more than 30% of cases arise from spontaneous mutations.
The major morbidity of the severe hemophilias A and B is arthropathy, a result of recurrent joint bleeding developing over the course of years in those with inhibitors or those who are untreated or undertreated. The major cause of hemorrhagic mortality is bleeding into critical closed spaces (e.g., intracranial). Central nervous system (CNS) bleeding occurs in 3% to 14% of patients, and mortality from CNS hemorrhage ranges from 20% to 50% with neurologic sequelae (including seizures, motor impairment, or mental retardation) observed in 40% to 50% of survivors. CNS bleeding episodes occur predominantly in patients with severe disease (<1% factor level). A more detailed discussion of the hemophilias and the molecular biology of factors VIII and IX can be found in Chapter 134 .
Transfusion Therapy for Hemophilia A and B
History of Transfusion for Hemophilia
Transfusion was first proposed by Schönlein and his student Hopf in 1832 as a treatment for “bleeders” who were suffering from exsanguinating hemorrhage, and these two were likely the first to have used the term Haemophilie to describe the disease. The first effective transfusion-based intervention for hemophilia is credited to Samuel Lane who, in 1840, infused 10 to 12 ounces of fresh human blood into a 12-year-old boy with postoperative hemorrhage after eye surgery for correction of a squint. Subsequently, a variety of interventions, using the infusion of human and animal blood and blood derivatives, were used in the therapy of hemorrhage in patients with congenital bleeding diatheses ( Table 136.1 ). Citrated plasma was first used in 1923 for the treatment of hemophilia by Feissly in a father-to-son transfusion. Development of modern blood banking in the 1930s and expansion of transfusion during and after World War II allowed for more widespread use of whole blood and subsequently frozen plasma in the treatment of hemophilia. Because of limited availability, the use of whole blood and components of whole blood for the treatment of hemophilia and other diseases was initially confined to larger metropolitan areas. In addition, volume constraints associated with the quantity of whole blood or plasma needed to achieve therapeutic levels of coagulation limited their usefulness.
Table 136.1
Development of Transfusion Therapy for Hemophilia
| 1832 | Schönlein proposes transfusion for exsanguination |
| 1840 | Lane transfuses whole blood to stop postoperative bleeding in hemophilia |
| 1905 | Weil reports use of human serum to treat hemophilia |
| 1911 | Addis fractionates plasma by acid method |
| 1923 | Feissly uses citrated plasma in ABO blood group-mismatched father-to-son transfusion for hemophiliaia |
| 1930s–1940s | Development of modern blood banking. Availability of whole blood and frozen plasma for therapy (allows levels of approximately 5%) |
| 1946 | Cohn develops ethanol fractionation of plasmaia |
| 1949 | Graham uses FFP in canine hemophilia modelia |
| 1945–1960 | Fractionation of plasmas with AHF activity |
| 1952 | Biggs distinguishes hemophilia B from hemophilia Aia |
| 1953 | Graham, Langdell, and Brinkhous develop quantitative assays to measure AHFia |
| 1958 | Barium precipitation of plasma to enrich for factor IX |
| 1963 | Wagner uses glycine precipitation to partially purify factor VIII |
| 1964 | Pool develops clinically useful cryoprecipitate for factor VIII deficiency (allows levels of >20%) |
| 1966 | Johnson uses PEG to partially purify factor VIII |
| 1967 | Brinkhous develops glycine and PEG method to produce large-scale high potency factor VIII product (allows levels of 100%) |
| 1965–1970 | Home infusion therapy |
| 1969 | Hoag produces large-scale prothrombin complex concentrate for factor IX deficiency |
| 1970s | HBsAg assay is developed |
| 1978–1985 | HIV contaminates blood supply and factor concentrates |
| 1979–1986 | Heat treatment of factor concentrates reduces transmission of hepatitis B and HIV |
| 1985 | Assay for HIV is licensed |
| 1982 | Immunoaffinity method of purification for factor VIII |
| 1986 | S/D method of treating infusible protein solutions to inactivate enveloped viruses |
| 1992–1993 | First recombinant factor VIII concentrates are licensed |
| 1998 | Recombinant factor IX concentrate is licensed |
| 1999 | Nucleic acid amplification testing of blood donor |
| 1999 | Recombinant factor VIIa approved for hemophilia A and B with inhibitor |
| 2007 | Recombinant factor VIIa approved for acquired hemophilia |
| 2011 | First plasma-derived factor XIII product approved by the FDA |
| 2011 | Successful report of AAV mediated gene therapy for factor IX deficiency |
AAV, Adeno-associated virus; AHF, Human antihemophilic factor; FDA, Food and Drug Administration; FFP, fresh-frozen plasma; HBsAg, hepatitis B surface antigen; HIV, human immunodeficiency virus; PEG, polyethylene glycol; S/D, solvent/detergent.
