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Hemophilia A
CHAPTER 110
Hemophilia A Surbhi Saini, MBBS and Amy L. Dunn, MD Hemophilia A (also known as classical hemophilia) results from congenital deficiency of factor VIII (FVIII). It is an X-linked recessive disorder that results in decreased or absent circulating FVIII activity, leading to lifelong bleeding tendency. Hemophilia A has an incidence of approximately 1:5000 male births and accounts for approximately 85% of cases of hemophilia. It affects all racial and ethnic groups equally.
Pathophysiology: FVIII is a plasma glycoprotein consisting of six domains, A1– A2–B–A3–C1–C2 (Fig. 110.1). The encoding gene is found on the long arm of the X chromosome (Xq.28). The mature protein is a heterodimer with a light chain consisting of domains A3–C1–C2 and a heavy chain with the domains A1–A2–B. The majority of FVIII is thought to be synthesized in hepatic endothelial cells, but it may also be produced in endothelial cells in general (e.g., elevated FVIII levels during liver failure). On release into the circulation, it is noncovalently linked to von Willebrand factor (VWF), which prevents enzymatic degradation of nascent FVIII. During coagulation, the tissue factor (TF)–FVIIa complex activates FX and FIX, leading to conversion of prothrombin to thrombin. The initial thrombin cleavage of the FVIII light chain causes FVIII to be released into the circulation and which is then activated to FVIIIa by further thrombin-mediated proteolysis. FVIIIa, along with FIXa, in the presence of calcium, then act as cofactors on a phospholipid surface during activation of factors X, V and, ultimately, thrombin. This is also known as the tenase complex. Patients with hemophilia A are unable to generate adequate thrombin due to lack of FVIII and become dependent on the TF pathway. Circulating tissue factor pathway inhibitor (TFPI) efficiently downregulates the TF–FVIIa pathway as well as FXa, leading to decreased thrombin and bleeding. Thrombin-activated fibrinolysis inhibitor (TAFI) production is also decreased in hemophilia, leading to more rapid dissolution of the fibrin clot. A large number of molecular defects have been described in hemophilia A, including large gene deletions, inversions, single gene rearrangements, deletions, and insertions. A list of mutations leading to hemophilia A can be found at http://hadb.org.uk/ as well as https://www.cdc. gov/ncbddd/hemophilia/champs.html.
Clinical Manifestations: The hallmark of hemophilia-related bleeding is delayed bleeding along with joint and muscle bleeding. As hemophilia A is X-linked, the vast majority of affected patients are male. Females, however, can be affected by extreme X-chromosome lyonization, or with gene abnormalities such as Turner syndrome. A1
A2
B
ap
A3
C1
C2
FIGURE 110.1 Domain structure of factor VIII. Transfusion Medicine and Hemostasis. https://doi.org/10.1016/B978-0-12-813726-0.00110-0 Copyright © 2019 Elsevier Inc. All rights reserved.
677
678
Surbhi Saini, MBBS and Amy L. Dunn, MD
Heterozygous female carriers of hemophilia A may exhibit a bleeding tendency, most commonly heavy menstrual bleeding and postsurgical bleeding. There is a high rate of spontaneous mutation within the F8 gene, and approximately 30% of newly diagnosed patients will have no family history of hemophilia. In general, the severity of bleeding depends on the percentage of residual clotting factor activity. Patients with levels of >5%–40% are classified as having mild hemophilia, patients with levels of 1%–≤5% as moderate and those with less than 1% activity as having severe disease. Approximately 60% of persons with hemophilia have severe disease. They suffer from spontaneous bleeding while those with mild to moderate disease typically bleed only when challenged with trauma or surgery. In the newborn period, the most common findings are bleeding and bruising after venipuncture, heel sticks, immunizations, and circumcision. Intracranial hemorrhage remains the most dreaded complication of hemophilia in the first 2 years of life and occurs in about 7%–10% of infants. Infants born of known carrier mothers should not undergo instrumented birth and should not be circumcised until testing for FVIII rules out hemophilia. Older children and adults may experience excessive bruising, epistaxis, soft tissue hematomas, intracranial bleeding, and hemarthrosis. The single largest preventable cause of morbidity is degenerative joint disease due to recurrent hemarthrosis. Females who carry hemophilia may also have bleeding symptoms such as menorrhagia, oral bleeding, bleeding with childbirth, surgical, and trauma-related bleeding.
Diagnosis: An X-linked inheritance pattern, elevated partial thromboplastin time (PTT), and decreased plasma FVIII levels confirm the diagnosis. The most commonly used PTT reagents may not detect mild deficiency of FVIII. Prenatal diagnosis can be performed in the case of a known family history. Cord blood testing of FVIII levels can also be performed at the time of delivery.
