Hemophilia A (Factor VIII Deficiency)

Hemophilia A is an inherited, X-linked, recessive disorder caused by deficiency of functional plasma clotting factor VIII (FVIII). In a significant number of cases, the disorder results from a new mutation. Rarely hemophilia A develops as an acquired autoimmune process.

Morbidity and death are primarily the result of hemorrhage, although infectious diseases (eg, HIV infection, hepatitis) became prominent, particularly in patients who received blood products prior to 1985.

Laboratory studies for suspected hemophilia include a complete blood cell count, coagulation studies, and an FVIII assay. In patients with an established diagnosis of hemophilia, periodic laboratory evaluations include screening for the presence of FVIII inhibitor and screening for transfusion-related or transmissible diseases such as hepatitis and HIV infection. Measurement of FVIII levels is important for monitoring FVIII replacement therapy. (See Workup.)

The treatment of hemophilia may involve prophylaxis, management of bleeding episodes, immune tolerance induction for patients with factor inhibitors, and treatment and rehabilitation of patients with hemophilia synovitis. Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center (see Treatment and Medication).[1]

Please see the following for more information:

• Acquired Hemophilia
• Hemophilia B (Factor IX Deficiency)
• Hemophilia C

Classification

The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or on plasma procoagulant levels; the latter are the most widely used criteria. Classification according to plasma procoagulant levels is as follows:

• Severe hemophilia - FVIII level less than 1% of normal (< 0.01 IU/mL)
• Moderate hemophilia - FVIII level 1-5% of normal (0.01-0.05 IU/mL)
• Mild hemophilia - FVIII level more than 5% but less than 40% of normal (>0.05 to < 0.40 IU/mL)

Severe disease presents in children younger than 1 year and accounts for 43-70% of hemophilia A cases. Moderate disease presents in children aged 1-2 years and accounts for 15-26% of cases. Mild disease presents in children older than 2 years and accounts for 15-31% of cases.

Clinical bleeding symptom criteria have been used because patients with FVIII levels of less than 1% occasionally have little or no spontaneous bleeding and appear to have clinically moderate or mild hemophilia. Furthermore, the reverse is true for patients with procoagulant activities of 1-5%, who may present with clinically severe disease.

Historical background

Hemophilia is one of the oldest described genetic diseases. An inherited bleeding disorder in males was recognized in Talmudic records of the second century.

The modern history of hemophilia began in 1803 with the description of hemophilic kindred by John Otto, followed by the first review of hemophilia by Nasse in 1820. Wright demonstrated evidence of laboratory defects in blood clotting in 1893; however, FVIII was not identified until 1937, when Patek and Taylor isolated a clotting factor from the blood, which they called antihemophilic factor (AHF).

A bioassay of FVIII was introduced in 1950. Although the intimate relationship between FVIII and von Willebrand factor (vWF) is now known, it was not appreciated at the time. In 1953, decreased FVIII levels in patients with vWF deficiency was first described. Further research by Nilson and coworkers indicated the interaction between these 2 clotting factors.

In 1952, hemophilia B was described and was named Christmas disease after the surname of the first patient who was examined in detail. The differentiation of hemophilia B from hemophilia A followed the observation that mixing plasma from a patient with "true hemophilia" with plasma from a patient with Christmas disease corrected the clotting time. Hemophilia A makes up approximately 80% of hemophilia cases.

In the early 1960s, cryoprecipitate (the precipitate from fresh frozen plasma that has been thawed and centrifuged) became the first concentrate available for the treatment of patients with hemophilia. In the 1970s, lyophilized (ie, freeze-dried) intermediate-purity concentrates were obtained from large pools of blood donors. The introduction of concentrated lyophilized products that are easy to store and transport dramatically improved the quality of life of patients with hemophilia and facilitated their preparation for surgery and home care.

Unfortunately, the large size of the donor pool—as many as 20,000 donors may contribute to a single lot of plasma-derived FVIII concentrate—heightened the risk of viral contamination of commercial FVIII concentrates. By the mid-1980s, the majority of patients with severe hemophilia had been exposed to hepatitis A, hepatitis B, and hepatitis C viruses and human immunodeficiency virus (HIV).

Viricidal treatment of plasma-derived FVIII concentrates has been effective in eliminating new HIV transmissions and virtually eliminating hepatitis B and hepatitis C exposures. The introduction of recombinant FVIII concentrate, and the gradual elimination of albumin from the production process used for these products, has virtually eliminated the risk of viral exposure.

Factor VIII production, processing, and structure

Primary sites of factor VIII (FVIII) production are thought to be the vascular endothelium in the liver and the reticuloendothelial system. Liver transplantation corrects FVIII deficiency in persons with hemophilia.

FVIII messenger RNA has been detected in the liver, spleen, and other tissues.[2] Studies of FVIII production in transfected cell lines have shown that following synthesis, FVIII moves to the lumen of the endoplasmic reticulum, where it is bound to several proteins that regulate secretion, particularly immunoglobulin binding protein, from which it has to dissociate in an energy-dependent process.

Cleavage of FVIII's signal peptide and the addition of oligosaccharides also occur in the endoplasmic reticulum. The chaperone proteins, calnexin and calreticulin, enhance both FVIII secretion and degradation.

A part of the factor FVIII protein in the endoplasmic reticulum is degraded within the cell. The other part enters the Golgi apparatus, where several changes occur to produce the heavy and light chains and to modify the carbohydrates. The addition of sulfates to tyrosine residues of the heavy and light chains is necessary for full procoagulant activity, with the sulfated region playing a role in thrombin interaction. This posttranslational sulfation of tyrosine residues impacts the procoagulant activity of factor VIII and its interaction with von Willebrand factor (vWF).

von Willebrand factor

FVIII circulates in plasma in a noncovalently bound complex with vWF, which plays significant roles in the function, production, stabilization, conformation, and immunogenicity of FVIII.[3] VWF has been termed FVIII-related antigen (FVIII-R); related terminology for FVIII is FVIII-coagulant (FVIII-C).

VWF appears to promote assembly of the heavy and light chains of FVIII and more efficient secretion of FVIII from the endoplasmic reticulum. It also directs FVIII into the Weibel-Palade bodies, which are the intracellular storage sites for vWF.

In plasma, vWF stabilizes FVIII and protects it from degradation. In the presence of normal vWF protein, the half-life of FVIII is approximately 12 hours, whereas in the absence of vWF, the half-life of FVIII-C is reduced to 2 hours.[4, 5, 6]

The clotting cascade

The role of the coagulation system is to produce a stable fibrin clot at sites of injury. The clotting mechanism has two pathways: intrinsic and extrinsic. See the image below.

Coagulation Cascade

The intrinsic system is initiated when factor XII is activated by contact with damaged endothelium. The activation of factor XII can also initiate the extrinsic pathway, fibrinolysis, kinin generation, and complement activation.

In conjunction with high-molecular-weight kininogen (HMWK), factor XIIa converts prekallikrein (PK) to kallikrein and activates factor XI. Activated factor XI, in turn, activates factor IX in a calcium-dependent reaction. Factor IXa can bind phospholipids. Then, factor X is activated on the phospholipid surface; activation of factor X involves a complex (tenase complex) of factor IXa, thrombin-activated FVIII, calcium ions, and phospholipid.

In the extrinsic system, the conversion of factor X to factor Xa involves tissue factor (TF), or thromboplastin; factor VII; and calcium ions. TF is released from the damaged cells and is thought to be a lipoprotein complex that acts as a cell surface receptor for factor VII, with its resultant activation. TF also adsorbs factor X to enhance the reaction between factor VIIa, factor X, and calcium ions. Factor IXa and factor XII fragments can also activate factor VII.

In the common pathway, factor Xa (generated through the intrinsic or extrinsic pathways) forms a prothrombinase complex with phospholipids, calcium ions, and thrombin-activated factor Va. The complex cleaves prothrombin into thrombin and prothrombin fragments 1 and 2.

Thrombin converts fibrinogen into fibrin and activates FVIII, factor V, and factor XIII. Fibrinopeptides A and B, the results of the cleavage of peptides A and B by thrombin, cause fibrin monomers to form and then polymerize into a meshwork of fibrin; the resultant clot is stabilized by factor XIIIa and the cross-linking of adjacent fibrin strands.

Because of the complex interactions of the intrinsic and extrinsic pathways (factor IXa activates factor VII), the existence of only one in vivo pathway with different mechanisms of activation has been suggested. See the image below.

The hemostatic pathway. APC = activated protein C (APC); AT-III = antithrombin III; FDP = fibrin degradation products; HC-II = heparin cofactor II; HMWK = high-molecular-weight kininogen; PAI = plasminogen activator inhibitor; sc-uPA = single-chain urokinase plasminogen activator; tc-uPA = two-chain urokinase plasminogen activator; TFPI = tissue factor pathway inhibitor; tPA = tissue plasminogen activator

FVIII and factor IX circulate in an inactive form. When activated, these 2 factors cooperate to cleave and activate factor X, a key enzyme that controls the conversion of fibrinogen to fibrin. Therefore, the lack of FVIII may significantly alter clot formation and, as a consequence, result in clinical bleeding.

Genetics

The gene for FVIII (F8C) is located on the long arm of chromosome X, within the Xq28 region. The gene is unusually large, representing 186 kb of the X chromosome. It is composed of 26 exons and 25 introns. Mature FVIII contains 2332 amino acids. See the image below.

Structural domains of human factor VIII. Adapted from: Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional structure of membrane-bound coagulation factor VIII: modeling of the factor VIII heterodimer within a 3-dimensional density map derived by electron crystallography. Blood. Feb 15 2002;99(4):1215-23; Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. NY: McGraw-Hill; 2001:1639-57; and Roberts HR. Thoughts on the mechanism of action of FVIIa. Presented at: Second Symposium on New Aspects of Haemophilia Treatment; 1991; Copenhagen, Denmark.

Approximately 40% of cases of severe FVIII deficiency arise from a large inversion that disrupts the FVIII gene. Deletions, insertions, and point mutations account for the remaining 50-60% of the F8C defects that cause hemophilia A.

Low FVIII levels may arise from defects outside the FVIII gene, as in type IIN von Willebrand disease, in which the molecular defect resides in the FVIII-binding domain of von Willebrand factor.

Hemophilia A

FVIII deficiency, dysfunctional FVIII, or FVIII inhibitors lead to the disruption of the normal intrinsic coagulation cascade, resulting in excessive hemorrhage in response to trauma and, in severe cases, spontaneous hemorrhage. Hemorrhage sites include joints (eg, knee, elbow), muscles, the central nervous system (CNS), and the gastrointestinal, genitourinary, pulmonary, and cardiovascular systems. Intracranial hemorrhage occurs most commonly in patients younger than 18 years and can be fatal.

Hemorrhage into joints

The hallmark of hemophilia is hemorrhage into joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint.

Human synovial cells synthesize high levels of tissue factor pathway inhibitor, resulting in a higher degree of factor Xa (FXa) inhibition, which predisposes hemophilic joints to bleed. This effect may also account for the dramatic response of activated factor VII (FVIIa) infusions in patients with acute hemarthroses and FVIII inhibitors.

