Background
The hemostatic system, consisting of the blood vessels and their content, blood, plays a crucial role in human survival. The importance of the plasma coagulation system in protecting life by preventing further blood loss following transection of a blood vessel is well recognized. Blood is usually maintained in a fluid state, without evidence of bleeding or clotting. The presence of an X-linked pattern of inheritance of a bleeding diathesis in families, referred to as hemophilia, has been recognized for hundreds of years (see image below).[1, 2, 3]
Obituary in the March 22, 1796, Salem Gazette (Massachusetts) for a 19-year-old man who bled to death after suffering a foot injury. Also detailed are the deaths of 5 brothers by various minor injuries. That hemophilia is due to a deficiency of a factor (F) in the blood was proven in 1840 by correction of the bleeding defect with transfusion of whole blood; this was followed in 1911 by the demonstration that normal plasma could shorten the whole blood clotting time of hemophilic blood. Then, in 1937, a factor from normal plasma was shown to be effective in accelerating the coagulation of hemophilic blood, and the term antihemophilic globulin was coined; this protein is now referred to as factor VIII-C (FVIII-C).
Further progress was achieved in the 1950s with the development of cryoprecipitate and plasma concentrates to treat hemophilia A (FVIII deficiency). The clinical and therapeutic observation that clotting time was corrected after transfusion of blood from one hemophilic patient to another was followed by the description of "plasma thromboplastin component" or factor IX deficiency. This second type of deficiency was referred to as hemophilia B to differentiate it from hemophilia A.
Clarification of the structure and function of the factor VIII molecule (FVIII-C, an X-linked gene product, also known as antihemophilic globulin) noncovalently bound to von Willebrand factor (vWF, an autosomal 12p gene product) in plasma clarified the separate roles of factor VIII-C (antihemophilic globulin) and von Willebrand factor proteins. This led to an understanding of the role of the different components of the factor VIII molecule in the physiology of normal hemostasis and to a recognition that hemophilia A and von Willebrand disease were caused by a deficiency of different proteins in the factor VIII complex.
An understanding of the reasons for the development of factor VIII inhibitors in persons with hemophilia or in persons with previously normal hemostasis (referred to as acquired hemophilia) expanded understanding of the antigenic structure of the factor VIII molecule. Cloning of the factor VIII gene was followed by the preparation of recombinantly derived factor VIII (rFVIII) as replacement therapy for the missing factor. Several different vectors have now been used to correct factor VIII deficiency in humans, with many questions still to be resolved.[4, 5] The potential role of increased levels of factor VIII in thrombophilic states continues to be explored.
Primary immunodeficiency diseases (PIDs) are associated with various autoimmune complications and several manifestations of autoimmunity. Acquired hemophilia is rare in childhood even though autoantibodies may develop in various forms of primary immunodeficiency diseases. However, acquired hemophilia may rarely form factor VIII inhibitors in patients with undefined primary immunodeficiency disease features that are suggestive of autosomal recessive hyper-immunoglobulin (Ig) E syndrome.[6]
This article deals only with factor VIII-C (antihemophilic globulin), the coagulant molecule, also referred to here as factor VIII. For information about the von Willebrand portion of the molecule, see von Willebrand Disease.
For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Kidneys and Urinary System Center. Also, see eMedicine's patient education articles Hemophilia and Blood in the Urine.
Pathophysiology
Factor VIII (FVIII-C; antihemophilic globulin) is an essential part of the hemostatic mechanism, participating as a cofactor in the second burst of thrombin generation, which leads to clot formation (see image below). An isolated deficiency of factor VIII-C is associated with a significant bleeding diathesis, demonstrating the importance of factor VIII in hemostasis.
The hemostatic pathway: role of factor VIII. Production, processing, structure, and half-life
Primary sites of factor VIII-C production are thought to be the liver and the reticuloendothelial system. Liver transplantation corrects factor VIII deficiency in persons with hemophilia, and persons with mild hemophilia with progressive liver disease have a rise in factor VIII levels, thus establishing the liver as the major site of factor VIII synthesis.