Differential Diagnosis: Hemophilia A and B are clinically indistinguishable, and individual factor levels must be used to clarify the diagnosis. Patients with mildly low FVIII levels and an autosomal inheritance pattern may have type 3 von Willebrand disease (vWD). Patients with type 3 vWD will have moderately low FVIIII and absent VWF multimers, along with essentially absent VWF antigen and ristocetin cofactor activity. In this case, the low FVIII levels are a result of increased proteolysis, not decreased production. vWD type 2N should also be considered in the setting of mildly low FVIII levels, autosomal inheritance, and poor response to recombinant FVIII therapy. In vWD type 2N, the pathophysiology involves decreased FVIII binding to VWF, leading to rapid proteolysis of FVIII. This type of vWD can be evaluated via a VWF to FVIII binding assay. Acquired low FVIII levels can also result from autoantibody formation.
Management Comprehensive Care: A series of federally funded comprehensive hemophilia treatment centers (HTCs) exist to care for persons with hemophilia. They are typically staffed with hematologists, orthopedists, physical therapists, nurses, genetic counselors, psychologists, and social workers who specialize in the care of patients with bleeding disorders. It has been shown that patients who receive their care in an HTC setting have a longer life expectancy.
Hemophilia A
679
Factor Concentrates: The mainstay of hemophilia care is FVIII replacement with intravenously delivered FVIII concentrates. Concentrates are either plasma derived, containing varying amounts of VWF, or recombinant products, and both undergo multiple viral and pathogen attenuation steps. No infectious complications have been reported because these steps were incorporated into the manufacturing process; however, the possibility of contamination with new infectious agents such as prions cannot be excluded with plasma-derived products. Infusions can be delivered in response to bleeding episodes (“demand therapy”) or to prevent bleeding (“prophylaxis”). To prevent or minimize long-term sequelae, demand therapy should be given as soon as possible after a bleeding episode is recognized. Because the need for urgent treatment is so important, many patients affected by hemophilia are proficient in self-infusion techniques. During a bleeding episode, factor replacement therapy should never be delayed to perform imaging or laboratory studies. The dose and frequency of factor delivery is calculated based on the half-life of the product, the intravascular volume of distribution (1 unit of FVIII per kilogram raises the plasma concentration by about 2%) and the desired clotting factor activity. For example, to raise the factor level of a 20 kg child with severe hemophilia to 100%, the dose should be 20 kg × 50 IU = 1000 IU. Correction to FVIII levels of 40% activity is considered hemostatic in most cases; however, in the setting of surgery or life-/limb-threatening hemorrhage, higher FVIII levels (80%–100%) are recommended. Postsurgical hemostasis should maintain FVIII levels above 50%–70% for the first week and above 30% for the second week. Ancillary measures such as compressive dressings, cauterization, packing, and splinting should also be implemented when appropriate. Additionally, antiplatelet agents should be avoided. Table 110.1 illustrates a suggested approach to factor replacement therapy for commonly encountered bleeding events. Standard plasma and recombinant products have a half-life of 8–12 h. Recently, novel techniques such as conjugation of the recombinant FVIII molecule to neonatal Fc receptors (rFVIIIFc) or polyethylene glycol (PEGylated FVIII), as well as development of single-chain forms with increased VWF binding, has made it possible to extend the product half-life to 18–24 h, primarily by inhibition of degradation of the infused product in the plasma. In some situations, this allows for decreased frequency of infusions for patients on prophylaxis, and/or achievement of higher trough levels improving their overall quality of life.
Prophylaxis: In developed countries, prophylactic therapy delivered one to four times per week is considered the standard of care and is the only therapy proven to prevent the long-term complication of degenerative joint disease. It is common practice to begin prophylaxis before the onset of recurrent joint bleeding, typically before the age of 3 years. Dosage can be individualized based on IV access, bleeding phenotype, and pharmacokinetics.