Bleeding into a joint may lead to synovial inflammation, which predisposes the joint to further bleeds. A joint that has had repeated bleeds (by one definition, at least 4 bleeds within a 6-month period) is termed a target joint. Commonly, this occurs in knees, though ankles and elbows are other commonly affected joints.

Repeated hemarthroses lead to progressive synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage, with subchondral bone-cyst formation. This results in permanent deformities, misalignment, loss of mobility, and extremities of unequal lengths.

Inhibitors

Approximately 30% of patients with severe hemophilia A develop alloantibody inhibitors that can bind FVIII. These inhibitors are typically immunoglobulin G (IgG), predominantly of the IgG4 subclass, that neutralizes the coagulant effects of replacement therapy. However, the inhibitors do not fix complement and do not result in the end-organ damage observed with circulating immune complexes

Inhibitors occur at a young age (about 50% by age 10 years), principally in patients with less than 1% FVIII. Both genetic and environmental factors determine the frequency of inhibitor development. Specific molecular abnormalities (eg, gene deletions, stop codon mutations, frameshift mutations) are associated with a higher incidence of inhibitor development. In addition, inhibitors are more likely to develop in Black children. Missense mutations are associated with a low risk of inhibitor development.[7]

The association of product used with the risk of inhibitor formation remains controversial. In a study of 574 patients with severe hemophilia A, 177 of whom developed inhibitors, the risks of inhibitor development were similar with recombinant and plasma-derived FVIII products. No association was found between the development of inhibitors and the vWF content of products, switching from a plasma-derived to a recombinant product, or switching among brands of FVIII products. Unexpectedly, however, inhibitors developed more often with second-generation full-length recombinant products than with third-generation products.[8]

A study with 303 previously untreated or minimally treated children with hemophilia demonstrated a increased risk of inhibitor formation in patients who used recombinant products.[9] However, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) concluded that "there is no clear and consistent evidence of a difference in the incidence of inhibitor development between the two classes of factor VIII medicines: those derived from plasma and those made by recombinant DNA technology."[10]

Due to conflicting data and challenging methodologic limitations, choice of initial treatment in previously untreated or minimally treated patients should be done in a collaborative fashion between patients/caregivers and treatment teams with experience in these issues.

In the United States, levels of FVIII inhibitors are most often measured by the Bethesda method. In this method, 1 Bethesda unit (BU) equals the amount of antibody that destroys one half of the FVIII in an equal mixture of normal plasma and patient plasma in 2 hours at 37°C. Inhibitor levels are described as low titer or high titer, depending on whether they are less than or more than 5 BU, respectively; high-titer inhibitor levels are typically far higher than 5 BU.

The Nijmegen modification uses immunodepleted FVIII–deficient plasma instead of an imidazole saline buffer to ensure pH control to prevent non–antibody-mediated loss of FVIII-C activity during the prolonged 2-hour incubation period.[11] The Bethesda assay tends to underestimate the titer of VIII autoantibody because of its characteristics, in contrast to a hemophilic antibody.[12] The Oxford assay is another modification of the Bethesda inhibitor test.

Acquired hemophilia

Acquired hemophilia is the development of FVIII inhibitors (autoantibodies) in persons without a history of FVIII deficiency. This condition can be idiopathic (occurring usually in people >50 y).  It can be associated with underlying collagen vascular disease or the peripartum period, or it may represent a drug reaction (eg, to penicillin). High titers of FVIII autoantibodies may be associated with malignancies, particularly lymphoproliferative malignancies.[13]

Hemophilia A is caused by an inherited or acquired genetic mutation that results in dysfunction or deficiency of factor VIII, or by an acquired inhibitor that binds factor VIII. Of genetic cases, up to approximately one third are the result of de novo mutations not present in the mother's X chromosome.

Inadequate factor VIII results in the insufficient generation of thrombin by the FIXa and FVIIIa complex by means of the intrinsic pathway of the coagulation cascade. This mechanism, in combination with the effect of the tissue-factor pathway inhibitor, creates an extraordinary tendency for impaired clotting in response to trauma and, especially in persons with severe hemophilia, for spontaneous bleeding.

Hemophilia A is inherited in an X-linked recessive pattern. The gene for FVIII is located on the long arm of the X chromosome in band q28. The factor VIII gene is one of the largest genes, making up approximately 0.1% of the DNA in the X chromosome; it is 186 kilobases (kb) long and has a 9-kb coding region that contains 26 exons. The mature protein contains 2332 amino acids and has a molecular weight of 300 kd. It includes three A domains, one B domain, and two C domains.

Intron 22 of the factor VIII gene, uniquely, contains two other genes. The first gene, F8A, is transcribed in a direction opposite to that of the factor VIII gene itself. The second gene, F8B, is transcribed in the 3' (normal) direction similar to the factor VIII gene. Sequences called A2 and A3, homologous to the F8A sequence, are present on the X chromosome, 300 kb telomeric to the factor VIII gene.

Homologous recombination of the factor VIII gene, with inversion and crossover involving the F8A sequence in intron 22 and the homologous distal sequence on the X chromosome, results in a split in the factor VIII gene, with the two parts aligned in opposite directions. This causes a disruption in the normal factor VIII coding sequence, with an inability to transcribe the complete, normal factor VIII protein, resulting in a loss of function.

The mutation in intron 22 occurs during spermatogenesis and is a common cause of severe factor VIII deficiency; it is present in approximately 40% of patients. It is easily detected using a Southern blot analysis of the patient's DNA. These patients are more likely to develop an inhibitor to factor VIII.

In one study, all detected inversions originated in a maternal grandparent during male meiosis (spermatogenesis), supporting the hypothesis that an unpaired Xq, rather than a paired X chromosome, is more likely to undergo an intrachromosomal inversion. The majority of mothers of persons with the sporadic, inversion-related severe hemophilia are carriers.[14]

The knowledge of the parental origin of the inversion mutation has important implications for genetic counseling.

Several other types of mutations have been described. Point mutations can lead to mild, moderate, or severe deficiency of factor VIII, depending on the effect of that mutation on factor VIII gene function.

Missense mutations, such as the G-to-A single-base substitution, alter the amino acid composition of the molecule, producing a dysfunctional molecule (FVIII antigen present with reduction in FVIII activity); these mutations are associated with mild, moderate, or severe factor VIII reductions and are associated with the development of factor VIII inhibitors. Intracellular accumulation of factor VIII induced by Arg 593→Cys and Asn 618→Ser missense mutations also result in reduction of cross-reacting material in severe hemophilia A.

Gene deletions lead to factor VIII deficiency, and large gene deletions result in severe hemophilia, with no detectable factor VIII antigen; such patients are more susceptible to inhibitor development. Insertions are apparently uncommon in the factor VIII gene, but they usually lead to severe hemophilia A.[15] Nonsense mutations and abnormal splicing may also occur.

Other causes of this disorder remain to be identified.

Combined factor V and factor VIII deficiency

Combined FV and FVIII deficiency is an autosomal recessive disorder, with clinical manifestations in affected females and males. The disorder is caused by mutations in one of two genes, lectin mannose binding protein 1 (LMAN1) or multiple coagulation factor deficiency 2 (MCFD2), which encode proteins involved in the intracellular transport of FV and FVIII; the coagulation factors themselves are normal.[16]

Hemophilia A is the most common X-linked genetic disease and the second most common factor deficiency after von Willebrand disease (vWD). The worldwide incidence of hemophilia A is approximately 1 case per 5000 males, with approximately one third of affected individuals not having a family history of the disorder. The prevalence of hemophilia A varies with the reporting country, with a range of 5.4-14.5 cases per 100,000 males. The number of males in the United States with hemophilia is estimated to be about 33,000.[17]

Approximately 50-60% of patients have severe hemophilia A (FVIII < 2% of normal), associated with the severest bleeding manifestations. Approximately 25-30% have moderate hemophilia (FVIII 2-5%) and manifest bleeding after minor trauma. Those with mild hemophilia A (FVIII 6-30%) make up 15-20% of all people with hemophilia; these patients develop bleeding only after trauma or surgery.

Acquired hemophilia A, caused by the development of an autoantibody to FVIII in a person with previously normal hemostasis, develops with a frequency of 1 case per 1 million population per year.[18] Acquired FVIII deficiency is observed in older populations, generally those older than 60 years.

The inherited, combined deficiency of factors V and VIII is a rare but recognized cause of a bleeding disorder. The prevalence is estimated to be 1 case per million population.[16]

Racial, sexual, and age-related differences in incidence

Hemophilia A occurs in all races and ethnic groups. In general, the demographics of hemophilia follow the racial distribution in a given population; for example, rates of hemophilia among whites, African Americans, and Hispanics in the US are similar.

Because hemophilia is an X-linked, recessive condition, it occurs predominantly in males. Females usually are asymptomatic carriers. However, mild hemophilia may be more common in carriers than previously recognized. In one study, five of 55 patients with mild hemophilia (factor levels 5-50%) were girls.[19]

Females may have clinical bleeding due to hemophilia if any of the following three conditions is present:

• Extreme lyonization (ie, inactivation of the normal FVIII allele in one of the X chromosomes)[20]

• Homozygosity for the hemophilia gene (ie, father with hemophilia and mother who is a carrier, two independent mutations, or some combination of inheritance and new mutations)

• Turner syndrome (XO) associated with the affected hemophilia gene

In genetic cases, significant deficiency in FVIII may be evident in the neonatal period. It continues through the life of the affected individual. The absence of hemorrhagic manifestations at birth does not exclude hemophilia.

With appropriate education and treatment, patients with hemophilia can live full and productive lives. Prophylaxis and early treatment with FVIII concentrate that is safe from viral contamination have dramatically improved the prognosis of patients with severe hemophilia. Nevertheless, approximately one quarter of patients with severe hemophilia aged 6-18 years have below-normal motor skills and academic performance and have more emotional and behavioral problems than others.[21]

Factor concentrates have made home-replacement therapy possible, improving patients' quality of life. In addition, the era of replacement therapy brought dramatic gains in life expectancy. For patients with severe hemophilia, life expectancy rose from 11 years or less before the 1960s to almost 60 years, prior to HIV epidemic in the 1980s.[2, 4]

Increasing evidence associates hemophilia with low bone mineral density and increased fracture risk in both children and adults. Physical inactivity (which may be worsened by arthropathy) and vitamin D deficiency seem to play a fundamental role.[22]

Viral infection from contaminated FVIII concentrate became a problem during the replacement era. Most patients with hemophilia who received plasma-derived products that were not treated to eliminate potential contaminating viruses became infected with HIV or hepatitis A, hepatitis B, or hepatitis C viruses.

The most serious of these was HIV infection. The first deaths of people with hemophilia due to acquired immunodeficiency syndrome (AIDS) were observed in the early 1980s. Rates of seroconversion were more than 75% for those with severe disease, 46% for moderate disease, and 25% for mild disease.

In the United States, death rates of patients with hemophilia increased from 0.4 deaths per million population in 1979-1981 to 1.2 deaths per million population in 1987-1989; AIDS accounted for 55% of all hemophilia deaths. Causes of death shifted from intracranial and other bleeding to AIDS and cirrhosis from hepatitis.