Factor VIII mRNA has been detected in the liver, spleen, and other tissues.[7] Studies of factor VIII production in transfected cell lines have shown that following synthesis, factor VIII 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 factor VIII's signal peptide and the addition of oligosaccharides also occur in the endoplasmic reticulum. The chaperone proteins, calnexin and calreticulin, enhance both factor VIII secretion and degradation.
A part of the factor VIII 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. ERGIC-53 is a chaperone protein in the Golgi apparatus that facilitates secretion of both factor VIII and factor V; a single mutation in ERGIC-53 has been identified as a cause of combined deficiency of factor VIII-C and factor V.
The secreted factor VIII-C glycoprotein in plasma is a heterodimer having a carboxy terminal–derived light chain (molecular weight [MW]: 80,000) in a metal-dependent association with the amino terminal–derived heavy chain (MW: 90,000-200,000) (see 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. The plasma concentration of factor VIII-C is approximately 200 ng/mL, whereas that of von Willebrand factor is approximately 10 mcg/mL. von Willebrand factor appears to promote assembly of the heavy and light chains of factor VIII and more efficient secretion of factor VIII from the endoplasmic reticulum. It also directs factor VIII into the Weibel-Palade bodies, which are the intracellular storage sites for von Willebrand factor.
In plasma, factor VIII is stabilized and protected from degradation because of its association with a 50-molar excess of von Willebrand factor protein; the light chain of factor VIII-C interacts noncovalently with the N-terminal region of the von Willebrand factor protein. In the presence of normal von Willebrand factor protein, the half-life of factor VIII-C is approximately 12 hours, whereas in the absence of von Willebrand factor, the half-life of factor VIII-C is reduced to 2 hours.[8, 9, 10]
Wide interindividual variations are found in the level of factor VIII following factor VIII infusions in patients with factor VIII deficiency. In an attempt to understand this phenomenon, extensive pharmacokinetic studies were performed in 32 patients with hemophilia A (30 with severe disease and 2 with mild disease) who received replacement therapy with rFVIII or a monoclonal antibody–purified preparation. The half-life of factor VIII was found to be significantly influenced by blood type and von Willebrand factor level. The half-life of factor VIII from patients with blood type O was much shorter half-life at 15 ± 0.9 hours compared with that of type A patients, who had a longer half-life of 19.7 ± 0.9 hours (significant at P = .003). Older patients with higher von Willebrand factor levels had factor VIII with longer half-lives.[11]
Physiologically, factors such as estrogens, pregnancy, exercise, and epinephrine can raise factor VIII levels. The extent of the exercise-induced rise in factor VIII levels was shown in a study of experienced athletes after a 42-km marathon run on a relatively cool, cloudy day.[12] A 3-fold increase in levels of factor VIII-C and von Willebrand factor antigen was found, along with a change in the von Willebrand factor multimer pattern. Several drugs and progressive liver disease can induce a rise in factor VIII levels in persons with mild hemophilia A.
Activation of FVIII
Activation of coagulation is accomplished by the conversion of a series of zymogens to enzymes, with participation of cofactors leading to the conversion of fibrinogen to a stable fibrin clot. Physiologic inhibitors play a crucial role in shaping the direction of this process. Tissue factor (TF), an integral cell membrane protein (which, unlike other zymogens in hemostasis, does not require previous activation), is usually present on cells not exposed to flowing blood or is produced by cells exposed to blood, only in response to specific stimuli.
When tissue factor becomes exposed to blood under altered normal or pathologic states, it binds with a high affinity to both factor VII and factor VIIa (activated FVII); factor VII bound to tissue factor is rapidly activated to factor IIa. The TF-FVIIa complex (extrinsic pathway tenase) is regulated by tissue factor and is the most potent activator of coagulation. TF-FVIIa activates factor X to factor Xa and factor IX to factor IXa; factor XIa activates factor IX to factor IXa at a slower rate than that achieved by the TF-FVIIa complex.