The advent of modern transfusion therapy for hemophilia came with the observation that the cold-insoluble precipitate remaining after the thawing of frozen plasma at 4°C contains high concentrations of factor VIII. Application of this procedure to the separation of components of the whole blood allowed for the production of a reduced-volume blood product known as cryoprecipitate . Cryoprecipitate derived from a single whole blood collection contains approximately 125 units of factor VIII and quickly replaced frozen plasma as the therapy of choice for the treatment of bleeding episodes in hemophilia A in the 1960s. The availability of cryoprecipitate made the treatment of bleeding episodes by patients in their homes, rather than at a hospital, a reality. In addition, the development of quantitative assays for factor VIII and factor IX meant that the two diseases could now be distinguished and the effects of transfusion therapy on circulating levels of factors could be more accurately assessed.
Before the discovery of plasma cryoprecipitate, significant advances had been made in the fractionation of plasma using ethanol, glycine, polyethylene glycol, a combination of glycine and polyethylene glycol, and calcium or barium to precipitate plasma proteins. These techniques, in conjunction with cold precipitation of frozen plasma, laid the groundwork that resulted in the production of the first factor VIII and factor IX concentrates for clinical use. These concentrates could be lyophilized and stored at temperatures up to 4°C with extended stability. Infusion of factor concentrates resulted in high circulating levels of factor VIII and factor IX without the complication of volume overload and paved the way for intensive infusion therapy for serious and life-threatening bleeding complications such as intracranial, retroperitoneal, and retropharyngeal hemorrhages and to prevent bleeding following surgery. Because they were produced from large pools of single plasma donations (>1000), initial concentrates were nearly universally contaminated with viral pathogens such as hepatitis B and non-A, non-B hepatitis (hepatitis C). Initial attempts to attenuate viral transmission using pasteurization and dry heat, instituted by manufacturers in the late 1970s and early 1980s, were found to limit the transmission of hepatitis B. Eventually, these techniques were found to inactivate the human immunodeficiency virus (HIV). Before the widespread application of these techniques, however, the majority of patients with severe hemophilia treated with concentrates between 1978 and 1985 were infected with HIV and hepatitis C virus. This tragic consequence of infusion therapy helped fuel the development of modern strategies to reduce the risk of viral transmission by products derived from human plasma. These strategies include careful screening of potential donors for risk factors leading to infection with transfusion-transmissible infections, more vigilant surveillance of the blood donor base for the appearance of new pathogens, development and implementation of testing specifically for markers of infectious agents, purification strategies that reduce viral contamination in final products, and physical and chemical viral inactivation methods to treat infusible products. Development and refinement in techniques of molecular biology in the 1970s and 1980s resulted in the cloning of the genes for many plasma proteins, including factor VIII and factor IX. Within the next decade, the production and licensure of biologically active recombinant factor VIII and factor IX products had become a reality. Concentrates of these recombinant products have been shown to be effective and have not been associated with the transmission of pathogens. Further development of recombinant products centered on the removal of all human and animal proteins in the production and formulation to further reduce the risk of inadvertent contamination with emerging pathogens, such as variant prions, and newly discovered agents, such as hepatitis G virus and other transfusion-transmitted viruses. In addition, episodic supply constraints incurred in the manufacture of recombinant proteins in mammalian cell culture systems resulting in supply shortages of recombinant factor VIII have led to greater interest in transgenic production of human plasma proteins compared with mammalian cell culture. With transgenic systems, raw material from which the protein of interest is purified (milk, plant tissue) can be produced in abundance.