With improved screening of donors, new methods of factor concentrate purification, and recombinant concentrates, infectious complications now are only historically important. However, even with these methods, some viruses (eg, parvovirus B-19) cannot be removed and may be transmitted through plasma-derived products. Other potential infectious agents include the prions that cause Creutzfeldt-Jakob disease. With the development of animal protein–free products, the risk of contamination with these agents may be decreased.

Intracranial hemorrhage and hemorrhages into the soft tissue around vital areas, such as the airway or internal organs, remain the most important life-threatening complications. The lifetime risk of intracranial bleeding is 2-8% and accounts for one third of deaths due to hemorrhage, even in the era of factor replacement. Of patients with severe hemophilia, 10% have intracranial bleeding, with a mortality rate of 30%.

Chronic debilitating joint disease results from repeated hemarthrosis, synovial membrane inflammation, hypertrophy, and, eventually, destructive arthritis. Early replacement of coagulation factors by means of infusion is essential to prevent functional disability. Thus, prophylactic therapy administered 2-3 times weekly, starting when patients are young, is considered the standard of care in most developed countries.

Before the widespread use of replacement therapy, patients with severe hemophilia had a shortened lifespan and diminished quality of life that was greatly affected by hemophilic arthropathy. Home therapy for hemarthroses became possible with factor concentrates. Prophylactic use of lyophilized concentrates that eliminate bleeding episodes help prevent joint deterioration, especially when instituted early in life (ie, at age 1-2 y).

A study from the Netherlands found that for patients with hemophilia A or B, age-standardized mortality, in comparison with the general Dutch male population, was 40% higher, with life expectancy being 6 years lower in persons with hemophilia. Nonetheless, death rates for persons with hemophilia had seen a consistent reduction over the previous four and a half decades. Death was most commonly caused by intracranial hemorrhages and malignancies.[23]

Starting in infancy, regular dental evaluation is recommended, along with instruction regarding proper oral hygiene, dental care, and adequate fluoridation. Encourage the patient to engage in appropriate exercise. Advise the patient against participating in contact and collision sports.

Patient and family education about early recognition of hemorrhage signs and symptoms is important for instituting or increasing the intensity of replacement therapy. This treatment helps prevent the acute and chronic complications of the disease, which range from those that can impair quality of life to those that are life-threatening.

Educating patients and family members about factor replacement administration at home has greatly enhanced the quality of life of patients with severe hemophilia by allowing prompt infusion for bleeds and markedly reducing the need for emergency department visits. Parents often can learn to infuse children as young as 2 years, and, by 8-10 years, most children with hemophilia can learn to self-infuse.

For patient education information, see Hemophilia.

For patients in whom hemophilia is suspected, inquire about the following:

• History of hemorrhage disproportionate to trauma
• History of spontaneous hemorrhage
• Bleeding disorders in the family
• Concomitant illness (especially those associated with acquired hemophilia, such as chronic inflammatory disorders, autoimmune diseases, hematologic malignancies, and allergic drug reactions)
• Recent pregnancy

For individuals with documented hemophilia, ascertain the type of deficiency (eg, factor VIII [FVIII], FIX, von Willebrand), degree of factor deficiency, known presence of inhibitors, and HIV/hepatitis status. For patients with mild-to-moderate disease, determine responsiveness to desmopressin acetate (DDAVP).[5]

Signs and symptoms of hemorrhage include the following:

• General - Weakness and orthostasis (related to anemia/hypovolemia secondary to bleeding)

• Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, refusal to use the joint (young children)

• Central nervous system (CNS) - Headache, stiff neck, vomiting, lethargy, irritability, spinal cord syndromes

• Gastrointestinal (GI) - Hematemesis, melena, frank red blood per rectum, abdominal pain

• Genitourinary - Hematuria, renal colic, post-circumcision bleeding

• Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, contusions, excessive bleeding with routine dental or other procedures

Evidence of infectious disease includes the following:

• HIV/AIDS-related symptoms

• Hepatitis-related symptoms

Newborn boys with severe hemophilia may present with prolonged bleeding at circumcision. Easy bruising may occur at the start of ambulation or primary dentition. Older patients may have a history of hemarthroses and prolonged bleeding with surgical procedures, trauma, and dental extraction, and may have spontaneous bleeding in soft tissues.

A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is diagnosed. Factors that elevate FVIII levels (eg, age, ABO blood type, stress, exercise) may mask mild hemophilia.

Weight-bearing joints and other joints are principal sites of bleeding in patients with hemophilia. The muscles most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is dangerous because of the large volume of blood loss and because compression of the femoral nerve may occur.

In the genitourinary tract, gross hematuria may occur in as many as 90% of patients. In the GI tract, bleeding may complicate common GI disorders. Bleeding in the CNS is the leading cause of hemorrhagic death in patients with hemophilia.

Acquired hemophilia

Acquired hemophilia due to an autoantibody in previously hemostatically normal individuals tends to affect elderly persons who have comorbid conditions, but may also develop post partum. Persons with acquired hemophilia may experience extensive, often life-threatening, bleeding before the condition is recognized.

In contrast to persons with severe inherited hemophilia A, in whom joint bleeding is common, patients with acquired hemophilia present with large intramuscular, retroperitoneal, limb, subcutaneous, genitourinary, gastrointestinal (GI), or excessive postoperative or postpartum bleeding. Bleeding into an extremity can result in findings that are easily confused with deep vein thrombosis. Massive upper extremity bleeding can be precipitated by a simple venipuncture. Bleeding can develop at any site.

Postpartum acquired hemophilia usually comes to attention 2-5 months after delivery, when bleeding symptoms supervene. Rarely, the inhibitor may develop during pregnancy.

Systemic signs of hemorrhage include the following:

• Tachycardia
• Tachypnea
• Hypotension
• Orthostasis

Organ system–specific signs and symptoms of hemorrhage include the following:

• Musculoskeletal (joints) - Tenderness, pain with movement, decreased range of motion, effusion, and warmth
• Central nervous system (CNS) - Abnormal neurologic exam findings, altered mental status, and meningismus
• Gastrointestinal (GI) - Can be painless; hepatic/splenic tenderness and peritoneal signs
• Genitourinary - Bladder spasm/distension/pain and costovertebral angle pain
• Other - Hematoma leading to location-specific signs (eg, airway obstruction, compartment syndrome)

Signs of infectious disease include the following:

• HIV/AIDS-related signs
• Hepatitis-related signs

Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. Other neonates may present with severe hematoma and prolonged bleeding from the cord or umbilical area.

After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers, when trauma-related soft-tissue hemorrhage occurs. Young children may also have oral bleeding when their teeth are erupting. Bleeding from gum and tongue lacerations is often troublesome because the oozing of blood may continue for a long time despite local measures.

As children grow and become more physically active, hemarthroses and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a life-threatening complication that requires urgent diagnosis and intervention.

Petechiae usually do not occur in patients with hemophilia. The reason is that petechiae are manifestations of capillary blood leakage, which is typically the result of vasculitis or abnormalities in the number or function of platelets.

Hemophilia is classified according to clinical severity as mild, moderate, or severe (see Table 1, below). Patients with severe disease usually have less than 1% factor VIII (FVIII) activity and experience spontaneous hemarthrosis and soft-tissue bleeding in the absence of apparent precipitating trauma. Patients with moderate disease have 1-5% FVIII activity and bleed with minimal trauma. Patients with mild hemophilia have more than 5% factor activity and bleed only after significant trauma or surgery.

Table 1. Hemophilia Severity, Factor Activity, and Hemorrhage Type (Open Table in a new window)

Direct the examination to identify signs related to spontaneous bleeding, or bleeding with minimal challenge, in the joints, muscles, and other soft tissues. Observe the patient's posture. Examine the weight-bearing joints, especially the knees and ankles, and, in general, the large joints for deformities or ankylosis. Look for jaundice and other signs of liver failure (eg, cirrhosis) and for signs of opportunistic infections in patients who are HIV positive.

Pseudotumors are produced by a slow expansion of repeated hemorrhages in bone or soft tissues. They can be restricted by the fascial planes of a muscle, cause resorption of neighboring bone by pressure-induced ischemia, or develop under the periosteum, leading to erosion of the bony cortex. They develop slowly over months to years and often are asymptomatic, unless pressure on the nerves or vascular compromise occurs.

Pseudotumors contain a brownish material and can become infected. The buttocks, pelvis, and thighs are common locations for a pseudotumor (see the images below).

Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional limb). This photo shows black-brown old blood, residual muscle, and bone.

Dissection of a pseudocyst.

Transected pseudocyst with chocolate brown-black old blood.

Photograph of a patient who presented with a slowly expanding abdominal and flank mass, as well as increasing pain, inability to eat, weight loss, and weakness of his lower extremity.

Plain radiograph of the pelvis showing a large lytic area.

Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.

Photograph depicting extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.

Laboratory studies for suspected hemophilia include a complete blood cell count, coagulation studies, and a factor VIII (FVIII) assay. Never delay indicated coagulation correction pending diagnostic testing.

On the hemoglobin/hematocrit assay, expect normal or low values. Expect a normal platelet count. On coagulation studies, the prothrombin time (which assesses the extrinsic coagulation pathway) and thrombin time are normal.

Usually, the activated partial thromboplastin time (aPTT) is prolonged; however, a normal aPTT does not exclude mild or even moderate hemophilia because of the relative insensitivity of the test. The aPTT is significantly prolonged in severe hemophilia.

For FVIII assays, levels are compared with a normal pooled-plasma standard, which is designated as having 100% activity or the equivalent of FVIII U/mL. Normal values are 50-150%. Values in hemophilia are as follows:

• Mild: > 5%
• Moderate: 1-5%
• Severe: < 1%

Aging, pregnancy, oral contraceptive use, and estrogen replacement therapy are associated with increased FVIII levels. Because FVIII is a large molecule that does not cross the placenta, the diagnosis can be made at birth with quantitative assay of cord blood.

Three main FVII assay methods are in use: one-stage and two-stage clotting assays and a two-stage chromogenic method. In approximately one-third of patients with mild hemophilia, FVIII levels on the automated one-stage FVIII assay are significantly higher than—typically, more than double—those of the two-stage coagulation assay.[24, 25]

Those discrepancies, which result from differences in the underlying FVIII mutations in these patients, can result in missed diagnoses or mismanagement due to underestimation of bleeding risk.[24, 26] Given the possibility of discrepant hemophilia A, as this condition is termed, use of the chromogenic FVIII assay combined with FVIII gene mutation analysis has been recommended for diagnosis of mild hemophilia A.[24]

Differentiation of hemophilia A from von Willebrand disease is possible by observing normal or elevated levels of von Willebrand factor antigen and ristocetin cofactor activity.  A caveat to this is the rare patient with type 2N von Willebrand disease in which the VW antigen and activity levels are normal but binding to FVIII is impaired, resulting in a short circulating half-life of Factor VIII and low levels. While type 2N von Willebrand disease is very rare, it is relevant to exclude this diagnosis, as those patients may require therapy with combined vWF/FVIII product rather than isolated FVIII concentrate. Bleeding time is prolonged in patients with von Willebrand disease, but conflicting reports of presence of elevation patients with hemophilia as well of lack of standardization and familiarity with proper performance of this assay limits the utility of the bleeding time as a diagnostic strategy.