Under normal conditions, a small amount of free factor VIIa (~4.34 ng/mL; ~1% of total FVII) circulates in plasma. The source of this small amount of free factor VIIa (a serine protease) in normal circulation remains unclear.[13] The free factor VIIa represents a low-grade activation of hemostasis, which is present at all times and is available to quickly accelerate thrombin generation whenever needed.
The importance of the factor IX to factor IXa activation by the TF-FVIIa complex is underscored by the fact that in patients with severely reduced levels of factor IX (hemophilia B), only approximately 10% of normally expected factor VIIa (~0.33 ng/mL) is spontaneously generated, whereas approximately half the normal amount of normal factor VIIa (~2.69 ng/mL) is found in patients with severe factor VIII-C deficiency (hemophilia A). The practical importance of this distinction is unclear because deficiency of factor VIII or factor IX is associated with a clinically indistinguishable bleeding disorder.
When factor VIII is exposed to thrombin or factor Xa, an initial and rapid 30-fold increase of its procoagulant activity takes place, with greater activation by thrombin, followed by a rapid loss of procoagulant activity of factor VIIIa. This activation accompanies proteolysis of both heavy and light chains of factor VIII at sites of tyrosine sulfate residues.
Thrombin also activates platelets, exposing the acidic inner leaflet phospholipids (phosphatidyl serine and phosphatidyl ethanolamine) to the outside, allowing factor VIIIa to bind specifically to the platelet membrane through its light chain, increasing factor VIII activity and allowing assembly of the tenase complex to proceed.[14, 15] This contributes to the development of platelet procoagulant activity, which is necessary for the second, larger burst in thrombin generation that is responsible for clot formation.
The complex of factor IXa, and its cofactor factor VIIIa, when assembled on a negatively charged phospholipid surface, represents the intrinsic pathway tenase complex. The binding of activated coagulation factors to a phospholipid surface localizes this process to sites of vascular damage. On a phospholipid surface, factor VIIIa increases the maximum velocity of factor X activation by factor IXa, by approximately 200,000-fold, leading to the large second burst of thrombin generation, following the initial small amounts of thrombin produced by the TF-FVIIa complex.
Inactivation of FVIII
Activation of factor VIII is followed by an immediate dissociation of the A2 subunit, leading to loss of activity of factor VIIIa; prolonged reaction of factor VIIIa with factor IXa leads to proteolysis of the A1 subunit and subsequent loss of factor VIIIa activity. Thus, the rapid decay of factor VIIIa results in loss of activity of the intrinsic tenase complex, self-limiting its proteolytic activity.
Another factor that critically determines the length of survival of factor VIIIa is activated protein C (APC), which, along with its cofactor, free protein S, is a potent anticoagulant. Thrombin, when bound to thrombomodulin on the surface of endothelial cells, loses its serine protease prothrombotic functions and instead supports the anticoagulant pathway by activating protein C in the presence of phospholipids and calcium. Cleavage of factor VIIIa by APC occurs at sites on both the A2 and A1 subunits. The primary substrate of APC appears to be factor Va rather than factor VIIIa, and, under physiologic conditions, the major reason for loss of factor VIIIa activity appears to be due to spontaneous dissociation of the A2 subunit of factor VIIIa, rather than APC-induced proteolysis of factor VIIIa.
In addition to APC, proteolysis of factor VIIIa may also be mediated by factor IXa, factor Xa, and thrombin; the relative importance of these pathways in vivo is unclear.
Factor V is another cofactor that has structural and functional similarities to factor VIII. A single mutation in the factor V gene leads to the production of an abnormal factor V (FV Leiden) whose activated form is less susceptible to degradation by APC, leading to a hypercoagulable state. It has been postulated that a similar mutation in the factor VIII gene might occur, leading to a thrombophilic state. However, analysis of mutant factor VIII proteins created in the laboratory showed that mutations at both the Arg 336 and Arg 562 sites (sites of APC cleavage) of factor VIII were necessary before the mutated factor VIII was resistant to APC-induced proteolysis.[16, 17]
Factor VIIIa is protected by von Willebrand factor from inactivation by APC, but von Willebrand factor is unable to prevent thrombin from activating factor VIII to factor VIIIa or prevent activation of factor VIII by factor Xa. The inhibitory and protective actions of von Willebrand factor probably result from the prevention by von Willebrand factor of the interaction of factor VIIIa with phospholipids and activated platelets. When thrombin cleaves factor VIII, von Willebrand factor is released, and factor VIIIa is freed and is capable of attaching to the platelet phospholipid, a site to which the factor VIIIa is brought by the interaction of von Willebrand factor with the platelet glycoprotein Ib receptor.
