Hemophilia A is an X-linked hereditary disorder caused by defective synthesis of factor VIII. Hemophilia A is less common than von Willebrand disease (VWD; Chap. 126), but it is more common than other inherited clotting factor abnormalities. The estimated incidence of hemophilia A is one in every 5000 to 7000 live male births. It occurs in all ethnic groups in all parts of the world.1
Sex-linked hemophilia was recognized at least as early as the 2nd century, when a rabbi correctly deduced that sons of hemophilic carriers were at risk for bleeding following circumcision.2 In the 19th century, several authors noted the sex-linked inheritance pattern of the disease and ascribed the hemorrhagic episodes to delayed blood coagulation. Morawitz3 developed the classic theory of blood coagulation, which recognized two major reactions: (1) conversion of prothrombin to thrombin by a tissue substance that Morawitz termed thrombokinase, and (2) conversion of fibrinogen to fibrin by thrombin. In 1911, Addis4 demonstrated that thrombin formed more slowly in hemophilic blood than in normal blood and that the defect could be corrected by small amounts of normal plasma. However, he incorrectly theorized that hemophilia resulted from prothrombin deficiency. As protein purification techniques improved throughout the 1930s and 1940s, thrombokinase was resolved into several distinct components. Brinkhous5 demonstrated that the prothrombin content of hemophilic plasma was normal and that the basic defect in hemophilia was the delayed conversion of prothrombin to thrombin. The defect could be corrected by a fraction of normal plasma containing the antihemophilic factor, later named factor VIII. In 1947, Pavlovsky6 observed that when blood from one patient with hemophilia was transfused into another patient with a similar clinical phenotype, the prolonged clotting time in the recipient was corrected. At the time, Pavlovsky did not recognize that he was dealing with two different types of hemophilia. This fact was recognized by Aggeler and coworkers7 in 1952, when they described a patient deficient in “plasma thromboplastin component”, a blood clotting factor different from factor VIII. A deficiency of “plasma thromboplastin component,” later termed factor IX, was identified as the cause of hemophilia B. A month later, Biggs and colleagues described a similar patient whose surname was Christmas, thus the synonym “Christmas disease.”8 Hemophilias A and B are the only two hereditary clotting factor defects inherited in a sex-linked pattern, and they are clinically indistinguishable, although data suggest that on the whole, hemophilia B may be less severe than hemophilia A.9 However, in an individual patient, the disorders cannot be distinguished without a specific assay for factor VIII or IX.
In 1964, a proposal to organize the growing number of coagulation factors into a cascade or waterfall mechanism was put forth by Davie and Ratnoff and by Macfarlane.10,11 In this scheme, each zymogen clotting factor was sequentially activated to a protease that subsequently activated the next zymogen until thrombin ultimately was produced. In this scheme, factors VIII and IX were considered to be proenzymes. Later, however, factor VIII, when activated by thrombin, was shown not to be a proenzyme but rather an essential cofactor for factor IXa. The waterfall hypothesis has been modified so that the primary role of the tissue factor–factor VII complex in the initiation of coagulation is emphasized (Chap. 113).12
ETIOLOGY AND PATHOGENESIS
Hemophilia A is a heterogeneous disorder resulting from defects in the factor VIII gene that leads to absent or reduced circulating levels of functional factor VIII. The reduced activity can result from a decreased amount of factor VIII protein, the presence of a functionally abnormal protein, or a combination of both. For factor VIII to be an effective cofactor for factor IXa, it must first be activated by thrombin, a reaction that results in the formation of a heterotrimer composed of the A1, A2, A3, C1, and C2 domains of factor VIII in a complex with calcium (Chap. 113).13 Activated factor VIII (factor VIIIa) and activated factor IX (factor IXa) associate on the surface of activated platelets, forming a functional factor X-activating complex (“tenase” or “Xase”).14 In the presence of factor VIIIa, the rate of factor X activation by factor IXa is dramatically enhanced. That hemophilia A and hemophilia B have similar clinical manifestations is not surprising, because both factor VIIIa and factor IXa are required to form the Xase complex. The lack of either activated protein leads to a similar lack of platelet surface Xase activity with subsequent decreased thrombin generation. In patients with hemophilia, clot formation is delayed because of the decreased thrombin generation. The clot that is formed is friable, easily dislodged, and highly susceptible to fibrinolysis, all of which lead to excessive bleeding and poor wound healing.15
Hemophilia A results when mutations occur in the factor VIII gene located on the long arm of the X-chromosome (X-q28). The disease occurs almost exclusively in males. Figure 123–1 shows the inheritance pattern of hemophilia A and hemophilia B. All the sons of affected hemophilic males are normal, whereas all the daughters are obligatory carriers of the factor VIII defect. Sons of carriers have a 50 percent chance of being affected, whereas daughters of carriers have a 50 percent chance of being carriers themselves.
Inheritance pattern of hemophilia. All daughters of a hemophilic male are carriers of hemophilia, whereas all sons are normal. Daughters of carriers have a 50 percent chance of being a carrier, whereas sons of carriers have a 50 percent chance of having hemophilia. X, normal; Xh, abnormal X chromosome with the hemophilic gene; XhY, hemophilic male; XX, normal female; XXh, carrier female; XY, normal male; Y, normal.