In patients with an established diagnosis of hemophilia, periodic laboratory evaluations include screening for the presence of FVIII inhibitor and screening for transfusion-related or transmissible diseases such as hepatitis and HIV infection. Screening for infection may be less important in patients who receive only recombinant FVIII concentrate.

Imaging studies for acute bleeds

Early and aggressive imaging is indicated, even with low suspicion for hemorrhage, after coagulation therapy is initiated. Imaging choices are guided by clinical suspicion and the anatomic location of involvement.

Head computed tomography (CT) scans without contrast are used to assess for spontaneous or traumatic intracranial hemorrhage. Perform magnetic resonance imaging (MRI) on the head and spinal column for further assessment of spontaneous or traumatic hemorrhage. MRI is also useful in the evaluation of the cartilage, synovium, and joint space.

Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions. This technique is not helpful for evaluating the bone or cartilage. Special studies such as angiography and nucleotide bleeding scan may be clinically indicated.

Laboratory confirmation of an FVIII inhibitor is clinically important when a bleeding episode is not controlled despite infusion of adequate amounts of factor concentrate. For the assay, the aPTT measurement is repeated after incubating the patient's plasma with normal plasma at 37°C for 1-2 hours. If the prolonged aPTT is not corrected, the inhibitor concentration is titrated using the Bethesda method. Ideally, the Nijmegen modification of the Bethesda inhibitor assay should be used to detect an inhibitor if the mixing test result is positive.[11]

By convention, more than 0.6 Bethesda units (BU) is considered a positive result for an inhibitor. Less than 5 BU is considered a low titer of inhibitor, and more than that is a high titer. The distinction is clinically significant, as patients with low-titer inhibitors may respond to higher doses of FVIII concentrate, while those with high-titer inhibitors require treatment with agents that bypass FVIII and consideration for induction of immune tolerance.

Caution is warranted when obtaining blood samples for coagulation assays from heparinized central lines, because of the effect of heparin contamination on all coagulation test results. The excess heparin causes false-positive results and/or higher inhibitor titer values than are actually present in the patient, because heparin is also an inhibitor of coagulation.

One study found significant heparin contamination in 45% of all specimens obtained through implanted venous access devices. These researchers suggested that all blood samples obtained from such devices, which are usually flushed with heparin, should be treated with heparinase before performing an inhibitor assay.[27]

Screening for carrier status can be performed by measuring the ratio of FVIII coagulant activity to the concentration of vWF antigen. A ratio that is less than 0.7 suggests carrier status.

The International Society on Thrombosis and Haemostasis has proposed nomenclature for the diagnosis and management of hemophilia carriers.[28] For hemophilia A, the nomenclature uses FVIII levels and clinical characteristics to distinguish the following categories for women/girls:

• Mild hemophilia A: FVIII > 0.05 and < 0.40 IU/mL
• Moderate hemophilia A: FVIII 0.01-0.05 IU/mL
• Severe hemophilia A: FVIII < 0.01 IU/ml, respectively
• Symptomatic carriage: FVIII ≥0.40 IU/mL with a bleeding phenotype
• Asymptomatic carriage: FVIII ≥0.40 IU/mL without a bleeding phenotype

Direct genetic testing for known gene mutation is a more accurate screening technique. Linkage analysis by restriction fragment length polymorphism (RFLP) in multiple family members can be used. Direct mutation analysis is available in several laboratories for unknown FVIII mutations. Inversion of the FVIII gene can be detected by Southern blot.

For prenatal testing, carriers whose mutation has been identified can have chorionic villus sampling at approximately 10-12 weeks' gestation or amniocentesis at 16-20 weeks' gestation to obtain fetal cells for DNA analysis or for linkage studies. If DNA analysis cannot be performed, then fetal blood obtained by fetoscopy at approximately 20 weeks' gestation can be assayed for the FVIII level.

All of those procedures carry a risk ranging from a low of 0.5% for maternal-fetal complications to a high of 1-6% for fetal death from fetoscopy. These procedures should be undertaken only after patients have received intense genetic and obstetric counseling. Genetic counseling before the woman becomes pregnant is ideal and may help couples make informed decisions before conception.

Noninvasive prenatal diagnosis using quantitative digital polymerase chain reaction testing of free fetal DNA in the maternal circulation has been reported. However, this technique remains a research tool.[29]

If the fetus is a female, the couple may elect to carry the pregnancy to term because carriers rarely have bleeding problems. If the fetus is a severely affected male, the couple must make a decision about continuing the pregnancy to term. With pregnancies that will be carried to term, prenatal diagnosis allows for planning of delivery so as to minimize the risk of intracranial hemorrhage (eg, avoidance of vacuum devices).[29]

Radiography for joint assessment is of limited value in acute hemarthrosis. Evidence of chronic degenerative joint disease may be visible on radiographs in patients who have been untreated or inadequately treated or in those with recurrent joint hemorrhages. In these patients, radiographs may show synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage that progresses with subchondral bone cyst formation.

Hemophilic arthropathy evolves through five stages, starting as an intra-articular and periarticular edema due to acute hemorrhage and progressing to advanced erosion of the cartilage with loss of the joint space, joint fusion, and fibrosis of the joint capsules.[6]  (See the image below.) For a discussion of the five-stage Arnold-Hilgartner classification of hemophilic arthropathy, see Imaging in Musculoskeletal Complications of Hemophilia.

Photograph of a hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required.

The treatment of hemophilia may involve prophylaxis, management of bleeding episodes, treatment of factor VIII (FVIII) inhibitors, and treatment and rehabilitation of hemophilia synovitis. Use of factor replacement products and other medications, including pain medications, is typically required.

Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center. These centers, which are found in many US cities, follow a multidisciplinary approach, with specialists in hematology, orthopedics, dentistry, and surgery; nurses; physiotherapists; social workers; and related allied health professionals. Patients treated at comprehensive care clinics have been shown to have better access to care, less morbidity, and better overall outcome.

Ambulatory replacement therapy for bleeding episodes is essential for preventing chronic arthropathy and deformities. Home treatment and infusion by the family or patient is possible in most cases. Prompt and appropriate treatment of hemorrhage is important to prevent long-term complications and disability.

Dose calculations are directed toward achieving an FVIII activity level of 30-40% for most mild hemorrhages, of at least 50% for severe bleeds (eg, from trauma) or prophylaxis of major dental surgery or major surgery, and 80-100% for life-threatening hemorrhage. Hospitalization is reserved for severe or life-threatening bleeds, such as large soft tissue bleeds; retroperitoneal hemorrhage or other internal bleeding; and hemorrhage related to head injury, surgery, or dental work.

Patients can be treated with prophylaxis or with intermittent, on-demand therapy for bleeding events. Prophylaxis has been shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints.[30, 31] According to a review of six randomized, controlled trials, preventive therapy started early in childhood, as compared with on-demand treatment, can reduce total bleeds and bleeding into joints, resulting in decreased overall joint deterioration and improved quality of life.[32]

In most developed countries with access to recombinant product, prophylaxis is primary (ie, therapy is started in patients as young as 1 y and continues into adolescence). A cost-benefit analysis indicates that this approach reduces overall factor use and significantly reduces morbidity.[33] In situations in which this is not feasible, secondary prophylaxis (ie, therapy after a target joint has developed, to prevent worsening of the joint) is instituted for a defined period.

For prophylaxis, dosing is designed to maintain trough levels of 2% or higher. This usually requires the administration of FVIII three times per week. Individualized therapy (ie, tailored prophylaxis) has been also used with success; the best approach has yet to be determined. Monoclonal antibodies (ie, emicizumab, marstacimab) may also be used for prophylaxis.

The treatment of patients with inhibitors of FVIII is difficult. Bleeding episodes in patients with low-titer inhibitors (ie, concentrations below 5 Bethesda units [BU]) occasionally can be overcome with high doses of factor VIII.[34] Options in other cases include a variety of agents that bypass FVIII, such as activated FVII and emicizumab; desensitization; and immune tolerance induction.

In patients who develop synovitis from joint bleeds, injection of radioisotopes into the joint to ablate the synovium (radiosynovectomy) can be used to decrease bleeding, slow progression of cartilage and bone damage, and prevent arthropathy. Unresponsive cases may require arthroscopic synovectomy or arthroplasty.[35]

Increasing evidence associates hemophilia with low bone mineral density; consequently, careful assessment and management of fracture risk are recommended. Regular exercise, fall prevention strategies, and optimization of calcium and vitamin D intake are recommended, along with prophylactic factor replacement therapy in severe hemophilia.[22]

Please see the following for more information:

• Acquired Hemophilia
• Hemophilia B (Factor IX Deficiency)
• Hemophilia C

Rapid transport to definitive care is the mainstay of prehospital care. Prehospital care providers should do the following:

• Apply aggressive hemostatic techniques
• Assist patients capable of self-administered factor therapy
• Gather focused historical data if the patient is unable to communicate

Before treating a patient with hemophilia, obtain the following information:

• The type and severity of factor deficiency
• The nature of the hemorrhage or the planned procedure
• The patient's previous treatments with blood products
• Whether inhibitors are present and if so, their probable titer
• Any previous history of desmopressin acetate (DDAVP) use (mild hemophilia A only), with the degree of response and clinical outcome.

Use aggressive hemostatic techniques. Correct coagulopathy immediately. Include a diagnostic workup for hemorrhage, but never delay indicated coagulation correction pending diagnostic testing. If possible, draw blood for the coagulation studies (see Workup), including 2 blue-top tubes to be spun and frozen for factor and inhibitor assays.

Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as pressure and ice. Mild hematuria may subside spontaneously. Do not aspirate hematomas or joints or cauterize bleeding sites unless specifically indicated, because these procedures may aggravate the bleeding.

Epistaxis and moderately severe hematuria may be adequately treated by achieving and maintaining FVIII levels in the range of 30-50%. Use a higher dose initially, followed by a gradual lowering of the dose after the bleeding is under control, and then continue FVIII replacement until clinical and objective evidence indicates resolution of the bleeding.

Acute joint bleeding and expanding, large hematomas require adequate factor replacement for a prolonged period until the bleed begins to resolve, as evidenced by clinical and/or objective methods. Relief of the intense pain with joint bleeds frequently requires the use of narcotic analgesics; relief of pain also accompanies cessation of bleeding after adequate factor replacement.

Life-threatening bleeding episodes are generally initially treated with FVIII levels of approximately 100%, until the clinical situation warrants a gradual reduction in dosage. Continuous intravenous infusions avoid the low troughs and excesses of intermittent bolus dosing, maintain adequate levels at all times, and reduce usage of expensive factor replacement product by approximately 30%.

If admission is indicated, disposition (intensive care unit vs floor) should be based on severity of hemorrhage and potential for morbidity and death. Choose the attending service based on the etiology and site of hemorrhage. Hematology/blood bank/pathology consultation is mandatory.