Desmopressin: Desmopressin, or DDAVP (1-deamino-8-d-arginine vasopressin), is a synthetic form of the hormone vasopressin. The product may be given intravenously, subcutaneously, or via nasal delivery. DDAVP causes release of FVIII and VWF from their endothelial storage sites. Patients with mild hemophilia A and some with
680
Surbhi Saini, MBBS and Amy L. Dunn, MD
TABLE 110.1 Suggested Approaches to Treatment of Bleeding Episodes
Bleed Site
Desired Activity
Length of Therapy
Ancillary Measures
Central nervous system
100%
7–14 days, then strongly consider prophylactic therapy for a minimum of 6 months
Continuous infusion FVIII; antiepileptic prophylaxis; surgical intervention
Oral cavity or mucosal bleeding
30%–60%
3–7 days
Antifibrinolytic therapy; custom mouthpiece; topical thrombin powder
Retropharynx
80%–100%
7–14 days
Continuous infusion FVIII; antifibrinolytic therapy
Nose
30%–60%
1–3 days
Packing, cautery; saline nose spray/ gel; nasal vasoconstrictor spray; antifibrinolytic therapy
Gastrointestinal tract
40%–80%
3–7 days
Antifibrinolytic therapy; endoscopy with cautery
Genitourinary tract
40%–60%
1–3 days
Vigorous hydration; evaluation for stones/urinary tract infection; avoid antifibrinolytic therapy; glucocorticoids
Muscle
40%–80%
Every other day until pain-free movement
Rest, ice, compression, elevation; physical therapy
Iliopsoas muscle
80%–100%
Until radiographic evidence of resolution
Continuous infusion FVIII; bedrest; physical therapy
Joint
40%–80%
1–2 days
Rest, ice, compression, elevation; physical therapy
Target joint
80% day 1, 40% days 2 and 4
3–4 days
Rest, ice, compression, elevation; physical therapy
moderate disease can be tested with DDAVP, and if they show a response by manifesting hemostatic levels or at least a threefold increase in FVIII, then DDAVP is often sufficient to treat mild bleeding symptoms such as nose, mouth, and soft tissue bleeding. FVIII storage pools become depleted after multiple doses, so this treatment is not adequate for lengthy therapy, and fluid intake must be monitored closely as hyponatremia may result, particularly in children less than 2 years of age and in the elderly. In most cases, life- or limb-threatening bleeding episodes require FVIII replacement.
Antifibrinolytic Therapies: Antifibrinolytic medications such as aminocaproic acid or tranexamic acid are used to prevent excessive fibrinolysis and are particularly useful in diminishing bleeding symptoms in locations with prominent fibrinolytic activity, such as the mouth, gastrointestinal tract, and uterus.
Liver Transplant: Liver transplantation has been performed in several patients with hemophilia as a result of severe liver disease. The transplant effectively cures the hemophilia.
Hemophilia A
681
Complications Infectious Complications: In the late 1970s and early 1980s, before incorporation of viral attenuation steps (mid-1980s for HIV and late 1980s for HBV and HCV) in factor manufacturing, many patients became infected with HCV and/or HIV from contaminated concentrates. Although many patients succumbed to these infections, there is a large cohort of long-term survivors as a result of highly active antiretroviral therapies for HIV and combination therapy for HCV.
Inhibitors: A serious complication of congenital hemophilia A is the development of inhibitory alloantibodies to FVIII. These inhibitory antibodies occur in approximately 20%–30% of patients with severe hemophilia, and to a lesser extent in those with mild and moderate disease (2%–3%). They are more likely to occur in the setting of a family history of inhibitors, in patients having large gene disruptions and in nonwhite patients. Nongenetic risk factors such as factor replacement during inflammatory states (known as the “danger theory”) and delivery via continuous infusion may play a role. To date, it is still debated whether antibody formation is influenced by the type of product used; however, some data suggest that plasma-derived products that contain VWF may be less immunogenic. Alloantibodies to FVIII in congenital hemophilia are most commonly directed against the A2 and C2 domains and often develop within the first 10–20 exposures to exogenous FVIII but can develop at any age. They typically neutralize both endogenous and exogenous FVIII, an important aspect in patients with mild–moderate disease who develop inhibitors because it changes their phenotype to severe disease. The antibody titer is measured using a Bethesda assay and is expressed in units (BU). One BU is the amount of antibody, which lowers the plasma factor level by 50%. Low-titer inhibitors (<5 BU) are often transient but may be persistent and carry clinical significance, while high-titer inhibitors (>5 BU) significantly impact patient care and quality of life. Autoantibodies can develop in patients without hemophilia, leading to a condition known as acquired hemophilia. These autoantibodies occur most commonly in the setting of pregnancy, malignancy, and autoimmune conditions; however, 50% of cases are idiopathic. Immune tolerance therapy (ITT) with repeated exposure to FVIII concentrate over a period of months to years may eradicate the antibody. ITT has been accomplished using both high-dose (100–200 IU/kg per day) and low-dose standard half-life concentrates (50 IU/kg thrice weekly) of FVIII. More recently, there is an increasing interest in the concept of decreased immunogenicity with the use of extended half-life products, particularly rFVIIIFc. While randomized controlled trials in previously untreated patients are awaited, these products could be considered in patients with refractory inhibitors. Patients treated with more frequent dosing have not only demonstrated less frequent breakthrough bleeding during ITT but also more frequently require central venous access device placement to ensure IV access. Both recombinant and vWFcontaining plasma-derived products have been used successfully. Additionally, immunosuppressive agents such as cyclosporine and rituximab have been used, with some success. Bleeding in the setting of a high-titer inhibitor often requires bypassing therapy with either high dosage of recombinant FVIIa or an activated prothrombin complex concentrate (see Chapter 41).