The factor VIII gene is very large, approximately 186 kb, with approximately 9 kb of exons. The gene contains 26 exons and 25 introns.16 Based on the sequence of the factor VIII gene in normal individuals and patients with hemophilia A, numerous specific mutations have been described16,17; as of 2015, more than 2000 specific variants in the factor VIII gene resulting in classic hemophilia have been described.17
Hemophilia A can result from multiple alterations in the factor VIII gene. These include gene rearrangements; missense mutations, in which a single base substitution leads to an amino acid change in the molecule; nonsense mutations, which result in a stop codon; abnormal splicing of the gene; deletions of all or portions of the gene; and insertions of genetic elements.18 The genetic defects leading to hemophilia have been reviewed.17
One of the most common mutations, accounting for 40 to 50 percent of severe hemophilia A patients, is a unique “combined gene inversion and crossing over” that disrupts the factor VIII gene.19,20 Figures 123–2 and 123–3 schematically depict the factor VIII gene and the mechanism of the “inversion–crossing over.”21 Within intron 22 are two other genes: (1) F8A(a1), which is transcribed in the 5′ direction, and (2) F8B, which is transcribed in the 3′ direction of the factor VIII gene. The hatched boxes in Figure 123–3 show two other extragenic homologous sequences (a2,a3) 5′ to the F8A gene that lies within intron 22 (a1). The presence of extragenic F8A sequences 5′ to the F8A gene within intron 22 is central to the inversion and translocation of part of the factor VIII gene from exon 1 to exon 22. The mechanism is homologous recombination between the F8A sequence that lies within intron 22 and one of the homologous extragenic sequences of the F8A gene 5′ to the factor VIII gene. During meiosis, crossing over of homologous sequences occurs between the F8A gene lying within intron 22 and one of the extragenic homologous F8A sequences 5′ to intron 22. Thus, the transcription of the complete factor VIII sequence is interrupted (Fig. 123–3). Figure 123–3 shows a common inversion and crossing over, but homologous recombinations can occur with either of the extragenic genes. Approximately 2 to 5 percent of the severe cases of hemophilia A carry the intron 1 inversion resulting in the separation of the F8 promoter-exon 1 sequence from the remainder of the F8 gene.22 The “inversion–crossing over” mutations result in severe hemophilia, and approximately 20 percent of these patients are susceptible to developing antibody inhibitors that neutralize factor VIII coagulant function.
Schematic of the factor VIII gene (FVIII). The FVIII gene is located at q28 on the long arm of the X chromosome. The region of the FVIII gene is enlarged on the second line. Note that two genes, designated a2 and a3, are 5′ to the FVIII gene. The hatched area indicated on FVIII corresponds to intron 22 shown on the third line. Within intron 22 (fourth line) are two nested genes, one designated F8A, which is transcribed in a direction opposite to that of the whole FVIII and is homologous to the a2 and a3 genes shown on line 2. G6PD, glucose-6-phosphate dehydrogenase. (Reproduced with permission from Scriver CR, Beaudet AL, Sly WS et al: Metabolic and Molecular Basis of Inherited Diseases, 8th ed. McGraw-Hill, New York, 1995.)
Schematic of inversion and crossing over at intron 22. Inversion and crossing-over of the a3 gene with its homologous sequence a1 nested within intron 22 are shown. Middle panel: When crossing over of the a1 gene nested within intron 22 and the a3 gene extragenic to FVIII occurs, a portion of FVIII is transcribed in a reverse manner from exon 1 through exon 22. Homologous recombination with the extragenic a2 gene is also possible. In some individuals there are two a2 or a3 extragenic sequences giving rise to four possible types of the “inversion–crossing over” mechanism. (Reproduced with permission from Antonarakis SE, Kazazian HH, Tuddenham EG: Molecular etiology of factor VIII deficiency in hemophilia A. Hum Mutat 1995;5(1):1–22.)
Of the different insertions in the factor VIII gene that have been reported, a few are long interspersed elements (LINEs) that are transposon sequences; that is, sequences that have been inserted frequently throughout the genome.23 Most of these insertions result in severe hemophilia.
In many cases of hemophilia, there is no family history of the disease, and at least 30 percent of the cases of hemophilia are a result of spontaneous (de novo) mutations. Most of these occur at CpG dinucleotides in the factor VIII gene.23 De novo occurrences of hemophilia usually result from a mutation in the gamete of a normal male; for example, a mutation in the germ cell of a maternal grandfather will give rise to the hemophilia gene in his daughters such that his grandsons may have hemophilia.18 Codons for the amino acid arginine (CGA [cytosine, guanine, adenine]) are frequently affected by mutations at CG doublets. A C→T transition often results in a stop codon with synthesis of a truncated factor VIII molecule and usually is associated with severe hemophilia A. However, a G→A transition results in a missense mutation, which often leads to a dysfunctional factor VIII molecule that may be associated with mild, moderate, or severe hemophilia. Some missense mutations result in the production of normal or near-normal amounts of factor VIII antigen, while the coagulant activity may be dramatically or only slightly reduced. Many other single-base substitutions have been described, resulting in hemophilia of varying degrees of severity.
Large deletions in the factor VIII gene almost always are associated with severe hemophilia. On the other hand, a small deletion that does not change the reading frame of the gene may result in milder disease. Patients with large deletions who have no detectable factor VIII antigen are more susceptible to the development of anti–factor VIII antibodies, although antibodies clearly also occur in patients without deletions.16,23
Hemophilia A in females is extremely rare, although an affected female offspring from a hemophilic father and carrier mother have been reported. Hemophilia A may occur in females with X chromosomal abnormalities such as Turner syndrome, X chromosomal mosaicism, and other X chromosomal defects.23,24 If the normal X chromosome is inactivated disproportionately (“imbalanced X inactivation”) in a carrier female, factor VIII levels may be sufficiently low to cause bleeding manifestations. Usually these manifestations are mild, but they may be serious during surgical procedures or following significant trauma.
PRENATAL DIAGNOSIS AND CARRIER DETECTION
A careful and complete family history is important for carrier detection.25 All daughters of a hemophilic father are obligatory carriers of the hemophilic defect. If a known carrier has a daughter, that daughter has a 50 percent chance of being a carrier.
Carrier detection is important when a daughter of a known carrier or a female offspring of a hemophilic patient wishes to become pregnant. At times, the history of hemophilia in the family is in a distant blood relative, and the gene for hemophilia may skip several generations. The current standard for identifying carrier status is through direct gene sequencing. Carriers who harbor the intron 22 inversion or intron 1 inversion can be identified using the Southern blot technique and polymerase chain reaction, respectively.22,25 If these mutations are found to be absent, sequencing of the complete coding region is performed.26
Use of markers for restriction fragment length polymorphism (RFLP) is simpler than direct sequencing of the coding region of the factor VIII gene, but use of the RFLP technique requires that the pedigree analyses include at least one hemophilic male whose mother is heterozygous for one or more RFLP markers.27,28 This technique is no longer considered to be the optimal approach in genotyping of affected males or carrier females.