Infusion Regimens and Dosing for Hemophilia
Traditionally, the mainstay of therapy for hemophilia involved the treatment of bleeding episodes with infusing products capable of replacing the missing factor VIII or IX. This so-called on-demand therapy is effective in staunching hemorrhages, but not before tissue damage has occurred. Bleeding is especially destructive in the synovium, where a vicious cycle develops in which the initial bleed results in a proliferative inflammatory response and hypertrophy of synovial tissues that then become more susceptible to further trauma and bleeding. The result in the short term is repeated bleeds into the same joint, resulting in what is referred to as a “target joint,” and eventually chronic joint destruction or hemophilic arthropathy. Patients with chronic arthropathy often require surgical intervention, including synovectomy, debridement, joint replacement, or even joint fusion.
With the availability of factor concentrates that allowed for the attainment of high plasma levels of factor VIII or IX, prophylactic therapy became possible. This approach was pioneered by Swedish treaters who demonstrated that the use of prophylactic regimens, wherein trough factor levels maintained at greater than 1% of normal, reduces the incidence of arthropathy and CNS hemorrhage. Greater availability of virally safe factor concentrates has allowed for the initiation of prophylactic regimens in early childhood. This “primary” form of prophylaxis has become the standard of care in developed countries. For prophylaxis, the National Hemophilia Foundation Medical and Scientific Advisory Council recommends infusion of factor VIII 25 to 50 U/kg 3 times a week or every other day for hemophilia A and factor IX 40 to 100 U/kg 2 or 3 times a week for hemophilia B. Prophylaxis is not universally practiced, however, owing to the high cost of factor concentrates, the requirement for frequent intravenous (IV) infusion, and the need for the placement of central venous catheters in some patients, especially small children, to obtain IV access. The cost factor makes primary prophylaxis and even on-demand treatment prohibitive to more than 60% of the hemophilia patients in the world.
To understand how prophylaxis was instituted in the United States, a survey of hemophilia treatment centers in March 2010 was conducted: 62 centers responded, and 32% (or 20 centers) initiated prophylaxis on a once-weekly schedule, 21% (13 centers) on a twice-weekly schedule, and 47% on a thrice-weekly schedule. This survey demonstrated the diversity in practice and deviation from the recommendation from the National Hemophilia Foundation. Alternative schedules for prophylaxis have been investigated. For example, the Canadian Hemophilia Primary Prophylaxis Study, a small, prospective, multicenter study, evaluated a tailored prophylaxis regimen in 25 patients with severe hemophilia A; patients were started at 50 U/kg once a week and were escalated to 30 U/kg twice weekly and then 25 U/kg on alternate days if one of the three situations occurred: development of a target joint, four bleeds in 3 months, or five or more bleeds occurred into any one joint. This seemed to be well-tolerated, resulting in 1.2 bleeds per year while maintaining good joint function; long-term follow-up of tailored prophylaxis is needed, but it may be a cost-effective and central line-sparing option.
Dosing regimens for the treatment of bleeding episodes in hemophilia have also evolved paralleling the availability of high-concentration pathogen-safe replacement products. Although no universal regimen for “on-demand” treatment has been established, certain trends prevail. In general, for non-life-threatening bleeding episodes, the goal of therapy is to achieve a plasma factor VIII or IX level of between 30% and 100%. For life-threatening bleeds or prophylaxis for surgical procedures, the goal is a level of 100% to be maintained by repeated bolus infusions or continuous infusion for a duration of 10 to 14 days or longer, depending on the severity of the bleed or surgical intervention.