Patients whose condition and bleeding are stabilized should be transferred to a comprehensive hemophilia care center for further treatment and monitoring. These centers offer a multidisciplinary approach by specialists experienced in hemophilia.

Further outpatient care for patients with minor hemorrhage (not life threatening) consists of continued hemostatic measures (eg, brief joint immobilization, bandaging). Hematologist or primary care physician follow-up care is indicated. The patient should continue factor replacement and monitoring.

If a patient has HIV seroconversion, arrange appropriate outpatient care at a specialty infectious disease clinic. These patients require monitoring of their CD4 count, observation for adverse effects of anti-HIV treatment, and monitoring for and treatment of possible opportunistic infections.

Various FVIII concentrates are available to treat hemophilia A. Fresh frozen plasma and cryoprecipitate are no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload.

Various purification techniques are used in plasma-based FVIII concentrates to reduce or eliminate the risk of viral transmission, including heat treatment, cryoprecipitation, and chemical precipitation. These techniques inactivate viruses such as hepatitis B virus, hepatitis C virus, and HIV. However, the transmission of nonenveloped viruses (eg, parvovirus and hepatitis A virus) and poorly characterized agents (eg, prions) is still a potential problem.

Many recombinant FVIII concentrates are currently available. The advantage of such products is the elimination of viral contamination. Third-generation products with no exposure to animal proteins further decrease this risk. The effectiveness of these products appears comparable to that of plasma-derived concentrates. Concerns regarding higher incidences of inhibitor development remains a complex problem, and selection of products, particularly with previously untreated or minimally treated patients, should ideally be done in conjunction with a provider with experience in hemophilia following a discussion of risks and benefits with the patient/caregiver.

With wider availability of improved products (ie, better stability, purity), use of continuous infusion for administration has incrementally increased. Continuous infusion of antihemophilic factors prevents the peaks and valleys in factor concentrations that occur with intermittent infusion; this benefit is particularly important when treatment is required for prolonged periods.

Besides improved hemostasis, continuous infusion decreases the amount of factor used, which can result in significant savings. The indications for this approach include the following:

• Intracranial hemorrhage
• Vascular compromise
• Iliopsoas bleeding
• Preparation for surgery

In most minor-to-moderate bleeding episodes, intermittent boluses are adequate. Intermittent boluses can also be used prophylactically, especially in the treatment of recurrent bleeding in target joints.

Doses of FVIII concentrate are calculated according to the severity and location of bleeding. Guidelines for dosing are provided in Table 2 below. As a rule, FVIII 1 U/kg increases FVIII plasma levels by 2%. The half life of infused factor is usually 8-12 hours. Incremental recovery (ie, the amount increase of factor activity per unit per kg) and half life vary from patient to patient and ideally should be individualized based on that patient's experience.

Target levels by hemorrhage severity are as follows:

• Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding) - Maintain an FVIII level of 30%

• Major hemorrhages (ie, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination) - Maintain an FVIII level of 50%

• Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent hemarthrosis) - Maintain an FVIII level of 80-90% until stabilization; after stabilization, maintain levels above 40-50% for a minimum of 7-10 days

Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia (Open Table in a new window)

Variations in responses related to patient or product parameters make determinations of factor levels important. These determinations are performed immediately after infusions and thereafter to ensure an adequate response and maintenance levels. Obtain factor level assays daily before each infusion to establish a stable pattern of replacement regarding the dose and frequency of administration.

Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP), is considered the treatment of choice for mild and moderate hemophilia A. It is not effective in the treatment of severe hemophilia. DDAVP stimulates a transient increase in plasma FVIII levels. Other possible mechanisms of action are noted.

DDAVP may result in sufficient hemostasis to stop a bleeding episode or to prepare patients for dental and minor surgical procedures. A test dose should be performed before prophylactic use. It can be intravenously administered at a dose of 0.3 mcg/kg of body weight in the inpatient setting. Its peak effect is observed in 30-60 minutes.

If the test dose produces an appropriate rise in the FVIII level, at least 1 week should elapse before performance of any procedures. This allows time for replenishment of endogenous stores of FVIII so that an adequate DDAVP-induced rise in FVIII is obtained for the procedure.

A concentrated DDAVP intranasal spray (1.5 mg/mL) is available for outpatient use. Its effectiveness is similar to that of the intravenous preparation, although its peak effect is observed later, at 60-90 minutes after administration.

Hyponatremia due to water retention is a potentially serious adverse effect. Patients should be advised to limit water intake for approximately 12-18 hours after the administration of DDAVP, until the antidiuretic effect passes, and should avoid three consecutive daily doses. Due to risk of hyponatremia, any use of IV fluids should be reviewed carefully and sodium levels may need to be monitored. In addition, patients should be alerted to the distinct drop in urine output they will experience after DDAVP administration, and the subsequent increase when the antidiuretic effect of DDAVP wanes.

Tachyphylaxis may occur even after first dose, but the drug can be effective again after several days. A minor adverse effect of DDAVP is facial flushing.

Musculoskeletal bleeding

The most common sites of clinically significant bleeding are joint spaces. Weight-bearing joints in the lower extremities are often target areas for recurrent bleeding. Joint hemorrhage is associated with pain and limitation in the range of motion, which is followed by progressive swelling in the involved joint.  Many patients report a prodrome of warmth or tingling of the joint prior to symptoms of frank hemorrhage.

Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain. Early infusion upon the recognition of initial symptoms of a joint bleed may often eliminate the need for a second infusion by preventing the inflammatory reaction in the joint. Prompt and adequate replacement therapy is the key to preventing long-term complications. Cases in which treatment begins late or causes no response may require repeated infusions for 2-3 days.

Do not aspirate hemarthroses unless they are severe and involve significant pain and synovial tension. Some hemarthroses may pose particular problems because they interfere with the blood supply. Arthrocentesis is indicated if septic arthritis is suspected.

Hip joint hemorrhages can be complicated by aseptic necrosis of the femoral head. Administer adequate replacement therapy for at least 3 days.

Guidelines on the management of acute joint bleeds and chronic synovitis in hemophilia were issued by the United Kingdom Haemophilia Centre Doctors' Organisation in 2017. Recommendations on hemostatic management of patients with hemophilia A without inhibitors were as follows[36] :

• All patients with severe hemophilia A and other patients at risk of joint bleeding should be offered home treatment
• The initial treatment of early and moderate bleeds should aim for a peak FVIII of 50 to 60 IU/dL; this is equivalent to 25 to 30 IU/kg for severe hemophilia A for standard and extended half-life products
• Early bleeds often do not require a second infusion, and moderate bleeds often respond to a single infusion but may require up to 2 infusions
• Children may require more frequent or higher doses, as they have a shorter factor half-life than adults
• For joint-immobilizing bleeds, higher initial doses are recommended, which aim to raise the peak FVIII level to 60 to 80 IU/dL; doses should be administered every 24 hr until complete resolution of pain; for severe bleeds, more frequent administration may be required in the initial 48 hr with standard FVIII

Recommendations for hemostatic management of patients with inhibitors to FVIII were as follows[36] :

• Inhibitor patients should be encouraged to be on a home treatment program, and bleeds should be treated as early as possible
• Activated prothrombin complex (aPCC) 50–100 μg/kg or recombinant FVIIa (rFVIIa) 270 μg/kg as a single dose (or 90 μg/kg 2-3 hourly) are equally acceptable treatments for joint or soft tissue bleeds, with repeated doses as necessary; the frequency of infusion and duration of treatment should be determined by the clinical response
• The total daily dose of aPCC should not exceed 200 IU/kg
• Tranexamic acid can be considered as adjunctive therapy to aPCC and rFVIIa
• Sequential alternating treatment of aPCC and rFVIIa can be considered for the management of limb/life-threatening bleeds

Deep intramuscular hematomas are difficult to detect and may result in serious muscular contractions. Appropriate and timely replacement therapy is important to prevent such disabilities.

Iliopsoas muscle bleeding may be difficult to differentiate from hemarthrosis of the hip joint. Physical examination usually reveals normal hip rotation but significant limitation of extension. Ultrasonography in the involved region may reveal a hematoma in the iliopsoas muscle. This condition requires adequate replacement therapy for 10-14 days and a physical therapy regimen that strengthens the supporting musculature.

Closed-compartment hemorrhages pose a significant risk of damaging the neurovascular bundle. These can occur in any area where fascial planes restrict the expanding hematoma and can cause neurovascular compression and compromise. They cause swelling, pain, tingling, numbness, and loss of distal arterial pulses. Infusion must be aimed at maintaining a normal level of FVIII. Other interventions include elevation of the affected part to enhance venous return and, rarely, surgical decompression.

Oral bleeding

Oral bleeding from the frenulum and bleeding after tooth extractions are not uncommon. Bleeding is aggravated by the increased fibrinolytic activity of saliva. If not treated appropriately, dental bleeding can persist and expand to sublingual, pharyngeal, facial, or dissecting neck hematomas or other serious bleeding.

Combine adequate replacement therapy with an antifibrinolytic agent (epsilon-aminocaproic acid [EACA] or tranexamic acid [TA]) to neutralize the fibrinolytic activity in the oral cavity. Topical agents such as fibrin sealant, bovine thrombin, and human recombinant thrombin can also be used.[37]

Hematoma in the pharynx or epiglottic regions frequently results in partial or complete airway obstruction; therefore, it should be treated with aggressive infusion therapy. Such bleeding may be precipitated by local infection or surgery.

Dental extractions or mucosal procedures can be handled with a single preprocedure dose of FVIII, to achieve a peak level of approximately 30%, along with a single 20 mg/kg dose of EACA.[38] Routine practice is to continue antifibrinolytic therapy in an outpatient setting for several days after the dental extraction.

Gastrointestinal bleeding

GI bleeds are much less common in persons with hemophilia than in those with von Willebrand disease and, therefore, require an evaluation for an underlying cause. Manage GI hemorrhage with repeated or continuous infusions to maintain nearly normal circulating levels of FVIII.

Intracranial bleeding

Intracranial hemorrhage is often trauma induced; spontaneous intracranial hemorrhages are rare. If CNS hemorrhage is suspected, immediately begin an infusion prior to radiologic confirmation. Maintain the factor level in the normal range for 7-10 days until a permanent clot is established.

All head injuries must be managed with close observation and investigated by imaging such as CT scanning or MRI. If the patient is not hospitalized, instruct the patient and his or her family regarding the neurologic signs and symptoms of CNS bleeding so that the patient can know when to return for reinfusion.

Inhibitors are antibodies that neutralize factor VIII (FVIII) and can render replacement therapy ineffective. They are found more commonly in patients with moderate to severe hemophilia (up to 30% of those with severe disease) who have received significant amounts of replacement therapy. Inhibitors develop in relatively young children, usually within their first 50 exposures to FVIII.

Rarely, inhibitors can develop in individuals without genetic hemophilia (eg, elderly persons, pregnant women). These occasionally are responsive to immunosuppressive therapy (eg, prednisone).