Prenatal diagnosis of hemophilia now can be performed almost routinely.29 If a carrier female has a fetus that can be identified as a female by chromosomal analysis of cells obtained by amniocentesis (at approximately 16 weeks of gestation), analysis of free fetal DNA, ultrasound or by chorionic villus sampling at week 10 of gestation, little concern exists regarding whether the female fetus is a carrier because carriers usually have no bleeding tendency. If the fetus is a male, sufficient cells can be obtained to perform DNA analysis using the methods described above. The decision on whether to carry an affected male fetus to term should be decided by the parents after they are appropriately counseled and provided with all the necessary genetic, clinical, and therapeutic information about hemophilia. As the treatment for hemophilia A improves, the decision to continue an affected pregnancy should become far easier.
Hemophilia A is characterized by excessive bleeding into various tissues of the body, including soft-tissue hematomas and hemarthroses that can lead to severe crippling hemarthropathy. Recurrent hemarthroses are characteristic of the disease. The disease has been broadly classified as mild, moderate, and severe, although overlap exists between these categories. Table 123–1 shows a classification based on the severity of clinical manifestations. A range of plasma factor VIII concentrations in percentages of normal and in units per milliliter is given for each category. Approximately 10 percent of individuals with factor VIII levels compatible with severe hemophilia may exhibit milder symptoms.30 Among other explanations, this phenotypic heterogeneity could be a result of coinheritance of thrombophilic mutations, such as the factor V Leiden mutation (R506Q).31 Severely affected patients (<1 percent factor VIII) frequently experience “spontaneous” bleeding without known trauma other than that associated with the usual day-to-day activities. Without effective treatment, recurrent hemarthroses, resulting in chronic hemophilic arthropathy, occur by young adulthood and are highly characteristic of the severe form of the disorder. However, bleeding episodes are intermittent, and some patients do not bleed for weeks or months. Except for intracranial bleeding, sudden death because of hemorrhage is rare in societies where clotting factor concentrates are freely available.
Table 123–1.Clinical Classification of Hemophilia ||Download (.pdf) Table 123–1. Clinical Classification of Hemophilia
|Classification ||Factor VIII Level ||Clinical Features |
|Severe ||≤1% of normal (≤0.01 U/mL) ||1. Spontaneous hemorrhage from early infancy |
| || ||2. Frequent spontaneous hemarthroses and other hemorrhages, requiring clotting factor replacement |
|Moderate ||1–5% of normal (0.01–0.05 U/mL) ||1. Hemorrhage secondary to trauma or surgery |
| || ||2. Occasional spontaneous hemarthroses |
|Mild ||6–40% of normal (0.06–0.40 U/mL) ||1. Hemorrhage secondary to trauma or surgery |
| || ||2. Rare spontaneous hemorrhage |
Moderately affected patients with hemophilia may have occasional hematomas. Hemarthroses, usually associated with a known trauma, may occur as well. These patients have greater than 1 percent but less than 5 percent of normal factor VIII activity.
Mildly affected patients with hemophilia, who have factor VIII levels between 6 to 40 percent, have infrequent bleeding episodes. The disease may go undiagnosed and be discovered only because of excessive hemorrhage postoperatively, following trauma, or after the toss and tumble of contact sports.
Most carriers have approximately 50 percent factor VIII activity and experience no bleeding symptoms, even with surgical procedures. Carriers with factor VIII levels significantly less than 50 percent, as a result of imbalanced X chromosome inactivation, may experience excessive bleeding after trauma (e.g., childbirth or surgery). Therefore, measurement of factor VIII level is recommended in all carriers.
Bleeding into joints accounts for approximately 75 percent of bleeding episodes in severely affected patients with hemophilia A.32,33 The normal synovium has few cells, but numerous capillaries beneath the synovial layer can be damaged by the mechanical trauma associated with daily use of joints. The joints most frequently involved, in decreasing order of frequency are knees, elbows, ankles, shoulders, wrists, and hips. Hinge joints are much more likely to be involved than are ball-and-socket joints. Hemarthroses usually occur when an affected child begins to walk.
Hemarthroses are heralded by an aura of mild discomfort that, over a period of minutes to hours, becomes progressively painful. The joint usually swells, becomes warm, and exhibits limited motion. Occasionally, the patient experiences a mild fever. Significant and sustained fever, however, suggests an infected joint. When joint bleeding does not respond to replacement therapy, one should suspect the presence of an inhibitor of factor VIII or an infected joint. Bleeding into the knee joint is more easily detected by physical findings than is bleeding into either the elbow or shoulder. When bleeding stops, the blood resorbs, and the symptoms gradually subside over a period of several days. If hemarthroses are treated early, pain usually subsides in 6 to 8 hours and disappears in 12 to 24 hours. However, repeated hemorrhage into the joints eventually results in extensive destruction of articular cartilage, synovial hyperplasia, and other reactive changes in the adjacent bone and tissues. Iron deposits from residual blood is a major factor in the pathogenesis of hemophilic arthropathy.33 Acute bleeding into a chronically affected joint may be difficult to distinguish from the pain of degenerative arthritis.
A major complication of repeated hemarthroses is joint deformity complicated by muscle atrophy and soft-tissue contractures (Fig. 123–4). Figure 123–5 shows the various radiologic stages of progressive destruction of joint cartilage and adjacent bone. Osteoporosis and cystic areas in the subchondral bone may develop, and progressive loss of joint space occurs. Figure 123–6 shows a magnetic resonance image (MRI) of a normal knee in comparison to a knee from an individual with severe hemophilia with arthropathy. Figure 123–7 depicts bleeding into a hemophilic ankle.
Hemophilic arthropathy. The chronic effects of repeated hemorrhage into the knees of a severely affected hemophilic patient are seen. Note contractures, and deformity with atrophy of muscle tissue.