682
Surbhi Saini, MBBS and Amy L. Dunn, MD
Joint Disease: Degenerative joint disease due to recurrent hemarthrosis is the single largest preventable cause of morbidity for patients with hemophilia A. The pathogenesis of this arthropathy is multifactorial, with iron and free radical formation being the most likely culprit triggering the degenerative changes. Recurrent hemarthrosis causes an inflammatory reaction resulting in a thickened, hyperemic synovium. This inflamed synovium participates in a vicious cycle of further bleeding, and ultimately the destruction of bone and articular cartilage. Unfortunately, the physical findings are often subtle in the early stages of joint disease, and investigation with magnetic resonance imaging may be required to demonstrate hemosiderin deposition and or hypertrophic synovium. More recently, point-of-care ultrasound protocols have proved timeefficient and user-friendly in detecting early joint bleeds and/or abnormalities and guiding treatment. Synovectomy, arthroscopic, or radionuclide has been used to address recurrent bleeding in these target joints, but degenerative it remains to be seen whether it can halt articular changes are common even in the setting of bleed reduction.
Recent Advances in Hemophilia Care Gene Therapy: Gene therapy has the potential to change the landscape in hemophilia care. For hemophilia A, progress in gene therapy has been slow, largely due to the large size of the F8 genome that requires transfer to a viral cassette. Currently, a codon-optimized F8 gene transfer strategy using an adeno-associated virus has shown promise in early clinical trials. Preclinical animal models suggest that liver-directed F8 gene transfer may prevent, and even eradicate preexisting inhibitors in patients with hemophilia.
Nonfactor Replacement Products: Development of a recombinant, monoclonal bispecific antibody that mimics the actions of the intrinsic tenase complex (Hemlibra ®, Emicizumab-kxwh), and hence obviates the need for FVIII replacement, has been a significant milestone in the treatment of patients with hemophilia A and inhibitors. A recently concluded phase III trial of this molecule has demonstrated safety and efficacy with once-weekly subcutaneous dosing. The concept of “rebalancing hemostasis” and thus increasing thrombin generation has been applied to the development of another category of products to treat hemophilia. Fitusiran (ALN-AT3SC), a small interfering RNA that decreases natural antithrombin levels, is currently undergoing an open label extension trial. Concizumab (monoclonal anti-TFPI antibody), inhibits TFPI leading to increase in thrombin generation via the TF-FVIIa pathway. Preliminary clinical trials are being conducted.
Further Reading Abshire, T., & Kenet, G. (2004). Recombinant factor VIIa: Review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost, 2(6), 899–909. Dunn, A. L., & Abshire, T. C. (2006). Current issues in prophylactic therapy for persons with hemophilia. Acta Haematol, 115, 162–171. Franchini, M. (2007). The use of desmopressin as a hemostatic agent: A concise review. Am J Hematol, 82, 731–735.
Hemophilia A
683
Gouw, S. C., van der Bom, J. G., & van den Berg, M. (2007). Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: The CANAL cohort study. Blood, 109, 4648–4654. Hay, C. R. M., & DiMichele, D. M. (2012). The principal results of the International Immune Tolerance Study: A randomized dose comparison. Blood, 119, 1335–1344. Hooiveld, M., Roosendaal, G., Vianen, M., van den Berg, M., Bijlsma, J., & Lafeber, F. (2003). Blood-induced joint damage: Longterm effects in vitro and in vivo. J Rheumatol, 30, 339–344. Manco-Johnson, M. J., Abshire, T. C., Shapiro, A. D., Riske, B., Hacker, M. R., Kilcoyne, R., et al. (2007). Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med, 357, 535–544. Soucie, J. M., Nuss, R., Evatt, B., Abdelhak, A., Cowan, L., Hill, H., et al. (2000). Mortality among males with hemophilia: Relations with source of medical care. The Hemophilia Surveillance System Project Investigators. Blood, 96, 437–442. Peyvandi, F., Mannucci, P. M., Garagiola, I., El-Beshlawy, A., Elalfy, M., Ramanan, V., et al. (2016). A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med, 374, 2054–2064. Pipe, S. W. (2016). New therapies for hemophilia. Hematol Am Soc Hematol Educ Program, 2016, 650–656.