The treatment of patients with inhibitors of FVIII is difficult. Assuming no anamnestic response, low-titer inhibitors (ie, concentrations below 5 Bethesda units [BU]) occasionally can be overcome with high doses of factor VIII.[34] There is no established treatment for bleeding episodes in patients with high-titer inhibitors.

Other approaches to treating patients with FVIII inhibitors include the following:

• Porcine FVIII, which has low cross-reactivity with human FVIII antibody
• Activated prothrombin complex concentrate (aPCC)
• Activated recombinant FVII (rFVIIa)
• Desensitization
• Immune tolerance induction (ITI)
• Monoclonal antibodies that bridge FIXa and FX (eg, emicizumab)

Emicizumab

Emicizumab is a first-in-class bispecific monoclonal antibody that performs the function of activated FVIII, bridging activated FIX and FX to restore the coagulation cascade, but is unaffected by FVIII inhibitors. In November 2017, following a priority review, the US Food and Drug Administration (FDA) approved emicizumab for routine prophylaxis of bleeding episodes in adult and pediatric patients (including newborns) with hemophilia A who have FVIII inhibitors. Approval was based on the HAVEN 1 and 2 clinical trials. In 2018, the FDA extended approval for use of emicizumab to patients without FVIII inhibitors, based on the HAVEN 3 trial results.[39]

The HAVEN 1 trial included 109 adult and adolescent males aged 12 years or older who had hemophilia A with inhibitors. Patients taking emicizumab experienced about 2.9 treated bleeding episodes per year, compared with about 23.3 treated bleeding episodes per year for patients who did not receive prophylactic treatment, representing an 87% reduction in the rate of treated bleeding episodes (P < 0.001). Emicizumab-treated patients also reported an improvement in hemophilia-related symptoms (painful swellings and joint pain) and physical functioning (pain with movement and difficulty walking).[40]

Interim results from the single-arm HAVEN 2 study in children aged younger than 12 years with hemophilia A with inhibitors who received emicizumab prophylaxis are consistent with the positive results from the HAVEN 1 study. After a median observation time of 12 weeks, only 1 of the 19 study patients receiving emicizumab reported a treated bleed.[41]

Three patients in the HAVEN 1 trial who experienced breakthrough bleeding despite emicizumab prophylaxis and were treated with aPCC developed thrombotic microangiopathy (TMA). Episodes of TMA occurred only in patients who received, on average, cumulative doses of aPCC of more than 100 U/kg daily for 24 hours or more. This complication appears to represent a unique interaction between emicizumab and aPCC, as no cases of TMA had previously been reported in patients receiving aPCC alone. Strategies for treating breakthrough bleeding in patients receiving emicizumab may include the use of recombinant FVIIa, FVIII in patients with a low inhibitor titer, and lower doses of aPCC.[42]

Recombinant activated factor VII

Recombinant activated FVII (rFVIIa) has become the first choice of bypassing agents.[43] Recombinant FVIIa is a vitamin K–dependent glycoprotein that is structurally similar to human plasma–derived FVIIa.[44] It is manufactured by using DNA biotechnology.

Intravenous recombinant FVIIa has been studied for the treatment of bleeding episodes and for providing hemostasis during surgery in patients with a particular bleeding diathesis.[43] Recombinant FVIIa is also effective and well tolerated in patients with acquired hemophilia and in those with Glanzmann thrombasthenia.

To date, recombinant activated FVIIa has proved to be relatively free of the risk of antigenicity, thrombogenicity, and viral transmission. However, the cost of this product and its short half-life have precluded its use as prophylaxis in patients with inhibitors for FVIII; furthermore, when it has been used for this indication, select patients have had severe complications related to bleeding.

In pediatric patients, off-label treatment with recombinant FVIIa significantly reduced blood product administration, with 82% of patients subjectively classified as responders. Clinical context and pH values before administration were independently associated with response and 28-day mortality. Thromboembolic adverse events were reported in 5.4% of patients.[45]

Desensitization

Desensitization in nonemergency situations also may be feasible. This approach comprises large doses of FVIII along with steroids or intravenous immunoglobulin (IVIG) and cyclophosphamide. Success rates of 50-80% have been reported. In life-threatening bleeding, methods to quickly remove the inhibiting antibody have been tried. Examples include vigorous plasmapheresis in conjunction with immunosuppression and infusion of FVIII with or without antifibrinolytic therapy.

Immune tolerance induction

In ITI, tolerance to FVIII is induced by means of regular exposure to FVIII over several months to years.[34, 46] The overall likelihood of success with ITI is 70% ± 10%.

Factors associated with successful outcome of ITI include the following[47] :

• Historical inhibitor titers < 200 BU and immediate pre-ITI titers < 10 BU
• Younger age at ITI initiation
• An interval of < 5 years between inhibitor diagnosis and ITI start
• ITI interruption < 2 weeks in duration

First described by Backmann in 1977, ITI has been used with variations in the dosing schedule for FVIII and with or without immunosuppressive therapy (eg, cyclophosphamide, prednisone). Most of the recent protocols that use FVIII alone have avoided use of immunosuppression because of the toxicity risk. This technique is well established in persons with congenital hemophilia with allo-antibodies but does not have a role in persons with acquired hemophilia A with auto-antibodies.

Rituximab, a chimeric human-mouse monoclonal antibody against CD20 that rapidly and specifically depletes B cells, has been used with success in ITI.[48, 49] A 4-week course of weekly rituximab, with or without prednisone and/or cyclophosphamide, has shown durable and complete responses in several small trials in patients with autoimmune hemophilia and inhibitor titers of 5 to more than 200 BU.[50] Rituximab appears to be more effective in treating inhibitors in acquired hemophilia than in hereditary hemophilia.[51, 52]

The choice of FVIII dosing regimen for ITI has ranged from 50 IU/kg 3 times weekly to 300 IU/kg/d. An international study in patients with severe hemophilia and high-titer inhibitors found no significant difference between low-dose and high-dose ITI in terms of the percentage of subjects achieving tolerance (70%) or in the time taken to achieve tolerance. However, the study was stopped early because of safety considerations involving bleeding (significantly more common early on in the low-dose arm) and lack of statistical power.[47]

Most of the care for children with severe hemophilia now takes place at home, in the community, and at school, allowing these children to participate in normal activities that are otherwise impossible. This approach resulted from the development of prophylactic regimens of factor concentrate infusions that are administered at home, usually by a parent.

The main goal of prophylactic treatment is to prevent bleeding symptoms and organ damage, in particular to joints. Hemophilia arthropathy that results from recurrent or target joint bleeding can be prevented by this method.

Prophylaxis is not universally accepted, with only about half the children with hemophilia A receiving this treatment modality in the United States. Reasons cited for the lack of acceptance include need for venous access, factor availability, repeated venipunctures, and cost, among others. Research questions that remain unanswered include when to initiate and stop infusions, dosing, and dose schedule.

Factor VIII prophylaxis

In 2014 the FDA approved a long-acting recombinant FVIII–Fc fusion protein (rFVIIIFc) product (Eloctate) for control of bleeding episodes, management of perioperative bleeding, and routine prophylaxis in patients with hemophilia A. For routine prophylaxis, rFVIIIFc is infused every 4 days, whereas other available recombinant FVIII products are administered every 2-3 days.[53, 54]

The rFVIIIFc product was developed by fusing rFVIII to the Fc portion of IgG1, which allows a naturally occurring pathway to prolong the product's duration of action. FDA approval was based on a study in 164 patients with hemophilia A in which the median rate of bleeding episodes with prophylactic use of rFVIIIFc was 1.6 per year, compared with 33.6 per year in patients receiving on-demand treatment.[53, 54] In an open-label extension study of rFVIIIFc in 211 patients, which included up to 5 years of follow-up, no inhibitors were observed, annualized bleed rates remained low in patients on individualized prophylaxis, and most patients maintained extended-dosing intervals (median of 3.5 days).[55]

Other rFVIII products are also approved by the FDA for routine prophylaxis (eg, NovoEight, Kogenate, Nuwiq, Adynovate, Kovaltry, Afstyla, Jivi). Adynovate and Jivi are pegylated rFVIII products that allow less frequent administration. For prophylaxis, Jivi is administered every 5 days and Adynovate is administered 2 times per week.

In the phase III PROPEL trial, which studied pharmacokinetic-guided prophylaxis with Adynovate, targeting FVIII trough levels of 1-3% or 8-12% both proved effective.[56] Patients with higher trough levels were more likely to be completely free of bleeds; in the second 6 months of the trial, rates with 1-3% vs 8-12% trough levels were as follows:

• Zero total bleeds - 42% vs 62% ( P = 0.055)
• Zero spontaneous bleeds - 60% vs 76% (P = 0.101)
• Zero spontaneous joint bleeds - 65% vs 85% (P = 0.026)

FVIII consumption varied widely in each treatment group, with overlapping ranges, emphasizing the need for personalized treatment. However, most patients in the 1-3% arm were able to achieve their target FVIII trough with approximately twice-weekly dosing, whereas most of those in the 8-12% arm needed to infuse every other day, or even daily.[56]

Anti-inhibitor coagulant complex prophylaxis

In 2013, the US Food and Drug Administration (FDA) expanded the indication for anti-inhibitor coagulant complex (Feiba NF) to include routine prophylaxis in patients with hemophilia A or B who have developed inhibitors. Approval was based on data from a pivotal phase III study in which a prophylactic regimen resulted in a 72% reduction in median annual bleed rate compared with on-demand treatment.[57] An earlier study showed a 62% reduction in all bleeding episodes with prophylaxis versus an on-demand regimen.[58]

Emicizumab

The bispecific monoclonal antibody emicizumab is approved for prophylaxis in adults and children (including newborns) who have hemophilia A with or without FVIII inhibitors. The HAVEN 3 trial demonstrated that emicizumab prophylaxis is also effective in patients without inhibitors.[39]

In this phase III trial, 152 patients 12 years of age or older who had been receiving episodic treatment with FVIII were randomized to emicizumab prophylaxis once weekly or every 2 weeks, or no prophylaxis. The annualized bleeding rate was 1.5 in patients receiving weekly dosing and 1.3 with biweekly dosing, versus 38.2 events in patients receiving no prophylaxis. More than half of the study patients who received prophylaxis had no treated bleeding events. Those patients who had previously received FVIII prophylaxis had significantly lower bleeding rates with emicizumab prophylaxis.[39]

Marstacimab

In October 2024 the FDA approved marstacimab (Hympavzi) for routine prophylaxis in congenital hemophilia A without factor VIII inhibitors, in patients aged 12 years or older. Approval was based on an open-label, multicenter study in 116 adult and pediatric patients with severe hemophilia A or  B, without inhibitors, in which marstacimab proved superior to on-demand factor replacement for bleeds and equivalent to prophylactic factor replacement. (Marstacimab is also approved for use in hemophilia B).[59, 60]

Marstacimab is a human monoclonal IgG1 antibody directed against the Kunitz domain 2 (K2) of the tissue factor pathway inhibitor (TFPI). TFPI is the primary inhibitor of the extrinsic coagulation pathway; neutralization of TFPI activity enhances coagulation by inactivating factor Xa/factor VIIa/tissue factor complex protease functions. Marstacimab is administered weekly by subcutaneous injection.