Various radiologic stages of hemophilic arthropathy. Stages 0 (normal joint) and 1 (fluid in the joint) are not shown. A. Stage 2. Some osteoporosis and epiphyseal overgrowth are present in knee 2. Epiphysis is wider in knee 2 than in knee 1 (arrows). B. Stage 3. Subchondral bone cysts (arrowheads). Joint spaces exhibit irregularities. C. Stage 4. Prominent bone cysts with marked narrowing of joint space (arrow). D. Stage 5. Obliteration of joint space with epiphyseal overgrowth (arrow).
Magnetic resonance imaging (MRI) of normal and hemophilic knees. A. MRI of normal knee. B. A transverse T2-weighted spin-echo image of the knee shows an effusion (*) and multiple foci of hemosiderin deposition (arrows) along the synovium lining the suprapatellar bursa. C. A sagittal T2-weighted spin-echo image of the knee shows dark foci of synovial hemosiderin deposition (white arrows) accompanied by narrowing of the femorotibial joint (black arrow). D. A sagittal STIR (short tau inversion recovery) image of the knee (in the same patient as B) demonstrates an effusion in the suprapatellar bursa (asterisks). The irregular, lumpy surface of the bursa represents thickened, hemosiderin-laden synovium. Femorotibial joint narrowing (black arrow) is associated with edema in the subchondral bone of the femoral condyle (white arrow). (Used with permission of Dr. Jordan Renner, University of North Carolina.)
A. A sagittal STIR (short tau inversion recovery) image of an ankle shows an effusion (white arrow). Edema in the distal tibia (asterisks) surrounds a debris-filled defect in the subchondral bone of the distal tibia (black arrows). B. A coronal proton density of the ankle in the same patient as in A shows the defect in the subchondral bone of the distal tibia (white arrow). Mild narrowing of the tibiotalar joint (black arrows) is more apparent laterally.
Repeated bleeding into a joint results in synovial hypertrophy and inflammation. The synovium is thickened and folded, leading to limited joint motion. The result is a tendency for repeated hemorrhages leading to a so-called target joint.32 Indeed, a target joint is defined by the occurrence of three or more spontaneous bleeds within a 6-month period. The joints most often involved are the knees, ankles, and elbows, which become chronically swollen. Chronic synovitis may persist for months or years unless the condition is adequately treated.
Infection of hemophilic joints is not common but must be suspected in all patients with fever, leukocytosis, or other systemic manifestations. Rapid diagnosis is mandatory, because infection of such joints leads to rapid loss of joint architecture and function. A painful and swollen joint may require aspiration, which should be performed by experienced personnel using meticulous aseptic techniques and appropriate factor replacement therapy prior to aspiration.
Soft-tissue hematomas are also characteristic of hemophilia A. Hemorrhage into subcutaneous connective tissues or into muscles may occur with or without a known trauma. Hematomas, once formed, may stabilize and slowly resorb. However, in moderately and severely affected patients, hematomas have a tendency to enlarge progressively and to dissect in all directions, unless appropriately treated. Rarely, retroperitoneal hematomas, after beginning in the iliopsoas muscle, can dissect superiorly through the diaphragm, into the chest, and sometimes even into the soft tissues of the neck, compromising the airway. A retroperitoneal hematoma is more likely to compromise renal function by causing ureteral obstruction. Figure 123–8 shows the computed tomography (CT) scan of a patient with a retroperitoneal hemorrhage. Other hematomas expand locally and may compress adjacent organs, blood vessels, and nerves. A rare, and often fatal, complication of an abdominal hematoma is perforation and drainage into the colon. Subcutaneous hematomas may dissect into muscle. Pharyngeal and retropharyngeal hematomas, sometimes complicating simple colds, may enlarge and obstruct the airway. Hemorrhage in or around the airway is a potentially life-threatening situation that requires prompt administration of factor VIII.
Computed tomography scan of a retroperitoneal hematoma in a patient with severe hemophilia A. Extent of the hematoma is indicated by the arrows.
Hemorrhages occur into muscle in the following order of frequency: calf, thigh, buttocks, and forearm. Recurrent or unresolved hematomas may lead to muscle contractures, nerve palsies, and muscle atrophy. Bleeding into the tongue (Fig. 123–9) or frenulum is particularly frequent in young children and usually is caused by trauma.
Photograph of a tongue hematoma caused by trauma.
Bleeding into fascia and muscle can result in a so-called compartment syndrome. This results when hemorrhage in a confined space compresses the arterial vasculature resulting in ischemic muscle injury. Compartment syndrome tends to occur in the distal part of the extremities, particularly in the flexor muscles, and sometimes requires urgent fasciotomy under cover of clotting factor replacement therapy. Bleeding into the myocardium or erect penis is very unusual, perhaps explained by the high concentration of tissue factor in these tissues.
Pseudotumors (Blood Cysts)
Pseudotumors are blood cysts that occur in soft tissues or bone. They are rare but dangerous complications of hemophilia (Fig. 123–10).34 They are classified into three types. One type is a simple cyst that is confined by tendinous attachments within the fascial envelope of a muscle. The second type initially develops as a simple cyst in soft tissues such as a tendon, but it interferes with the vascular supply to the adjacent bone and periosteum, resulting in cyst formation and resorption of bone. The third type is thought to result from subperiosteal bleeding that separates the periosteum from the bony cortex. Most pseudotumors are not associated with pain unless rapid growth or nerve compression occurs. As the volume of the cyst increases, the cyst compresses and destroys the adjacent muscle, nerve, and/or bone or expands around structures like ureters causing renal failure. Pseudotumors usually contain either serosanguineous fluid or a viscous brownish material surrounded by a fibrous membrane (Fig. 123–10). Pseudotumors have a tendency to expand over several years and eventually become multiloculated. Some reach enormous size and involve so many structures that make them inoperable. Erosion through surrounding tissues and penetration into viscera or through the skin can occur, usually as a late event. Sinus tracts from the pseudotumor predispose to infection and septicemia. Pseudotumors often develop in the lower half of the body, usually in the thigh, buttock, or pelvis, but they can occur anywhere, including the temporal bone. CT or MRI is useful for diagnosis. Needle biopsies of pseudotumors should be avoided because of the risk of infection and hemorrhage. A reliable treatment is operative removal of the entire mass because the pseudotumor likely will reform if it is not completely removed. Embolization, percutaneous drainage, and radiotherapy of a pseudotumor have been reported and may be of value in hemophiliacs with inhibitors when surgery is not possible.35 Surgical treatment of patients with large pseudotumors should be done in a hemophilia treatment center with a specialized multidisciplinary team of experts.36
Retroperitoneal pseudotumor. A and B. Magnetic resonance imaging and computed tomography scan of pseudotumor arising from the iliopsoas muscle compressing the kidney and other adjacent structures. Loculations and calcifications can be seen. C. Gross specimen after surgical removal, weighting approximately 6 pounds. D. Cross-section of pseudotumor shows peripheral red hemorrhage, centrally caseified blood and necrosis. Note the thick capsule that surrounds the tumor.