The majority of prophylaxis regimens aim at achieving a trough factor level of approximately 1%. Primary prophylaxis, instituted in young children, is aimed at preventing any joint bleeding episodes that would eventually result in chronic arthropathy. Secondary prophylaxis refers to limited or prolonged periods of prophylactic therapy, instituted after a serious bleed or the development of repeated bleeding into a single joint (target joint); tertiary prophylaxis entails the initiation of prophylaxis subsequent to the onset of joint disease. The landscape of prophylaxis regimens is changing and the novel agents, with less frequent, subcutaneous administration may replace the more traditional practice; as of August 2020, the current Medical and Scientific Advisory Council of the National Hemophilia Foundation did not recommend a preferred prophylaxis regimen.
To prevent the development of a target joint and chronic arthropathy, many hemophilia treatment centers have recently adopted a regimen of two, three, or more infusions after hemarthrosis (aggressive on-demand treatment). Specific dosing regimens for bleeding episodes have been developed by treaters and treatment centers. Although slight variations in indications and target plasma levels of factor VIII and factor IX among treatment centers exist, representative dosing regimens are similar and are presented in Table 136.3 .
Table 136.2
Dosing Regimens for Traditional Factor Replacement in Bleeding and Prophylaxis in Hemophilia
Data from DiMichele D. Hemophilia 1996: New approach to an old disease. Pediatr Clin North Am . 1996;43:709; Mannucci PM. Haemophilia treatment protocols around the world: towards a consensus. Haemophilia . 1998;4:421; and Lusher J. Treatment of Congenital Coagulopathies , AABB Press; 1999.
| Site | Factor Level (%) | Dose Hemophilia A (U/kg) | Dose Hemophilia B (U/kg) | Duration of Treatment | Comments |
|---|---|---|---|---|---|
| Joint | 30–70 | 15–35 | 30–70 | 1–3 days | Splinting, temporary splinting, no weight bearing |
| Life threatening (e.g., intracranial, retropharyngeal, retroperitoneal) | 80–100 | 40–50 | 80–100 | 1–14 days | Antifibrinolytic therapy with retropharyngeal bleeds |
| Soft tissue | 30–50 | 15–25 | 30–50 | 2–5 days | Higher levels can be used for compartment syndrome |
| Surgery | 80–100 | 40–50 | 80–100 | 10–14 days (or shorter for minor procedures) | Significant blood loss can occur into large muscles of the lower extremity and the iliopsoas |
| Oral | 20–50 | 10–25 | 20–50 | 1–2 days | Antifibrinolytic therapy |
| Gastrointestinal a | 30–100 | 15–50 | 30–100 | 2–3 days | Should be evaluated for source |
| Genitourinary b | 30–50 | 15–25 | 30–50 | 1–2 days | Avoid antifibrinolytic therapy |
| Prophylaxis c | 50 | 25 | 50 | qod or 3×/week |
qod, Every other day.
b Painless spontaneous hematuria often requires no treatment other than fluid intake. Persistence requires treatment and evaluation.
c Use of a schedule of 25 U/kg qod and a dose of 40 U/kg with an interval of 2 days between the next dose may increase compliance by decreasing infusions to three per week.
Treatment of Hemophilia
Products Available for Treatment of Factor VIII Deficiency
Factor VIII Concentrates
In high-income countries, the current standard of care for the treatment and prevention of bleeding episodes in patients with severe hemophilia A and in patients with a mild or moderate disease who do not respond to 1-deamino 8-d arginine vasopressin (DDAVP) is the infusion of recombinant or plasma-derived factor VIII. Recovery of recombinant factor VIII ranges from 1.5% to 2.5%/IU/kg so that dosing assumes a rise in plasma factor VIII activity of 2% for every 1 IU/kg infused. Available concentrates are optimized to enhance viral clearance during purifications and undergo one or more viral inactivation steps during manufacture. Plasma-derived factor VIII concentrates, treated with multiple purification and viral inactivation steps, are also available and have an excellent recent record of safety.