Hemophilia A Surbhi Saini, MBBS and Amy L. Dunn, MD Hemophilia A (also known as classical hemophilia) results from congenital deficiency of factor VIII (FVIII). It is an X-linked recessive disorder that results in decreased or absent circulating FVIII activity, leading to lifelong bleeding tendency. Hemophilia A has an incidence of approximately 1:5000 male births and accounts for approximately 85% of cases of hemophilia. It affects all racial and ethnic groups equally.
Pathophysiology: FVIII is a plasma glycoprotein consisting of six domains, A1– A2–B–A3–C1–C2 (Fig. 110.1). The encoding gene is found on the long arm of the X chromosome (Xq.28). The mature protein is a heterodimer with a light chain consisting of domains A3–C1–C2 and a heavy chain with the domains A1–A2–B. The majority of FVIII is thought to be synthesized in hepatic endothelial cells, but it may also be produced in endothelial cells in general (e.g., elevated FVIII levels during liver failure). On release into the circulation, it is noncovalently linked to von Willebrand factor (VWF), which prevents enzymatic degradation of nascent FVIII. During coagulation, the tissue factor (TF)–FVIIa complex activates FX and FIX, leading to conversion of prothrombin to thrombin. The initial thrombin cleavage of the FVIII light chain causes FVIII to be released into the circulation and which is then activated to FVIIIa by further thrombin-mediated proteolysis. FVIIIa, along with FIXa, in the presence of calcium, then act as cofactors on a phospholipid surface during activation of factors X, V and, ultimately, thrombin. This is also known as the tenase complex. Patients with hemophilia A are unable to generate adequate thrombin due to lack of FVIII and become dependent on the TF pathway. Circulating tissue factor pathway inhibitor (TFPI) efficiently downregulates the TF–FVIIa pathway as well as FXa, leading to decreased thrombin and bleeding. Thrombin-activated fibrinolysis inhibitor (TAFI) production is also decreased in hemophilia, leading to more rapid dissolution of the fibrin clot. A large number of molecular defects have been described in hemophilia A, including large gene deletions, inversions, single gene rearrangements, deletions, and insertions. A list of mutations leading to hemophilia A can be found at http://hadb.org.uk/ as well as https://www.cdc. gov/ncbddd/hemophilia/champs.html.
Clinical Manifestations: The hallmark of hemophilia-related bleeding is delayed bleeding along with joint and muscle bleeding. As hemophilia A is X-linked, the vast majority of affected patients are male. Females, however, can be affected by extreme X-chromosome lyonization, or with gene abnormalities such as Turner syndrome. A1
A2
B
ap
A3
C1
C2
FIGURE 110.1 Domain structure of factor VIII. Transfusion Medicine and Hemostasis. https://doi.org/10.1016/B978-0-12-813726-0.00110-0 Copyright © 2019 Elsevier Inc. All rights reserved.
677
678
Surbhi Saini, MBBS and Amy L. Dunn, MD
Heterozygous female carriers of hemophilia A may exhibit a bleeding tendency, most commonly heavy menstrual bleeding and postsurgical bleeding. There is a high rate of spontaneous mutation within the F8 gene, and approximately 30% of newly diagnosed patients will have no family history of hemophilia. In general, the severity of bleeding depends on the percentage of residual clotting factor activity. Patients with levels of >5%–40% are classified as having mild hemophilia, patients with levels of 1%–≤5% as moderate and those with less than 1% activity as having severe disease. Approximately 60% of persons with hemophilia have severe disease. They suffer from spontaneous bleeding while those with mild to moderate disease typically bleed only when challenged with trauma or surgery. In the newborn period, the most common findings are bleeding and bruising after venipuncture, heel sticks, immunizations, and circumcision. Intracranial hemorrhage remains the most dreaded complication of hemophilia in the first 2 years of life and occurs in about 7%–10% of infants. Infants born of known carrier mothers should not undergo instrumented birth and should not be circumcised until testing for FVIII rules out hemophilia. Older children and adults may experience excessive bruising, epistaxis, soft tissue hematomas, intracranial bleeding, and hemarthrosis. The single largest preventable cause of morbidity is degenerative joint disease due to recurrent hemarthrosis. Females who carry hemophilia may also have bleeding symptoms such as menorrhagia, oral bleeding, bleeding with childbirth, surgical, and trauma-related bleeding.
Diagnosis: An X-linked inheritance pattern, elevated partial thromboplastin time (PTT), and decreased plasma FVIII levels confirm the diagnosis. The most commonly used PTT reagents may not detect mild deficiency of FVIII. Prenatal diagnosis can be performed in the case of a known family history. Cord blood testing of FVIII levels can also be performed at the time of delivery.