Many severely affected patients with hemophilia experience episodes of spontaneous and asymptomatic hematuria. The urine may be brown or red, depending upon the rate of bleeding. Most bleeding arises from the renal pelvis, usually from one kidney but occasionally from both. Appropriate studies to exclude a structural lesion in the kidneys should be performed. Administration of factor replacement and hydration is usually sufficient to arrest the bleeding. Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid should be avoided in individuals with hematuria because of the risk of forming clots and producing obstructing clots in the ureter.
Intracranial bleeding is one of the most dangerous hemorrhagic events in hemophilic patients.37 Currently, bleeding into the brain is a leading cause of death in hemophilic patients. Hemorrhage into the central nervous system may be “spontaneous” but usually follows trauma, which may be trivial. Symptoms often occur soon after trauma, but sometimes are delayed. For example, symptoms of a subdural hematoma may be delayed for days or several weeks. Hemorrhage into the brain parenchyma or a subdural or epidural hematoma should always be suspected in hemophilic patients with unusual headaches. When intracranial bleeding is suspected, the patient should be treated immediately with factor VIII and diagnostic procedures, such as CT scans or MRI studies should be delayed until after treatment is initiated. Although lumbar puncture has been performed safely in severe hemophilic patients without replacement therapy, replacing factor VIII to a level of approximately 50 percent of normal prior to the procedure is advisable.
Hemorrhage into the spinal canal is an uncommon neurologic complication in hemophilia, mostly related to trauma that can result in paraplegia. Bleeding may occur within the spinal cord itself, but epidural bleeding compressing the cord is more common.
Peripheral nerve compression is a frequent complication of muscle hematomas, particularly in the extremities. Compression of the femoral nerve by a hematoma in the iliopsoas muscle can result in sensory loss over the lateral and anterior thigh, weakness and atrophy of the quadriceps, and loss of the patellar reflex. The ulnar nerve is the next most frequently involved peripheral nerve. Bleeding may occur in any muscle and may compress local neural blood supply. This situation can be followed by permanent neuromuscular defects and multiple contractures.
Mucous Membrane Hemorrhage
Mucous membrane bleeding is common in hemophilia. Epistaxis and hemoptysis, often resulting from allergic reactions or trauma, can be associated with local structural lesions involving the upper and/or lower respiratory tract. Treatment of epistaxis by cautery or nasal packing sometimes is followed by recurrent bleeding because of sloughing of the cauterized area or dislodging of a poorly formed clot when the packing is removed. Gastrointestinal hemorrhage has a 1.3 percent annual incidence and is mostly associated to older age and complications of advanced liver disease. Ingestion of antiinflammatory drugs for relief of pain of hemophilic arthropathy is a frequent cause of upper gastrointestinal hemorrhage, and a history of ingestion of aspirin and other antiinflammatory drugs should be specifically addressed (and proscribed) when assessing the etiology of such bleeding.38
Dental and Surgical Bleeding
Hemophilic patients are treated with clotting factor preoperatively and postoperatively to prevent bleeding. Mildly or sometimes moderately affected patients may go unrecognized until surgery results in excessive bleeding at the surgical site. Bleeding may be delayed for several hours or, occasionally, for several days. Surgery in such patients is characterized by delayed wound healing because of poor clot formation.15 Prolonged bleeding and subsequent infection of the wound hematoma may further complicate healing. Appropriate factor VIII replacement therapy, sometimes supplemented by anti-fibrinolytic agents, can prevent intraoperative and postoperative hemorrhages.
Dental extraction is the most frequent surgical procedure performed on hemophilic patients. Loss of deciduous teeth seldom causes excessive bleeding, but extraction of permanent teeth may result in excessive hemorrhage that can persist intermittently for several days to weeks unless appropriate treatment is administered. In the untreated patient with severe hemophilia, life-threatening, dissecting pharyngeal and/or sublingual hematomas may result from dental procedures or from administration of regional block anesthesia.
Patients with severe hemophilia A have a prolonged activated partial thromboplastin time (aPTT). The prothrombin time (PT) and thrombin clotting time (TCT) are normal. Different combinations of aPTT reagents and instrumentation exhibit varying sensitivities to factor VIII levels. In mild hemophilia, the aPTT may be only slightly prolonged or at the upper limit of normal, especially if factor VIII activity is 20 percent or greater. The aPTT is corrected when hemophilic plasma is mixed with an equal volume of normal plasma. If the hemophilic plasma contains an anti-factor VIII inhibitor antibody, the aPTT on a similar mixture is prolonged, but incubation of the mixture for 1 or 2 hours at 37°C is sometimes required to detect the prolongation. A definitive diagnosis of hemophilia A should be based on a specific assay for factor VIII activity.
Functional factor VIII coagulant activity is measured by one-stage clotting assays based on the aPTT. Chromogenic assays for factor VIII activity also are used widely, but do not always agree with one-stage assays.39 Although infrequently measured in practice, factor VIII antigen is measured by immunologic assays, which detect normal and most abnormal factor VIII molecules. If the factor VIII antigen level is normal but the clotting activity is reduced, the patient has a dysfunctional factor VIII molecule. Such patients have antigen-positive hemophilia, also referred to as cross-reacting material (CRM)-positive.40 Patients in whom both the factor VIII antigen level and activity are nearly undetectable are said to be CRM-negative.