Recombinant Factor VIII Products
Highly purified recombinant factor VIII concentrates have been licensed in North America, Europe, and Japan since the early 1990s. These are either full-length or B domain–deleted molecules (the B domain is not required for activity in coagulation) that are expressed in mammalian cell culture (Chinese hamster ovary, embryonic hamster, or human kidney cell lines) and are purified using immunoaffinity techniques. The development of these recombinant products was fueled primarily by concerns regarding the safety of the human blood donor pool and the viral epidemics that occurred within the hemophilia population with the use of early plasma-derived products. As with highly purified plasma-derived factor VIII concentrates, the first-generation recombinant products contain animal or human proteins in cell culture and final formulation for stability. “Second-generation” products (Kogenate FS, Bayer, Refacto, Pfizer) contain animal or human proteins in cell culture only. Third-generation products (Advate, Takeda Pharmaceutical Company Limited; Xyntha, Pfizer) do not have human proteins or other additives in the cell culture or as a stabilizer. Recombinant production methods that do not rely on the human plasma resource theoretically should provide for unlimited supply.
The first extended half-life recombinant factor VIII product, Eloctate, Biogen Idec, synthesized in a human embryonic kidney cell line, was US Food and Drugs Administration (FDA) approved in June 2014. It is a B domain–deleted factor VIII covalently linked to human immunoglobulin G1; this Fc fusion protein has extended the half-life of factor VIII: in adults, almost 20 hours, 12 to 17 years old almost 16.5 hours, 6 to 11 years old about 14.5 hours and 2 to 5 years old, 12 hours. Almost all of the patients (99%) receiving Eloctate for 6 months were able to use the product every 3 days or longer to maintain a factor VIII level of 1% to 3%. Eloctate, Biogen Idec, has been used on-demand, for prophylaxis and in the perioperative setting. For prophylaxis, Biogen Idec recommends 50 IU/kg every 4 days and suggests personalizing the dose based on response, 25 to 65 IU/kg at 3 to 5-day intervals. The package insert also indicates that children less than 6 years old, may require more frequent or higher doses (up to 80 IU/kg). For minor and moderate bleeds, Eloctate 20 to 30 IU/kg can be given every 24 to 48 hours; however, in children less than 6 years old, Eloctate should be given every 12 to 24 hours. For major bleeding episodes, Eloctate 40 to 50 IU/kg should be given every 12 to 24 hours and in children less than 6 years old, Eloctate should be given every 8 to 24 hours. Many other long-acting factor VIII products are currently available.
Intermediate- and High-Purity Plasma-Derived Concentrates
Intermediate-purity plasma-derived concentrates are prepared from cryoprecipitated plasma or fresh-frozen plasma (FFP), from which factor VIII is further purified using precipitation, gel permeation, ion exchange, or affinity chromatography, often in combination. Specific factor VIII coagulant activity in these products ranges from 2 to more than 100 IU/mg of protein, and many of the methods used also copurify significant amounts of von Willebrand factor (vWF), making them useful for the treatment of some patients with von Willebrand disease (vWD; see later discussion on the treatment of vWD). More highly purified plasma-derived concentrates are produced using heparin ligand or immunoaffinity purification methods and have specific activities ranging from 140 to greater than 3000 IU/mg. To stabilize the factor VIII molecule, the majority of these products are formulated by adding human albumin before lyophilization: Alphanate (Grifols USA) and Koate-DVI (Talecris Biotherapeutics).