In the rare disorder of inherited combined deficiencies of factor V and factor VIII, the prothrombinase complex (extrinsic tenase) in which factor Va participates is also deficient, in addition to the deficiency in the tenase complex caused by deficiency of factor VIIIa.
Antigenic structure
The 6 structural domains in the antigenic regions of factor VIII are, in the following order, A1-A2-B-A3-C1-C2, with 3 amino acid–rich regions (AR1, AR2, AR3). Initially, factor VIIIa, resulting from limited proteolytic cleavage, is a heterodimer of a heavy chain (with A1 and A2 domains) and a light chain (with A3-C1-C2 domains) bound to von Willebrand factor. This is further cleaved to a heterotrimer by thrombin.
The carboxy terminal C2 domain binds von Willebrand factor and phospholipids; the negatively charged head of phosphatidylserine, an O-phospho-L-serine, binds factor VIIIa.[14] The C2 domain can bind either phosphatidylserine or von Willebrand factor, but not both at the same time. Interestingly, a high degree of conservation of amino acids exists between the A and C domains of factor V and factor VIII (both activated by thrombin and both substrates for APC), and both factors are suggested to have evolved from a primordial gene, with divergence of amino acids in the B domain of the molecules. Gene structure is discussed in Causes.
Epidemiology
Frequency
United States
The overall estimated frequency of hemophilia A (FVIII deficiency) is 1 case per 5,000-10,000 live male births. Approximately 50-60% of patients have severe hemophilia A (FVIII-C < 2% of normal) associated with the severest bleeding manifestations. Persons with moderately severe hemophilia (FVIII-C of 2-5%) constitute 25-30% of patients with hemophilia and manifest bleeding after minor trauma. Persons with mild hemophilia A (FVIII-C of 6-30%) comprise 15-20% of all people with hemophilia; these patients develop bleeding only after significant trauma or surgery.
Acquired hemophilia A, caused by the development of an autoantibody to factor VIII in a person with previously normal hemostasis, develops with a frequency of 1 case per 1 million population per year.
The inherited, combined deficiency of factor V and factor VIII is a rare but recognized cause of a bleeding disorder in the United States.
International
Hemophilia A is found in all ethnic groups in the world. Alloantibodies and autoantibodies to factor VIII (FVIII inhibitors) have been reported from many parts of the world.[18] The inherited combined factor V and factor VIII deficiency has been reported in patients from Europe, Tunisia, the Middle East, Iran, China, and India.
The distribution of the mutations within the factor VIII gene in 31 Taiwanese, unrelated hemophilia A patients demonstrated that 12 (38.7%) severe males and 1 (3.2%) severe female were genotyped with the recurrent IVS22 and IVS1 inversion.[19] Eleven mutations were novel: 7 caused missense substitutions, and 4 resulted in truncated proteins.
Abu-Amero et al performed detailed clinical examinations, including plasma factor VIII-C measurements) of 20 unrelated Arab patients with severe hemophilia A.[20] Intron 22 inversion was common (detected in 11 patients [55%]); 8 base substitutions (6 of which were novel) were detected in 9 patients (45%), without the presence of insertions or deletions. Some base substitutions (8) were detected, in which 6 were potentially pathologic and which correlated well with the severe clinical phenotype that was observed.[20] Abu-Amero et al recommend larger studies with more Arab patients from various Arab countries determine the prevalence of various mutations in Arabs.