Differential Diagnosis: Hemophilia A and B are clinically indistinguishable, and individual factor levels must be used to clarify the diagnosis. Patients with mildly low FVIII levels and an autosomal inheritance pattern may have type 3 von Willebrand disease (vWD). Patients with type 3 vWD will have moderately low FVIIII and absent VWF multimers, along with essentially absent VWF antigen and ristocetin cofactor activity. In this case, the low FVIII levels are a result of increased proteolysis, not decreased production. vWD type 2N should also be considered in the setting of mildly low FVIII levels, autosomal inheritance, and poor response to recombinant FVIII therapy. In vWD type 2N, the pathophysiology involves decreased FVIII binding to VWF, leading to rapid proteolysis of FVIII. This type of vWD can be evaluated via a VWF to FVIII binding assay. Acquired low FVIII levels can also result from autoantibody formation.
Management Comprehensive Care: A series of federally funded comprehensive hemophilia treatment centers (HTCs) exist to care for persons with hemophilia. They are typically staffed with hematologists, orthopedists, physical therapists, nurses, genetic counselors, psychologists, and social workers who specialize in the care of patients with bleeding disorders. It has been shown that patients who receive their care in an HTC setting have a longer life expectancy.
Hemophilia A
679
Factor Concentrates: The mainstay of hemophilia care is FVIII replacement with intravenously delivered FVIII concentrates. Concentrates are either plasma derived, containing varying amounts of VWF, or recombinant products, and both undergo multiple viral and pathogen attenuation steps. No infectious complications have been reported because these steps were incorporated into the manufacturing process; however, the possibility of contamination with new infectious agents such as prions cannot be excluded with plasma-derived products. Infusions can be delivered in response to bleeding episodes (“demand therapy”) or to prevent bleeding (“prophylaxis”). To prevent or minimize long-term sequelae, demand therapy should be given as soon as possible after a bleeding episode is recognized. Because the need for urgent treatment is so important, many patients affected by hemophilia are proficient in self-infusion techniques. During a bleeding episode, factor replacement therapy should never be delayed to perform imaging or laboratory studies. The dose and frequency of factor delivery is calculated based on the half-life of the product, the intravascular volume of distribution (1 unit of FVIII per kilogram raises the plasma concentration by about 2%) and the desired clotting factor activity. For example, to raise the factor level of a 20 kg child with severe hemophilia to 100%, the dose should be 20 kg × 50 IU = 1000 IU. Correction to FVIII levels of 40% activity is considered hemostatic in most cases; however, in the setting of surgery or life-/limb-threatening hemorrhage, higher FVIII levels (80%–100%) are recommended. Postsurgical hemostasis should maintain FVIII levels above 50%–70% for the first week and above 30% for the second week. Ancillary measures such as compressive dressings, cauterization, packing, and splinting should also be implemented when appropriate. Additionally, antiplatelet agents should be avoided. Table 110.1 illustrates a suggested approach to factor replacement therapy for commonly encountered bleeding events. Standard plasma and recombinant products have a half-life of 8–12 h. Recently, novel techniques such as conjugation of the recombinant FVIII molecule to neonatal Fc receptors (rFVIIIFc) or polyethylene glycol (PEGylated FVIII), as well as development of single-chain forms with increased VWF binding, has made it possible to extend the product half-life to 18–24 h, primarily by inhibition of degradation of the infused product in the plasma. In some situations, this allows for decreased frequency of infusions for patients on prophylaxis, and/or achievement of higher trough levels improving their overall quality of life.
Prophylaxis: In developed countries, prophylactic therapy delivered one to four times per week is considered the standard of care and is the only therapy proven to prevent the long-term complication of degenerative joint disease. It is common practice to begin prophylaxis before the onset of recurrent joint bleeding, typically before the age of 3 years. Dosage can be individualized based on IV access, bleeding phenotype, and pharmacokinetics.