Emicizumab-kxwh (Hemlibra, Genentech)
Emicizumab is a humanized bispecific antibody that binds both IX and X, essentially mimicking the factor VIII function and is given subcutaneously. In 2017, the results of the phase 3 HAVEN-1 study demonstrated that weekly subcutaneous dosing in patients >12 years old with inhibitors had a significant reduction in annualized bleeding rate (ABR); group A patients were receiving bypass agents on demand and given weekly emicizumab; group B did not receive emicizumab and group C patients were receiving prophylaxis with bypass agents plus emicizumab. There was an 87% reduction in ABR in group A vs group B. The treatment was well tolerated with the most common side effect being local injection site reactions (15%). However, three patients receiving high-dose activated prothrombin complex concentrate (aPCC) with emicizumab prophylaxis developed thrombotic microangiopathy (TMA). In the HAVEN-2 study, a phase 3 study of children 2 to 12 years old with hemophilia A and inhibitors, patients were randomly assigned to three different dosing schedules: group A received emicizumab 1.5 mg/kg weekly, group B 3 mg/kg every 2 weeks and Group C 6 mg/kg weekly monthly; ABR was 0.3, 0.2, and 2.2 respectively. The most common side effects were local reactions and nasopharyngitis. There were no reports of TMA or thrombosis. Two patients developed anti-drug antibodies: in one patient there was a loss of drug efficacy and in the other, the antibody resolved without intervention. Patients without inhibitors have also benefited from emicizumab prophylaxis, as demonstrated in the HAVEN 3 study, evaluating weekly (group A), every other week prophylaxis (group B), no emicizumab (group C), and weekly dosing with prophylactic factor VIII (group D); there was a 96% and 97% reduction in the ABR for groups A and B, with over 50% of participants not having any bleeds. Local reactions were the most common and there was no TMA, thrombosis, antidrug antibodies or inhibitors. HAVEN-4 included patients with and without inhibitors receiving monthly emicizumab (a small cohort received 4 weekly doses prior to starting the monthly dosing) and the ABR was 2.4, with side effects being similar to those seen in HAVEN-3. Emicizumab can be given from infancy to adults at a loading dose of 3 mg/kg weekly for four doses; thereafter it can be given weekly (1.5 mg/kg), every 2 weeks (3 mg/kg), or monthly (6 mg/kg). Since different vial sizes cannot be mixed and volume may exceed the maximum for a single injection, patients need to receive multiple injections for one dose but compared to 104 to 156 (twice–thrice weekly) IV administrations/year, patient satisfaction remains high. There are two black box warnings for emicizumab: TMA with the use of high-dose aPCC and thrombosis. For surgery or breakthrough bleeding, patients may need factor VIII replacement or a bypassing agent.
Clotting based coagulation tests, including activated partial thromboplastin time (aPTT), factor VIII levels (other factor levels), Bethesda assays, aPTT-based activated protein C resistance and activated clotting time will not be accurate in patients who are using emicizumab (PTT can be shortened-normal) and secondary to the long half-life of emicizumab, these abnormalities in clotting assays may persist for up to 6 months after the last dose; therefore, chromogenic (with bovine factor IXa and Xa) or immune-based assays for Factor VIII and Bethesda monitoring can be used. In the HAVEN trials, drug monitoring levels or coagulation assays were not used for clinical decision making and using animal models, emicizumab approximates a factor VIII level of 10% to 20%. If an inhibitor is suspected, anti-drug antibodies may be sent (commercial test not available); if an emicizumab level is needed, emicizumab calibrators and controls are available from r 2 Diagnostics.
Novel Direction for Factor VIII Deficiency
Many of the new products, like emicizumab, improve global hemostasis without the replacement of the Factor VIII product. Fitusiran, Sanofi, is in clinical trials and is a small inhibitory messenger RNA blocking antithrombin production and enhancing thrombin generation. This drug is given monthly, subcutaneously, and has been studied in patients with moderate or severe hemophilia A or B with or without inhibitors and has not yet been licensed. The Phase 1 study assessed pharmacokinetics and pharmacodynamics of weekly versus monthly dosing, demonstrating that there was a dose-dependent reduction in antithrombin with the monthly dosing; no thrombotic events were reported. A Phase 2 study of fitusiran at 50 and 80 mg, showed promising results with an ABR of 0.84 and suppression of antithrombin. Two thrombotic events were reported in patients using fitusiran: an atrial thrombosis and a fatal cerebral sinus venous thrombosis, in a patient receiving concurrent high-dose Factor VIII replacement; therefore, trials were temporarily halted and bleeding management guidelines for patients on fitusiran were published in December 2017. The current Phase 3 fitusiran trial was put on hold by Sanofi in October 2020 due to additional reports of thrombotic events.