VWD sometimes is confused with hemophilia A. The basic defect in VWD is reduced activity of von Willebrand factor (VWF), which acts as a carrier of factor VIII in vivo (Chap. 126). Thus, in VWD, factor VIII levels are reduced, although considerable variability exists. Although factor VIII is synthesized normally in patients with VWD, the half-life of factor VIII is markedly shortened because the VWF “carrier” molecule is decreased or absent. Other abnormalities in VWD that distinguish VWD from hemophilia A are decreased VWF antigen level, and decreased VWF activity, often measured using the ristocetin cofactor activity assay and a prolonged closure time using the platelet function analyzer PFA-100. In type III VWD, factor VIII levels may be very low (<5 percent of normal), making it difficult to distinguish from classical hemophilia. The lack of a sex-linked pattern of inheritance in the family will help in the differential diagnosis.
Another variant of VWD that is particularly difficult to distinguish from hemophilia A is VWD-Normandy, in which VWF multimers are normal but plasma factor VIII levels are low.41 Several mutations causing VWD-Normandy have been described, but all of them result in decreased binding of factor VIII to VWF.42 The result is shortening of the intravascular survival of factor VIII and thus reduced factor VIII activity. The Normandy variant of VWD should be suspected in patients with mild hemophilia A who do not exhibit a sex-linked recessive inheritance pattern.
Hemophilia A must be distinguished from other hereditary blood clotting factor deficiencies that exhibit a prolonged aPTT, including deficiencies of factors IX, XI, and XII, prekallikrein, and high-molecular-weight kininogen. Only deficiencies of factors VIII and IX cause chronic crippling hemarthroses with a family history suggestive of an X-linked bleeding disorder. Only specific assays can distinguish hemophilia A from factor IX deficiency (hemophilia B). Factor XI deficiency occurs in males and females and is a milder hemorrhagic disorder compared to severe hemophilia A or B. Factor XI deficiency can be confused with mild hemophilia A or B on screening laboratory tests, but specific assays distinguish them. Deficiencies of factor XII, prekallikrein, and high-molecular-weight kininogen can be distinguished from hemophilia because they are not associated with bleeding. Mild hemophilia A, with factor VIII levels of approximately 10 to 20 percent of normal, must be distinguished from combined deficiency of factors V and VIII.43,44 Both the PT and aPTT are moderately prolonged in the combined disorder.44
General principles applicable to therapy for hemophilia A include avoidance of aspirin, nonsteroidal antiinflammatory drugs, and other agents that interfere with platelet aggregation. Acetaminophen or relatively specific cyclooxygenase (COX)-2 inhibitors such as celecoxib have been recommended, but these drugs can be harmful when taken in excessive doses or for prolonged periods. Patients should be advised of the numerous nonprescription analgesics and herbals that contain aspirin or other antiplatelet agents. Addictive narcotic agents should be used with great caution and only when clearly indicated, because drug dependency can be a major problem for patients with hemophilia. In general, intramuscular injections should be avoided unless the patient receives adequate replacement therapy. In the absence of prophylactic therapy, patients with hemophilia A must be treated as early as possible to avoid bleeding complications. Surgical procedures in hemophilic patients should be scheduled early in the week to avoid “weekend crises.” Ample supplies of factor VIII should be available in the blood bank or pharmacy to ensure rapid access to treatment when needed. All hemophilic patients should have access to home treatment and periodic examinations at a comprehensive hemophilia treatment center. Prophylactic therapy is recommended in all severely affected patients, and it should be initiated before the onset of recurrent hemarthroses (primary prophylaxis) or as directed. Secondary prophylaxis for an established “target” joint may be necessary.45
Factor VIII Replacement Therapy
Hemorrhagic episodes in patients with hemophilia A can be managed by replacing factor VIII. Several products are available for use in raising factor VIII to hemostatic levels (Table 123–2). Fresh-frozen plasma and cryoprecipitate both contain factor VIII and once were the only products available for treatment. A disadvantage of plasma is that large volumes must be infused to achieve and maintain even minimal factor VIII levels. The highest factor VIII level that can be achieved with plasma is approximately 20 percent of normal, which is not always attainable or sufficient for hemostasis. Cryoprecipitate, containing approximately 80 U of factor VIII in 10 mL of solution, can be used to attain normal factor VIII levels, but individual bags of cryoprecipitate must be pooled; the factor VIII dose can only be estimated; and the product must be stored frozen. Several commercial lyophilized factor VIII concentrates, using cryoprecipitate of pooled normal human plasmas as starting material (2000 to 20,000 donors), are available and do not have the disadvantages of plasma and cryoprecipitate (Table 123–2). Factor VIII concentrates have been sterilized by heating in solution, by superheating to 80°C after lyophilization, and by exposure to organic solvent-detergents that inactivate lipid-enveloped viruses, including HIV and hepatitides B and C viruses, but do not inactivate parvovirus or hepatitis A.46,47 Parvovirus infection does not occur frequently in hemophilia A patients because parvovirus is transmitted by cellular elements of the blood. Nevertheless, seroconversion to B19 parvovirus has been observed in patients receiving plasma-derived concentrates undergoing solvent-detergent extraction or pasteurization.
Table 123–2.Currently Available Factor VIII Productsa ||Download (.pdf) Table 123–2. Currently Available Factor VIII Productsa
| ||Origin ||Viral Inactivation |
|Intermediate purity || || |
| Humate Pb ||Plasma ||Pasteurizationc |
Solvent-detergentd, heat treatedi
Solvent-detergent, heat treatedi
|Ultrapuree || || |
|Recombinant || || |
Some of these products contain significant amounts of VWF (see Table 123–2). Plasma-derived factor VIII concentrates prepared by monoclonal antibody techniques, and subjected to viral inactivation techniques, are highly purified and, barring breakdown in manufacturing procedures, are considered to be safe in terms of transmission of viral diseases.