Desmopressin: Desmopressin, or DDAVP (1-deamino-8-d-arginine vasopressin), is a synthetic form of the hormone vasopressin. The product may be given intravenously, subcutaneously, or via nasal delivery. DDAVP causes release of FVIII and VWF from their endothelial storage sites. Patients with mild hemophilia A and some with
680
Surbhi Saini, MBBS and Amy L. Dunn, MD
TABLE 110.1 Suggested Approaches to Treatment of Bleeding Episodes
Bleed Site
Desired Activity
Length of Therapy
Ancillary Measures
Central nervous system
100%
7–14 days, then strongly consider prophylactic therapy for a minimum of 6 months
Continuous infusion FVIII; antiepileptic prophylaxis; surgical intervention
Oral cavity or mucosal bleeding
30%–60%
3–7 days
Antifibrinolytic therapy; custom mouthpiece; topical thrombin powder
Retropharynx
80%–100%
7–14 days
Continuous infusion FVIII; antifibrinolytic therapy
Nose
30%–60%
1–3 days
Packing, cautery; saline nose spray/ gel; nasal vasoconstrictor spray; antifibrinolytic therapy
Gastrointestinal tract
40%–80%
3–7 days
Antifibrinolytic therapy; endoscopy with cautery
Genitourinary tract
40%–60%
1–3 days
Vigorous hydration; evaluation for stones/urinary tract infection; avoid antifibrinolytic therapy; glucocorticoids
Muscle
40%–80%
Every other day until pain-free movement
Rest, ice, compression, elevation; physical therapy
Iliopsoas muscle
80%–100%
Until radiographic evidence of resolution
Continuous infusion FVIII; bedrest; physical therapy
Joint
40%–80%
1–2 days
Rest, ice, compression, elevation; physical therapy
Target joint
80% day 1, 40% days 2 and 4
3–4 days
Rest, ice, compression, elevation; physical therapy
moderate disease can be tested with DDAVP, and if they show a response by manifesting hemostatic levels or at least a threefold increase in FVIII, then DDAVP is often sufficient to treat mild bleeding symptoms such as nose, mouth, and soft tissue bleeding. FVIII storage pools become depleted after multiple doses, so this treatment is not adequate for lengthy therapy, and fluid intake must be monitored closely as hyponatremia may result, particularly in children less than 2 years of age and in the elderly. In most cases, life- or limb-threatening bleeding episodes require FVIII replacement.
Antifibrinolytic Therapies: Antifibrinolytic medications such as aminocaproic acid or tranexamic acid are used to prevent excessive fibrinolysis and are particularly useful in diminishing bleeding symptoms in locations with prominent fibrinolytic activity, such as the mouth, gastrointestinal tract, and uterus.
Liver Transplant: Liver transplantation has been performed in several patients with hemophilia as a result of severe liver disease. The transplant effectively cures the hemophilia.
Hemophilia A
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Complications Infectious Complications: In the late 1970s and early 1980s, before incorporation of viral attenuation steps (mid-1980s for HIV and late 1980s for HBV and HCV) in factor manufacturing, many patients became infected with HCV and/or HIV from contaminated concentrates. Although many patients succumbed to these infections, there is a large cohort of long-term survivors as a result of highly active antiretroviral therapies for HIV and combination therapy for HCV.
Inhibitors: A serious complication of congenital hemophilia A is the development of inhibitory alloantibodies to FVIII. These inhibitory antibodies occur in approximately 20%–30% of patients with severe hemophilia, and to a lesser extent in those with mild and moderate disease (2%–3%). They are more likely to occur in the setting of a family history of inhibitors, in patients having large gene disruptions and in nonwhite patients. Nongenetic risk factors such as factor replacement during inflammatory states (known as the “danger theory”) and delivery via continuous infusion may play a role. To date, it is still debated whether antibody formation is influenced by the type of product used; however, some data suggest that plasma-derived products that contain VWF may be less immunogenic. Alloantibodies to FVIII in congenital hemophilia are most commonly directed against the A2 and C2 domains and often develop within the first 10–20 exposures to exogenous FVIII but can develop at any age. They typically neutralize both endogenous and exogenous FVIII, an important aspect in patients with mild–moderate disease who develop inhibitors because it changes their phenotype to severe disease. The antibody titer is measured using a Bethesda assay and is expressed in units (BU). One BU is the amount of antibody, which lowers the plasma factor level by 50%. Low-titer inhibitors (<5 BU) are often transient but may be persistent and carry clinical significance, while high-titer inhibitors (>5 BU) significantly impact patient care and quality of life. Autoantibodies can develop in patients without hemophilia, leading to a condition known as acquired hemophilia. These autoantibodies occur most commonly in the setting of pregnancy, malignancy, and autoimmune conditions; however, 50% of cases are idiopathic. Immune tolerance therapy (ITT) with repeated exposure to FVIII concentrate over a period of months to years may eradicate the antibody. ITT has been accomplished using both high-dose (100–200 IU/kg per day) and low-dose standard half-life concentrates (50 IU/kg thrice weekly) of FVIII. More recently, there is an increasing interest in the concept of decreased immunogenicity with the use of extended half-life products, particularly rFVIIIFc. While randomized controlled trials in previously untreated patients are awaited, these products could be considered in patients with refractory inhibitors. Patients treated with more frequent dosing have not only demonstrated less frequent breakthrough bleeding during ITT but also more frequently require central venous access device placement to ensure IV access. Both recombinant and vWFcontaining plasma-derived products have been used successfully. Additionally, immunosuppressive agents such as cyclosporine and rituximab have been used, with some success. Bleeding in the setting of a high-titer inhibitor often requires bypassing therapy with either high dosage of recombinant FVIIa or an activated prothrombin complex concentrate (see Chapter 41).