Mortality/Morbidity
Intracranial bleeding was the major cause of death in individuals with hemophilia until the acquired immunodeficiency syndrome (AIDS) epidemic, which, from the late 1970s into the 1990s, became the major cause of death in this population. These individuals experience significant morbidity from frequent joint and other bleeding episodes.
Hepatitis remains a major cause of morbidity and mortality because of its progression to chronic liver disease[21] ; chronic fatigue is caused by the ongoing active viral illness and/or is related to antiviral therapy. Portal hypertension, variceal bleeding, ascites, and upper gastrointestinal (GI) hemorrhage occur as liver disease progresses. Hepatocellular carcinoma can develop as a consequence of chronic hepatitis. Emerging pathogens potentially transmitted by blood or blood products (eg, prions) will change the pattern of morbidity and mortality in the future. See Complications for a description of transfusion-transmitted illnesses.
The development of an alloantibody further complicates an already burdensome disease.
Acquired factor VIII inhibitors (autoantibodies) are associated with significant morbidity and at least a 20% mortality rate at present, but higher mortality rates prevailed earlier when currently available products to treat inhibitor patients were unavailable.
The tremendous physical, psychologic, and financial burden borne by patients and their families because of the restraints imposed by recurrent bleeding must be dealt with intensively. In this setting, human immunodeficiency virus (HIV) infection adds another layer of burden.[22] Therefore, the drug addiction and abuse in this population is not surprising. All of these issues require close, coordinated care delivered by a multidisciplinary team.
Patients with combined factor V and factor VIII deficiency develop all of the complications known to develop in patients with hemophilia A due to the necessity of frequent blood or blood product replacement. The absence of a safer source of factor V, such as purified factor V concentrate, to correct the factor V deficiency requires the repeated use of fresh frozen plasma (FFP), with its potential for transmitting illnesses.
Race
Factor VIII deficiency (hemophilia A) has no ethnic or racial predilection. Middle Eastern Jews and persons from Tunisia, Iran, India, Europe, and the United States have been reported with the combined deficiency of factor V and factor VIII.
Sex
Otherwise healthy males with a single copy of the abnormal factor VIII gene in their only X chromosome have bleeding manifestations. The severity of bleeding generally depends on their basal level of factor VIII-C, but it is also influenced by the co-inheritance of other bleeding or thrombophilic mutations.
Carrier females, usually asymptomatic, have one affected and one normal X chromosome; lower levels of factor VIII-C than that expected with a carrier state have been found in such females (see image below).
Possible genetic outcomes in individuals carrying the hemophilic gene. One explanation is that an unbalanced inactivation of the normal X chromosome during early embryonal development results in a preponderance of the abnormal X chromosome, thus leading to a lower basal level of factor VIII-C. A combination of this unbalanced inactivation with a new factor VIII gene mutation has been shown to result in severely reduced factor VIII levels in a female (severe female hemophilia).[23]
Some data have cast doubt on a correlation between the pattern of X chromosome inactivation and the wide variation in levels of factor VIII or factor IX found in carriers of hemophilia A or B because researchers did not find a skewed pattern of inactivation of the appropriate X chromosome in carriers with either low or high levels of factor VIII or factor IX.[24] Lower basal levels of factor VIII-C in carriers is associated with a bleeding disorder, although this is less severe than that observed in the corresponding hemophilic male, due to the presence of higher basal levels of factor VIII or factor IX in the clinically symptomatic carrier.
Females with hemophilia, although rare, can arise from the union of a male with hemophilia and a carrier female; in females with X-chromosomal abnormalities, such as Turner syndrome (XO); in an X-autosome translocation involving a breakpoint in the factor VIII gene; or due to uniparental isodisomy, in which the affected female inherits 2 copies of the mutated X chromosome (and all other X chromosomal genes) from her mother. Apparently, this last example may be incompatible with life. Interestingly, isodisomy was the documented cause of male-to-male transmission of hemophilia A in one case, in which the affected male passed his abnormal X chromosome and his Y chromosome to his son, with no contribution of an X chromosome from his mother.[4]
Acquired factor VIII inhibitors develop in either sex.