Another novel therapeutic being evaluated in clinical trials in subjects with hemophilia A or B with or without inhibitors is concizumab, Novo Nordisk, a humanized monoclonal antibody to the K2 domain of tissue factor pathway inhibitor (TFPI), which impedes binding of TFPI to the active site of Factor Xa. In a Phase 2 trial, patients were given daily subcutaneous doses, with potential dose escalation if bleeding occurred; ABR was reduced by 78% in patients with inhibitors and three patients developed anti-drug antibodies without clinical correlations. In March 2020, concizumab trials were halted due to three thrombotic events but trials resumed in August 2020.
Gene Therapy for Factor IX Deficiency
A landmark paper was published in December 2011 describing a phase 1 trial of the first six patients with severe factor IX deficiency who received one peripheral IV injection of an adeno-associated virus (AAV) expressing a factor IX gene, at three different doses. This vector was selected as it does not integrate into the host genome and a capsid of AAV serotype 8 was added to avoid immunogenicity. Another advantage of using this serotype is the propensity for it to home to the liver. Sixty-seven percent of the patients in the trial no longer needed prophylaxis and the other 33% needed less factor. Patients who received the highest dose experienced a transient elevation of the alanine aminotransferase, between weeks 7 and 10, which resolved with prednisolone; this effect correlates with finding AAV8-capsid specific T cells in the peripheral blood. These authors published an update on the long-term outcome of 10 men (22 to 64 years old) treated with gene therapy using the AAV8 construct; the additional four patients received the high dose of the vector and had on average 5% factor IX levels, with a decrease in bleeding episodes, sustained over 4 years.
More recent trials in gene therapy take advantage of a point mutation in the factor IX gene, known as Factor IX Padua, which synthesizes about eightfold higher Factor IX than wild type; factor IX–R338L was engineered with a liver-specific promoter and infused at a dose of 5 × 10 11 vector genomes/kg in 10 men with severe hemophilia B with ABR reduction from 11.1 to 0.4 after infusion and average factor IX levels of 33.7 ± 18.5%. Two patients had an asymptomatic elevation of liver enzymes, which resolved after a short course of prednisone.
Gene Therapy for Factor VIII Deficiency
Due to the large size of the factor VIII gene, advances in gene therapy for hemophilia A have been much slower than for hemophilia B, with the first report for gene therapy in hemophilia A coming 8 years after the landmark hemophilia B publication. Nine men with severe hemophilia A received a single dose of AAV vector encoding a B domain deleted human factor VIII (AAV5-hVIII-SQ, BMN-280, BioMarin) at three doses with one receiving a low dose, one intermediate dose, and the remaining seven at a high dose, with the patients in the low and intermediate groups having factor VIII less than 3 IU/dL and 6/7 high-dose participants had >50 IU/dL, which persisted at 1 year. After the first patient in the high-dose group had an elevated ALT, the remainder of the group were given prophylactic prednisone. There were no neutralizing antibodies. In 2020, there was a 3-year follow-up of 15 patients who had received a dose of AAV5-hVIII-SQ; 13 of the 15 patients at 2 to 3 years who received a dose of 2 or 4 × 10 13 vector genomes/kg had factor VIII levels in the moderate range (mean 13% to 20%) with ABR of 0 and reduction of factor VIII from 139 to 155 infusions/year to 0 to 0.5. This product is not yet licensed in the United States, awaiting further safety data from an additional 2-year follow-up.