Concizumab

In December 2024, the US Food and Drug Administration (FDA) approved the TFPI antagonist concizumab (Alhemo) for routine prophylactic use in adults and pediatric patients aged 12 years or older with hemophilia A with factor VIII inhibitors or hemophilia B with factor IX inhibitors; treatment is aimed at preventing bleeding episodes or decreasing their frequency. Approval was based on a multi-national, multi-center, randomized, open-label, phase 3 trial in patients with hemophilia A or B, with inhibitors. Compared with patients who received no prophylaxis, those who underwent treatment with concizumab achieved an 86% reduction in annualized bleeding rates.[61, 62]

Assessing adherence to prophylaxis

The Validated Hemophilia Regimen Treatment Adherence Scale–Prophylaxis (VERITAS-Pro) prophylaxis is a patient/parent questionnaire that uses six subscales (time, dose, plan, remember, skip, communicate), each containing four items, to assess patient adherence to prophylactic hemophilia treatment. In a study of 67 patients with hemophilia, including 53 with severe FVIII deficiency, Duncan et al found a strong correlation between VERITAS-Pro scores and adherence assessments (eg, infusion log entries).[63]

Pain management can be challenging in patients with severe hemophilia. Acute bleeding in joints and soft tissues can be extremely painful. This requires immediate analgesic relief.

Hemophilic chronic arthropathy is painful. Narcotic agents have been used, but their benefit for long-term therapy is limited by side effects, the development of tolerance, and the risk of addiction.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can be effective in managing acute and chronic arthritic pain, but significant caution must be used in dose and frequency due to concerns for increased risk of bleeding. Although they pose a risk of GI bleeding, their effects on platelet function are reversible. Avoid aspirin because of its irreversible effect on platelet function. Other analgesics may include acetaminophen in combination with small amounts of codeine or synthetic codeine analogs.

HIV-associated immune thrombocytic purpura is an exceedingly serious complication in patients with hemophilia because it may result in lethal intracranial bleeding. Correct platelet counts to greater than 50,000/mL. Steroids are of limited effectiveness, and intravenous immunoglobulin or anti-Rh(D) generally induces only transient remissions. Anti-HIV medications and splenectomies may result in long-term improvement of thrombocytopenia.

Allergic reactions are occasionally reported with the use of factor concentrates, and these can be severe. Premedication or adjustment of the rate of infusion may resolve the problem. It is quite possible that residual cell line proteins (from mouse or hamster cell lines) may contribute to this, and change of product to different source cell line can be considered.

Do not circumcise boys born to mothers who are known or thought to be carriers of hemophilia unless disease in the infant has been excluded with appropriate laboratory testing. Perform blood assays of FVIII with cord blood. When a cord blood sample is not available, obtain a sample from a superficial limb vein; avoid femoral and jugular sites.

Routine immunizations that require injection (eg, diphtheria, tetanus toxoids, and pertussis [DPT] or measles-mumps-rubella [MMR] vaccines) may be given by means of a deep subcutaneous (rather than deep intramuscular) injection with a fine-gauge needle. Administer the hepatitis B vaccine (now routinely administered to all children) soon after birth to all infants with hemophilia. Administer the hepatitis A vaccine to those individuals with hemophilia and no hepatitis A virus antibody in their serum.

The Italian hemophilia and vaccinations (HEVA) project notes that most experts agree that individuals with hemophilia should be vaccinated according to the schedule for the general population, and that in addition, these patients should be vaccinated against hepatitis A virus and hepatitis B virus infection, particularly if they are candidates for plasma‐derived FVIII products. The HEVA project also provides the following general recommendations on vaccination in patients with hemophilia[64] :

• Children and adults with hemophilia should receive mandatory and recommended vaccinations as per the institutional vaccination schedule, regardless of their baseline factor VIII level
• Subcutaneous administration of vaccines is preferred over intramuscular administration, regardless of disease severity, to reduce the risk of bleeding
• With vaccines that require intramuscular administration, providing factor replacement prior to vaccination is advisable
• Apply ice to the injection site before and after vaccine administration
• Avoid rubbing the injection site after vaccination; instead, provide compression
• Use the thinnest possible needle for vaccine injection

The HEVA project included the following recommendations on vaccination of hemophilia patient subgroups[64] :

• Use of live attenuated vaccines is contraindicated in immunocompromised patients
• Immunocompromised patients should be vaccinated against pneumococcal infection and influenza
• Patients aged ≥65 years should be vaccinated against pneumococcus and influenza as per the institutional vaccination schedule
• Patients travelling to areas where yellow fever and/or typhus are endemic should be vaccinated against those diseases

The World Federation of Hemophilia (WFH), in collaboration with the European Association for Haemophilia and Allied Disorders, European Haemophilia Consortium, and US National Bleeding Disorders Foundation, has issued the following recommendations on COVID-19 vaccination for people with bleeding disorders[65] :

• People with bleeding disorders are not at greater risk of contracting COVID-19 or developing a severe form of the disease, so they are not considered a priority group for vaccination
• Administer the vaccine intramuscularly, using the smallest-gauge needle available (25-27 gauge); however, some vaccines must be administered using the accompanying needle-syringe combination, in which case the use of an alternative needle may not be possible or desirable
• Apply pressure to the injection site for at least 10 minutes afterwards, to reduce bleeding and swelling. Additionally, patients should inspect/palpate the injection area several minutes and 2-4 hours later to assess for delayed hematoma
• Discomfort in the arm for 1-2 days after injection should not be alarming unless it worsens and is accompanied by swelling. Any adverse events (eg, hematoma, allergic reaction) should be reported to a hemophilia treatment center
• Patients should immediately contact their physician or go to the nearest hospital emergency department if they experience an allergic reaction, as it can be life-threatening; patients with a history of allergic reactions to extended half-life clotting factor concentrates containing polyethylene glycol (PEG) should discuss vaccine choice with their physician because some vaccines contain PEG as an excipient
• In patients with severe/moderate hemophilia, administer the vaccine after a factor VIII injection. For patients with a basal FVIII above 10%, no hemostatic precautions are required
• Patients on emicizumab (with or without an inhibitor) can be vaccinated by intramuscular injection at any time, without hemostatic precautions and without receiving a dose of FVIII

In severe hemophilia, consider prophylactic or scheduled factor VIII. Prophylactic replacement of FVIII is used to maintain a measurable level at all times, with the goal of avoiding hemarthrosis and the vicious cycle of repetitive bleeding and inflammation that results in destructive arthritis.[66] This goal is achieved by administering factor 2-3 times a week. The National Bleeding Disorders Foundation has recommended the administration of primary prophylaxis, beginning at the age of 1-2 years.

Carrier testing is valuable for women who are related to obligate carrier females or males with hemophilia. Carrier testing may prevent births of individuals with major hemophilia. This testing can be offered to women interested in childbearing who have a family history of hemophilia. Prenatal diagnosis is important even if termination of the pregnancy is not desired, because plans for delivery and neonatal management can be made.

Preimplantation genetic diagnosis has been used as a possible alternative to prenatal diagnosis in combination with in vitro fertilization to help patients avoid having children with hemophilia or other serious inherited diseases.[67, 68, 69] The genetic diagnosis is made by using single cells obtained during biopsy from embryos before implantation. For this, fluorescence in situ hybridization is used. This technique circumvents pregnancy termination. However, it is expensive and has limited success rates, with a 22% chance for a live birth.[29]

Generally, individuals with severe hemophilia should avoid high-impact contact sports and other activities with a significant risk of trauma. However, mounting evidence suggests that appropriate physical activity improves overall conditioning, reduces injury rate and severity, and improves psychosocial functioning. Kumar et al reported that aerobic exercise on a stationary cycle resulted in significant improvement in hemostatic indices in post-adolescent patients with mild-to-moderate hemophilia A.[70]

Patients with severe hemophilia can bleed from any anatomic site after negligible or minor trauma, or they may even bleed spontaneously. Any physical activity may trigger bleeding in soft tissues. Prophylactic factor replacement early in life may help to prevent bleeding during activity as well as help to prevent chronic arthritic and muscular damage and deformity.

With the cloning of FVIII and advances in molecular technologies, the possibility of a cure for hemophilia A with gene therapy was conceived.[71] Although the development of gene therapy for hemophilia A faced several complications, including the large size of the FVIII gene, preclinical studies in mice and dogs with hemophilia resulted in long-term correction of the bleeding disorders and, in some cases, a permanent cure.[72] Possible approaches to gene therapy for hemophilia A include the following[73] :

• Ex vivo gene therapy, in which cells to be transplanted are genetically modified to secrete factor VIII and then are reimplanted into the recipient

• In vivo gene therapy, in which a vector (typically a virus altered to include FVIII DNA) is directly injected into the patient[74]

• Nonautologous gene therapy, in which cells modified to secrete FVIII are packaged in immunoprotected devices and implanted into recipients

The FDA approved the first gene therapy for hemophilia A, valoctocogene roxaparvovec (Roctavian), in June 2023. It is a one-time, single-dose IV adeno-associated virus vector–based gene therapy indicated for severe hemophilia A (congenital FVIII deficiency with FVIII activity < 1 IU/dL) in adults without preexisting antibodies to adeno-associated virus serotype 5 (AAV5) detected by an FDA-approved test. 

Approval was based on the phase 3, open-label, single-group GENEr8-1 trial (n=134). Among the 132 HIV-negative participants, the mean FVIII activity level at weeks 49 through 52 increased by 41.9 IU/dL (P < 0.001; median change, 22.9 IU/dL). After week 4 following infusion, the 112 participants enrolled from a prospective noninterventional study decreased their annualized rates of FVIII concentrate use by 98.6%, and their rates of treated bleeds decreased by 83.8% (P < 0.001 for both comparisons).[75]  

The usefulness of AAV-based gene therapy such as valoctocogene roxaparvovec is limited by the fact that approximately one third of patients with hemophilia A have antibodies to AAV5. Ex vivo gene therapy offers a potential alternative in such cases.[76] Gao et al reported that this approach can result in stable, long-term engraftment of FVIII-producing cells. These researchers transduced endothelial colony-forming cells (ECFCs) and placenta-derived mesenchymal stromal cells (PMSCs) with a lentiviral vector that expressed FVIII, and administered the cells by intramuscular injection. Use of ECFCs and PMSCs together produced better results than either cell type separately, and engraftment rates were higher in neonatal mice than in adult mice.[77]

Implantation of liver-derived stem cells that have been expanded in vitro is under consideration, as these could theoretically induce a steady-state production of quantities of factor sufficient to prevent spontaneous bleeding.

Management should be provided in coordination with a comprehensive hemophilia care center. Specific consultations may be indicated with a hematologist, blood bank, pathologist, or others, as indicated by hemorrhagic complications. Early hematology consultation for management of inhibitors is essential. Annual dental evaluation is recommended.

A genetic counselor may be consulted. Genetic testing for hemophilia A is available and must be offered to potential carriers. Prenatal testing is performed by using amniocentesis or chorionic villus biopsy.