Factor VIII produced by recombinant DNA techniques is available, safe, and effective. There are new “third-generation” factor VIII products that are manufactured without exposure to animal or human protein. Although all factor VIII products, both recombinant and plasma-derived, are currently safe and effective, some physicians and patients prefer products that are not exposed to human or animal proteins during the manufacturing process.
The dose of factor VIII can be determined as follows. If 1 U of factor VIII per milliliter of plasma is considered 100 percent of normal, the dose required to raise the level to a given value depends upon the patient’s plasma volume (approximately 5 percent of body weight in kilograms) and the level to which factor VIII is to be raised. Thus, the plasma volume of a 70 kg adult is approximately equivalent to 3500 mL (5 percent × 70 kg = 3.5 kg = 3500 g, approximately equivalent to 3500 mL). To achieve normal factor VIII levels of 1 U/mL (100 percent), 3500 U of factor VIII should be given. This scenario assumes a 100 percent recovery of the administered dose. Recovery has approached 100 percent in studies, but depends upon the method of assay and the factor VIII standard used for comparison.48 After the initial dose of factor VIII, further doses of factor VIII are based on a half-life of 8 to 12 hours. Thus, after a loading dose of 3500 U of factor VIII, a dose of 1750 U could be given in 12 hours. However, for practical purposes, the dose of factor VIII is based on the knowledge that 1 U of factor VIII per kilogram of body weight raises the circulating factor VIII level by approximately 0.02 U/mL. Thus, to raise the factor VIII level to 100 percent, that is, 1 U/mL, the dose of factor VIII required is approximately 50 U per kilogram of body weight, assuming the patient’s baseline factor VIII level is less than 1 percent of normal. The site and severity of hemorrhage determine the frequency and dose of factor VIII to be infused.
Table 123–3 summarizes the recommended doses of factor VIII for various types of hemorrhage.48 These doses are not based on rigorous randomized studies, and recommendations vary among hemophilia centers. Given the high cost of factor VIII, some physicians prefer to use lower doses.
Table 123–3.Doses of Factor VIII for Treatment of Hemorrhage* ||Download (.pdf) Table 123–3. Doses of Factor VIII for Treatment of Hemorrhage*
|Site of Hemorrhage ||Desired Factor VIII Level (% of Normal) ||Factor VIII Dose† (U/kg Body Weight) ||Frequency of Dose‡ (Every No. of Hours) ||Duration (Days) |
|Hemarthroses ||30–50 ||~25 ||12–24 ||1–2 |
|Superficial intramuscular hematoma ||30–50 ||~25 ||12–24 ||1–2 |
|Gastrointestinal tract ||50–100 ||50 ||12 ||7–10 |
|Epistaxis ||30–50 ||~25 ||12 ||Until resolved |
|Oral mucosa ||30–50 ||~25 ||12 ||Until resolved |
|Hematuria ||30–100 ||~25–50 ||12 ||Until resolved |
|Central nervous system ||50–100 ||50 ||12 ||At least 7–10 days |
|Retropharyngeal ||50–100 ||50 ||12 ||At least 7–10 days |
|Retroperitoneal ||50–100 ||50 ||12 ||At least 7–10 days |
Factor VIII can be given as a constant infusion to hospitalized patients. Following a loading dose to raise factor VIII to the desired level, 150 to 300 U of factor VIII per hour can be infused. Factor VIII levels can be conveniently monitored in blood obtained from veins other than the vein into which factor VIII was infused intravenously.49 In selected patients, factor VIII can be given outside the hospital in a continuous infusion using pump devices.50
During the 1970s, 1-desamino-8-d-arginine vasopressin (DDAVP; desmopressin) was found to cause a transient increase in factor VIII in normal subjects and in patients with mild to moderate hemophilia. After a dose of DDAVP (0.3 mcg per kilogram body weight), given intravenously or subcutaneously, factor VIII levels increase two- to threefold above baseline in most, but not all, mildly or moderately affected hemophilia A patients. Patients with severe hemophilia A do not respond to DDAVP.51 A concentrated intranasal spray of DDAVP also can be used (150 mcg in each nostril for adults and 150 mcg in one nostril for children weighing less than 50 kg). The degree of response to the drug should always be determined in patients before a bleeding episode, because occasionally mildly or moderately affected patients do not respond. The peak response to DDAVP usually occurs 30 to 60 minutes after dosing. In patients with mild or moderate hemophilia A and in carriers whose baseline factor VIII levels are less than 0.5 U/mL, DDAVP may be used in lieu of blood products. The mechanism by which DDAVP increases factor VIII is unknown.
Repeated administration of DDAVP results in a diminished response to the agent (tachyphylaxis). In many patients, the response to the second DDAVP dose averages 30 percent less than the response to the first dose, and the response rate may be even less after additional doses.52 DDAVP is a potent antidiuretic. As a result, hyponatremia has been reported in some patients whose water intake exceeds approximately 1 L per 24 hours after dosing. There is no convincing evidence to indicate that DDAVP administration is associated with thrombosis in hemophilic patients.
Antifibrinolytic agents, such as ε-aminocaproic acid (EACA) and tranexamic acid, have been used to enhance hemostasis in patients with hemophilia A.53,54 Fibrinolytic inhibitors may be given as adjunctive therapy for bleeding from mucous membranes and are particularly valuable as adjunctive therapy for dental procedures. The usual oral dose of tranexamic acid for adults is 1 g four times per day. EACA can be given as a loading dose of 4 to 5 g followed by 1 g/h by continuous IV infusion in adults. Another regimen of EACA is 4 g every 4 to 6 hours orally for 2 to 8 days, depending upon the severity of the bleeding episode. Antifibrinolytic therapy is contraindicated in the presence of hematuria because clots resistant to lysis may obstruct the ureters.