Combined factor V and factor VIII deficiency is an autosomal recessive disorder with clinical manifestations in affected females and males.[5, 25, 26, 27, 28]
Age
A prenatal diagnosis of hemophilia A can be made by using markers for restriction fragment length polymorphisms, by chromosomal analysis of cells obtained by amniocentesis at approximately 16 weeks' gestation, or by chorionic villus sampling at approximately 10 weeks' gestation.
A postnatal evaluation is triggered by a history of bleeding, which can start immediately after birth (eg, intracranial bleeding) or may be delayed in those with mild hemophilia. Oral bleeding starts with teething and cuts and abrasions to the lips, tongue, and frenulum, followed by joint and muscle bleeding with the start of ambulation.
In a single-center study, the age at which bleeding starts was found to vary. Approximately 44% of affected children bled within the first year of life, whereas others did not experience their first bleeding episode until age 4 years. Recurrent episodes of joint bleeding usually started approximately 6 months after the first bleeding episode; 50% of patients had their first bleeding episode by age 1.22 years, whereas the mean age for the first joint bleed was 1.91 years. These data support the concept that primary prophylaxis need not begin at the same age in all patients.[29]
Because of the increasing safety of recombinant factor VIII concentrates, advances in therapy, home treatment, and the long-term physical and psychologic benefits of being able to lead a normal lifestyle, the Medical Advisory and Safety Committee of the National Hemophilia Foundation has endorsed the use of recombinant products wherever feasible. As early as 1994, the committee recommended prophylactic treatment as the optimal approach to hemophilic care.
A survey of written guidelines and practices of obstetricians, hematologists, and neonatologists at medical centers in the United States for the management of pregnant carriers, newborns with hemophilia, and infants with intracranial hemorrhage showed that more than 94% of these major facilities had no written guidelines.
As a result of data obtained from this survey, it has been suggested that vacuum devices and fetal scalp monitors not be used in the vaginal delivery of known carriers of hemophilia and that all infants with intracranial hemorrhage and women with postpartum hemorrhage be evaluated for a bleeding disorder. A national registry of these cases would provide the type of information necessary to develop rational national guidelines to help improve care for pregnant women with bleeding disorders.[30, 31]
Acquired factor VIII deficiency is observed in older populations, generally those older than 60 years. Inhibitors that develop in patients with hemophilia are now likely to be found in a younger age group, due to the practice of starting prophylactic replacement therapy at a younger age.
Bleeding in patients with a combined deficiency of factor V and factor VIII starts in childhood as the child starts ambulating, with the earliest possible evidence at the time of circumcision after birth.
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| Type of Hemorrhage | Desired FVIII-C Activity | Dose and Duration of Therapy |
| Minor Uncomplicated hemarthroses Superficial large hematomas | 20-30% | 10-15 U/kg IV q12-24h for 1-2 d |
| Moderate Hematoma with dissection Oral/mucosal hemorrhages and epistaxis* Hematuria | 25-50% | 15-25 U/kg IV q12-24h for 3-7 d (shorter time for oral hemorrhages; higher dose for hematuria) |
| Dental extraction(s)† | 50-100% | 25-50 U/kg IV q12h for 2-5 d |
| Major Pharyngeal/retropharyngeal Retroperitoneal GI bleeding CNS bleeding surgery | ~50-100% until bleeding is controlled; then, gradually decrease the dosage to the minimum that is required to prevent rebleeding | 25-50 U/kg IV q12h for 5-10 d |
| *Concomitant administration of EACA or AMCA (both inhibitors of fibrinolysis) can help reduce the dose of concentrate that is required to treat such bleeding. Approximately 50% of the initial dose is given as the second dose approximately 8 hours after the first; all subsequent doses are given every 12 hours. †For dental extractions, a single preoperative dose of factor VIII of 15 U/kg and oral or intravenous Amicar at 5 g is given, followed by an Amicar maintenance dose of 1 g/h, as discussed below, for 5-7 days, with a gradual taper. | ||
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