1-Deamino 8-d Arginine Vasopressin
The preferred product for the treatment of patients with mild or moderate hemophilia A is the synthetic octapeptide DDAVP, a vasopressin analog. DDAVP causes a release of factor VIII (and vWF) from endothelial cells, raising plasma factor VIII by approximately threefold (range 2- to 12-fold) in patients with hemophilia in whom the disease is caused by decreased production or secretion of a functional protein or a protein that has decreased activity. To be effective, DDAVP relies on a partial quantitative deficiency of factor VIII; thus, patients with severe hemophilia will not benefit from its use if the causative mutation results in no synthesis, secretion, or a nonfunctional protein. In a retrospective study assessing response to a DDAVP challenge in mild or moderate hemophilia, 57% of patients with mild hemophilia had a positive response, and several who failed the initial challenge had a response after a mean of 6 years, increasing the response rate to 71% in the mild group. The response to DDAVP in an individual patient is typically reproducible, and effective response must be documented before its routine use or as prophylaxis for bleeding in surgical procedures (see box on 1-Deamino 8-d Arginine Vasopressin Trial ). IV and intranasal preparations are available. The IV product has been used in a subcutaneous route of administration. The intranasal preparation more easily allows a patient to administer the compound on an as-needed basis in a home therapy regimen. The phenomenon of tachyphylaxis, the decreased effectiveness of repeated doses of the same compound, occurs after several, typically three, consecutive doses.
1-Deamino 8-D Arginine Vasopressin Trial
- 1.
Collect citrated plasma from the patient immediately before DDAVP infusion for testing with the post infusion blood specimen.
- 2.
Administer DDAVP IV (0.3 μg/1 kg) in 25–50 mL normal saline.
- 3.
Wait approximately 30 min after the infusion, carefully observing the patient for possible adverse side effects (increased blood pressure, facial flushing, signs or symptoms of hyponatremia).
- 4.
Collect post-DDAVP infusion specimen in sodium citrate at 60, 120, and 240 min.
- 5.
Compare the pre- and post-DDAVP factor VIII and vWF:Ag levels to confirm a therapeutic response, threefold increase from baseline (for mild or moderate hemophilia, response is defined as twofold increase in factor VIII: C levels or an absolute level above 0.31 U/mL at 1 h).
Injectable DDAVP (Sanofi Aventis) is available in 4 μg/mL. The recommended dose is 0.3 μg/kg, mixed in 30 mL normal saline (for children <10 kg, 10 mL normal saline), infused IV slowly over 30 minutes. This dose can be repeated after 12 to 24 hours. DDAVP nasal spray Stimate (CSL Behring) is available in a metered-dose pump that delivers 0.1 mL (150 μg) per activation (spray). The dose is one activation for patients weighing less than 50 kg and two activations in separate nostrils for those weighing more than 50 kg. In general, only three consecutive doses of DDAVP should be used unless otherwise advised by an experienced hemophilia treater. Because DDAVP is a vasopressin analog, there is a risk of fluid retention with its use. Changes in fluid balance can result in hyponatremia and seizures, especially when DDAVP is used in individuals on nonfluid-restricted or salt-restricted diets (e.g., elderly or very young patients or surgical patients undergoing fluid replacement with solutions with concentrations <0.9% sodium). For this reason, DDAVP is not recommended for children younger than 2 years of age. Caution is advised with the use of DDAVP in patients at risk for arterial thrombosis because there have been reports of myocardial infarction and cerebral thrombosis with its use.
Plasma/Cryoprecipitate
In communities where virally inactivated factor VIII concentrates are not available, cryoprecipitate provides an effective alternative to therapy with concentrates for hemophilia A and vWD patients. Cryoprecipitate is a small-volume product (10 to 15 mL) enriched in factor VIII, vWF, fibrinogen, fibronectin, and factor XIII. Dosing can be calculated assuming approximately 80 to 150 IU of factor VIII per bag of cryoprecipitate (derived from a 450-mL single whole blood donor collection unit). Thus, a typical 1750-IU dose (50% correction for a 70-kg patient) would require between 10 and 21 bags or units.
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