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Surbhi Saini, MBBS and Amy L. Dunn, MD
Joint Disease: Degenerative joint disease due to recurrent hemarthrosis is the single largest preventable cause of morbidity for patients with hemophilia A. The pathogenesis of this arthropathy is multifactorial, with iron and free radical formation being the most likely culprit triggering the degenerative changes. Recurrent hemarthrosis causes an inflammatory reaction resulting in a thickened, hyperemic synovium. This inflamed synovium participates in a vicious cycle of further bleeding, and ultimately the destruction of bone and articular cartilage. Unfortunately, the physical findings are often subtle in the early stages of joint disease, and investigation with magnetic resonance imaging may be required to demonstrate hemosiderin deposition and or hypertrophic synovium. More recently, point-of-care ultrasound protocols have proved timeefficient and user-friendly in detecting early joint bleeds and/or abnormalities and guiding treatment. Synovectomy, arthroscopic, or radionuclide has been used to address recurrent bleeding in these target joints, but degenerative it remains to be seen whether it can halt articular changes are common even in the setting of bleed reduction.
Recent Advances in Hemophilia Care Gene Therapy: Gene therapy has the potential to change the landscape in hemophilia care. For hemophilia A, progress in gene therapy has been slow, largely due to the large size of the F8 genome that requires transfer to a viral cassette. Currently, a codon-optimized F8 gene transfer strategy using an adeno-associated virus has shown promise in early clinical trials. Preclinical animal models suggest that liver-directed F8 gene transfer may prevent, and even eradicate preexisting inhibitors in patients with hemophilia.
Nonfactor Replacement Products: Development of a recombinant, monoclonal bispecific antibody that mimics the actions of the intrinsic tenase complex (Hemlibra ®, Emicizumab-kxwh), and hence obviates the need for FVIII replacement, has been a significant milestone in the treatment of patients with hemophilia A and inhibitors. A recently concluded phase III trial of this molecule has demonstrated safety and efficacy with once-weekly subcutaneous dosing. The concept of “rebalancing hemostasis” and thus increasing thrombin generation has been applied to the development of another category of products to treat hemophilia. Fitusiran (ALN-AT3SC), a small interfering RNA that decreases natural antithrombin levels, is currently undergoing an open label extension trial. Concizumab (monoclonal anti-TFPI antibody), inhibits TFPI leading to increase in thrombin generation via the TF-FVIIa pathway. Preliminary clinical trials are being conducted.
Further Reading Abshire, T., & Kenet, G. (2004). Recombinant factor VIIa: Review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost, 2(6), 899–909. Dunn, A. L., & Abshire, T. C. (2006). Current issues in prophylactic therapy for persons with hemophilia. Acta Haematol, 115, 162–171. Franchini, M. (2007). The use of desmopressin as a hemostatic agent: A concise review. Am J Hematol, 82, 731–735.
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Gouw, S. C., van der Bom, J. G., & van den Berg, M. (2007). Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: The CANAL cohort study. Blood, 109, 4648–4654. Hay, C. R. M., & DiMichele, D. M. (2012). The principal results of the International Immune Tolerance Study: A randomized dose comparison. Blood, 119, 1335–1344. Hooiveld, M., Roosendaal, G., Vianen, M., van den Berg, M., Bijlsma, J., & Lafeber, F. (2003). Blood-induced joint damage: Longterm effects in vitro and in vivo. J Rheumatol, 30, 339–344. Manco-Johnson, M. J., Abshire, T. C., Shapiro, A. D., Riske, B., Hacker, M. R., Kilcoyne, R., et al. (2007). Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med, 357, 535–544. Soucie, J. M., Nuss, R., Evatt, B., Abdelhak, A., Cowan, L., Hill, H., et al. (2000). Mortality among males with hemophilia: Relations with source of medical care. The Hemophilia Surveillance System Project Investigators. Blood, 96, 437–442. Peyvandi, F., Mannucci, P. M., Garagiola, I., El-Beshlawy, A., Elalfy, M., Ramanan, V., et al. (2016). A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med, 374, 2054–2064. Pipe, S. W. (2016). New therapies for hemophilia. Hematol Am Soc Hematol Educ Program, 2016, 650–656.