Before elective surgery is planned, a hematologist should be consulted to arrange adequate coverage with antihemophilic factors and to arrange close follow-up to ensure that factor levels are sufficient during the operation and in the recovery and healing period.

Consult an orthopedic surgeon in cases of permanent joint deformities resulting from recurrent hemarthrosis, as may occur in relatively neglected cases or, occasionally, in cases of repetitive bleeding in a single joint despite intensive prophylactic replacement of factor and physiotherapy. Open surgical or arthroscopic synovectomy may decrease bleeding and pain in the affected joint.

In patients who develop synovitis from joint bleeds, intra-articular injection of radioisotopes to ablate the synovium (radiosynovectomy) can be used to decrease bleeding, slow progression of cartilage and bone damage, and prevent arthropathy. Yttrium-90 and rhenium-186 have proved equally effective for radiosynovectomy.[78] A review by Rodriguez-Merchan et al concluded that radiosynovectomy is effective, safe, and well tolerated.[78]

The review by Rodriguez-Merchan included 500 synovectomies in 443 joints of 345 patients with chronic hemophilic synovitis. One to three injections were administered, with a 6-month interval between injections. On average, the number of hemarthroses decreased by 64.1%, articular pain decreased by 69.4%, the degree of synovitis decreased by 31.3%, and the World Federation of Haemophilia score improved by 19%. Only four complications (0.9%) occurred. In 28 joints (6.3%), arthroscopic synovectomy or total knee replacement was eventually required.[35]

The following organizations have released guidelines for the management of hemophilia A. Key diagnostic and treatment recommendations have been reviewed and integrated throughout the article.  

• United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) (2017): Guidelines for the management of acute joint bleeds and chronic synovitis in haemophilia ^[36]
• Italian hemophilia and vaccinations (HEVA) project (2019): Consensus statements on vaccination in patients with haemophilia ^[64]
• World Federation of Hemophilia (2020): COVID-19 vaccination guidance for people with bleeding disorders ^[65]

Factor VIII (FVIII) is the treatment of choice for acute or potential hemorrhage. Recombinant FVIII concentrate is generally the preferred source of FVIII. Prophylactic administration of FVIII is often recommended for patients with severe disease. The FVIII activity level should be corrected to 100% of normal for potentially serious hemorrhage (eg, central nervous system, trauma related, gastrointestinal [GI], genitourinary, epistaxis) and to 30-50% of normal for minor hemorrhage (eg, hemarthrosis, oral mucosal, muscular).

One unit of FVIII is the amount of FVIII in 1 mL of plasma (1 U/mL or 1%). The volume of distribution of FVIII is that of plasma, approximately 50 mL/kg. The difference between the desired FVIII activity level and the patient's native FVIII activity level can be calculated by simple subtraction and expressed as a fraction (eg, 100% - 5% = 95% or 0.95). 

To determine the number of units of FVIII needed to correct the FVIII activity level, use the following formula:

• Units FVIII = (weight in kg)(50 mL plasma/kg)(1 U FVIII/mL plasma)(desired FVIII level minus the native FVIII level)

As an example, an 80-kg individual diagnosed with hemophilia with known 1% FVIII activity level presents to the emergency department with a severe upper GI bleed. The correct dose of FVIII to administer in this case would be calculated as follows:

• Units FVIII = (80 kg)(50 mL/kg)(1 U FVIII/mL)(0.99) = 3960

The next dose should be administered 12 hours after the initial dose and is one half the initial calculated dose. Minor hemorrhage requires 1-3 doses of FVIII. Major hemorrhage requires many doses and continued monitoring of FVIII activity with the goal of keeping the trough activity level at no lower than 50%. Continuous infusions of FVIII may be considered for major hemorrhage.  It is important to recall that response to factor replacement and half-life of product varies substantially across the population and that therapy should ideally be individualized for the patient. Peak and trough values drawn after a treatment and just prior to next treatment can be very helpful in individualizing therapy.

The specific factor product that patients use is often part of their individualized treatment plan. Patients, or parents of young children, will usually be well educated on their dosing/products. This information also can be found on institutional treatment center/blood bank databases.

Other medicinal adjuncts to FVIII (eg, desmopressin acetate [DDAVP], antifibrinolytics) often are useful in achieving hemostasis and can lessen the need for FVIII infusion. Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, are especially useful for oral mucosal bleeds but are contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria.

Monoclonal antibodies have entered clinical practice for prophylaxis in patients with hemophilia. They offer the benefit of subcutaneous rather than intravenous administration and, with some agents, efficacy in patients with FVIII inhibitors.

Class Summary

FVIII concentrates replace deficient FVIII in patients with hemophilia A, with the goal of achieving a normal hematologic response to hemorrhage or preventing hemorrhage. Recombinant products should be used initially and subsequently in all newly diagnosed cases of hemophilia that require factor replacement. Agents that bypass FVIII activity in the clotting cascade (eg, activated FVII) are used in patients with FVIII inhibitors.

Antihemophilic factor recombinant (Advate, Adynovate, Afstyla)

These are synthetic products and are the most commonly used form of treatment when the administration of clotting protein factor VIII is indicated. In hemophilia A patients, it temporarily restores hemostasis

Antihemophilic factor/von Willebrand factor complex (Alphanate, Humate P, Wilate)

Antihemophilic factor (factor VIII; FVIII) and von Willebrand Factor (vWF) are constituents of normal plasma, which are required for clotting. Temporarily increases the plasma level of FVIII, thus minimizing the hazard of hemorrhage in patients with hemophilia A; FVIII is an essential cofactor in activation of factor X, leading to formation of thrombin and fibrin. Indicated for control and prevention of bleeding episodes for hemophilia A in adults and children (brand dependent).  These concentrates have different ratios of the amount of FVIII and vWF in the product, and prescribers should familiarize themselves with these differences to optimize dosing.

Anti-inhibitor coagulant complex (Feiba, Feiba NF)

This agent is a freeze-dried, sterile human plasma fraction with FVIII inhibitor–bypassing activity. It contains factors II, IX, and X, mainly nonactivated, and FVII, mainly in the activated form. It may shorten the activated partial thromboplastin time of plasma containing factor VIII inhibitors.

Anti-inhibitor coagulant complex is indicated for prevention and control of spontaneous hemorrhage or bleeding during surgical interventions, in hemophilia patients who have autoantibodies or alloantibodies to coagulation factors. It is also indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B who have developed inhibitors.

Factor VIIa, recombinant (Factor VIIa, Eptacog alfa, Factor VIIa recombinant-jncw)

Recombinant activated factor (FVIIa) is indicated for the treatment of bleeding episodes in patients with hemophilia A and inhibitors. When complexed with tissue factor, this agent can activate the conversion of coagulation factor X to factor Xa as well as coagulation factor IX to IXa. Factor Xa, in complex with other factors, then converts prothrombin to thrombin, which leads to the formation of a hemostatic plug by converting fibrinogen to fibrin and thereby inducing local hemostasis. This process may also occur on the surface of activated platelets.

Factor VIII, human plasma derived (Antihemophilic Factor (Human), Hemofil M, Koate DVI)

These are pooled plasma products (high purity) with factor VIII, which is necessary for stable clot formation and for maintenance of hemostasis.

Class Summary

Monoclonal antibodies are used to bind to one specific substance in the body (eg, molecules, antigens). This binding is very versatile and can mimic, block, or cause changes to enact precise mechanisms (eg, bridging molecules, replacing or activating enzymes or cofactors, immune system stimulation).

Emicizumab (Emicizumab-kxwh, Hemlibra)

Emicizumab is a first-in-class bispecific monoclonal antibody that bridges activated FIX and FX to restore the function of activated FVIII. It is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients (including newborns) with hemophilia A with or without factor VIII inhibitors.

Rituximab (Riabni, Rituxan, Rituximab-abbs)

Rituximab is a monoclonal antibody directed against the CD20 antigen on B-lymphocytes. It is recommended as second-line therapy in immune tolerance induction regimens for patients with FVIII inhibitors, especially those with high inhibitor titers. This agent binds to, and mediates destruction of, B-cells, thereby decreasing production of FVIII inhibitors and autoimmunization.

Class Summary

Desmopressin transiently increases the FVIII plasma level in patients with mild hemophilia A.

Desmopressin (DDAVP, Minirin, Nocdurna)

Desmopressin causes a transient increase (up to four-fold) in FVIII plasma levels of patients with mild hemophilia A. It also produces a dose-dependent increase in plasminogen activator. It is useful for minor hemorrhage episodes only. It may be useful in patients with FVIII inhibitors.

Desmopressin increases the cellular permeability of the collecting ducts, resulting in renal reabsorption of water. This can result in hyponatremia, which can be severe, particularly with repeat dosing. Tachyphylaxis may occur even after first dose, but drug can be effective again after several days.

Class Summary

These agents are used in addition to factor VIII replacement for oral mucosal hemorrhage and prophylaxis, as the oral mucosa is rich in native fibrinolytic activity. Their use is contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract, because they can cause obstructive uropathy or anuria. They should not be used in combination with prothrombin complex concentrate (PCC).

Aminocaproic acid (Amicar)

This lysine inhibits fibrinolysis by blocking the binding of plasminogen to fibrin and inhibiting plasminogen and conversion to plasmin, resulting in the inhibition of fibrinolysis. The principal drawbacks of this agent are that thrombi formed during treatment are not lysed, and its effectiveness is uncertain. It has been used to prevent recurrence of subarachnoid hemorrhage.

This agent is widely distributed. Its half-life is 1-2 hours. Peak effect occurs within 2 hours. Hepatic metabolism is minimal.

Tranexamic acid injection (Cyklokapron)

This agent is an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin. It also inhibits the proteolytic activity of plasmin.

Class Summary

These therapies are designed to introduce a functional copy of a transgene encoding the human coagulation factor VIII. 

Valoctocogene roxaparvovec (Roctavian)

Valoctocogene roxaparvovec is an adeno-associated virus serotype 5 (AAV5)–based gene therapy vector, designed to introduce a functional copy of a transgene encoding the B-domain deleted SQ form of human coagulation FVIII (hFVIII-SQ). The expressed hFVIII-SQ replaces the missing coagulation FVIII needed for effective hemostasis. It is indicated for severe hemophilia A (congenital factor VIII deficiency with factor VIII activity <1 IU/dL) in adults without preexisting antibodies to AAV5 detected by an FDA-approved test. 

Concizumab (Alhemo, Concizumab-mtci)

Tissue factor pathway inhibitor (TFPI) antagonist indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with hemophilia A (congenital factor VIII deficiency) with FVIII inhibitors.

Marstacimab (Hympavzi, Marstacimab-hncq)

Human monoclonal IgG1 antibody directed against tissue factor pathway inhibitor (TFPI). TFPI is the primary inhibitor of the extrinsic coagulation pathway; neutralization of TFPI activity enhances coagulation by inactivating factor Xa/factor VIIa/tissue factor complex protease functions. Marstacimab is indicated for routine prophylaxis in hemophilia A (congenital factor VIII deficiency) without factor VIII inhibitors, in patients aged ≥12 years.