Fibrin glue, otherwise known as fibrin tissue adhesive, has been used as adjunctive therapy to factor VIII in hemophilic patients.55 Briefly, fibrin glue contains fibrinogen, thrombin, and factor XIII. Fibrinolytic inhibitors are added to some commercial products. The fibrinogen–factor XIII mixture is placed on the injury site and clotted with a human thrombin solution containing calcium. As a result, the fibrin clot is crosslinked and anchored to tissue. It is especially useful for hemostasis in patients undergoing dental surgery who receive a preextraction bolus of factor VIII followed by application of fibrin glue to the tooth socket. Fibrin glue also has been used as adjunctive therapy to factor VIII following orthopedic procedures and circumcision. It is very valuable for controlling bleeding when applied to the bed of a surgical wound following removal of large pseudotumors. Some hemophilia centers prepare their own “homemade” fibrin glue using cryoprecipitate as a source of fibrinogen and factor XIII.
Treatment of Minor or Moderate Hemorrhage
On occasion, superficial cuts and abrasions are managed with local measures, that is, application of pressure sometimes suffices to control bleeding, although oozing may continue intermittently for several hours. Topical thrombin is of little value in this type of bleeding. In general, cautery should be avoided because bleeding may restart when the cauterized area is sloughed.
When replacement therapy for epistaxis is needed, the factor VIII level should be raised to approximately 30 to 50 percent of normal. For treatment of hematuria, patients should be instructed to drink large quantities of fluids. If hematuria is mild, uncomplicated, and painless, factor VIII replacement may not be necessary unless the hematuria persists. Gross or protracted hematuria requires replacement therapy. In these patients, factor VIII levels of at least 50 percent of normal or higher are needed, probably because urine is rich in urokinase that rapidly lyses clots.
Hemophilic patients requiring endoscopic procedures first should be treated with factor VIII to raise levels to at least 0.5 U/mL before the procedure. Only one dose may be necessary if endoscopy is uncomplicated. In cases of biopsies, severe abrasions or perforations following endoscopy, factor VIII replacement should be continued until healing of the lesion is complete. For expanding soft-tissue hematomas, factor VIII therapy should be started immediately and maintained until the hematoma begins to resolve. With effective therapy, the patient usually experiences rapid relief from pain. For treatment of acute hemarthroses, prompt administration of factor VIII decreases the occurrence of extensive degenerative joint changes, deformity, and muscle wasting. For chronic synovitis and for bleeding into “target” joints, daily administration of factor VIII to raise levels to 100 percent of normal for 6 to 8 weeks (“secondary prophylaxis”) is usually indicated.
Treatment of Major Nonsurgical Hemorrhages
Any hemorrhage in a patient with hemophilia A may become major, but the following hemorrhages are common and frequently life-threatening: retropharyngeal, retroperitoneal, and central nervous system bleeding, whether subdural, subarachnoid, or into the brain parenchyma.56
For treatment of retropharyngeal bleeding, particularly that associated with a sensation of tightness in the throat, pain in the neck, dysphagia, or difficulty breathing, patients should receive factor VIII immediately in doses sufficient to raise factor VIII levels to normal (1.0 U/mL). Near-normal levels should be maintained until bleeding ceases and the hematoma begins to resolve. For retroperitoneal hemorrhage, early treatment is required, and therapy should be continued for 7 to 10 days; otherwise, bleeding may recur upon resumption of activity.
Immediate administration of factor VIII, sufficient to raise the level to normal, should be started upon the first sign of an intracranial hemorrhage or following a history of head trauma. Even asymptomatic patients with a history of head trauma should receive at least one dose of factor VIII as a prophylactic measure, and this dose should be given before diagnostic procedures such as a CT scan. Treatment of a known intracranial hemorrhage should be maintained for a minimum of 7 to 10 days, and the circulating factor VIII level should be kept normal throughout this period. Prolonged secondary prophylaxis is often indicated following an intracerebral hemorrhage, particularly in patients with HIV disease, who seem to have a high recurrence rate. Evacuation of subdural hematomas and surgical removal of hematomas involving the brain parenchyma can be performed, depending upon location. Despite aggressive replacement therapy, however, mortality from central nervous system bleeding is high.
Replacement of Factor VIII for Surgical Procedures
For major surgical procedures, factor VIII should be raised to normal levels before operation and maintained for 7 to 10 days or until healing is complete. Treatment can be started a few hours before surgery and continued intraoperatively using a continuous infusion or boluses every 8 to 12 hours. Postoperatively, factor VIII levels should be monitored at least one or two times per day to ensure that adequate levels are maintained. Because factor VIII may be “consumed” during surgery, factor VIII levels should be monitored intraoperatively and doses of factor VIII higher than normal may be required. Bone and joint surgery may require longer periods of factor VIII coverage. Replacement of knee, hip, ankle, and elbow joints may be required for intractable pain associated with loss of function, and several weeks of replacement therapy may be needed postoperatively.57
Home therapy using available factor VIII concentrates was introduced in the United States in 1977 and was a major advance in the treatment of all forms of hemophilia.58,59 Current practice for home therapy is to treat patients at home using a regular prophylactic regimen. Patients, age 6 years and older, can be taught to treat themselves with factor VIII. The training of patients and their families for home therapy is best accomplished in a regional comprehensive hemophilia diagnostic and treatment center or an affiliate of one of these centers. Patients are given an adequate quantity of factor concentrates and the supplies required for intravenous administration. Prompt treatment of hemarthroses and hematomas made possible by home therapy has markedly improved the morbidity and mortality associated with hemophilia. In addition, the quality of life of hemophilia A patients has improved dramatically.59,60
The advent of stable and safe factor VIII concentrates has made prophylactic therapy for hemophilia A in severely affected patients feasible. Such therapy is now the treatment of choice for all severely affected hemophilia patients (unfortunately, such treatment is not available or affordable for all patients). Administration of 25 to 40 U of factor VIII per kilogram of body weight three times per week or every other day markedly decreases the frequency of hemophilic arthropathy and other long-term effects of hemorrhagic episodes.60,61,62 Primary prophylaxis is usually initiated before the age of 2 years or after the first joint bleed, which is usually when the child begins to walk. Central venous catheters may be required sometimes for very young children; however, they are associated with a risk of infections and thrombosis.63 Secondary prophylaxis is started after the onset of hemarthrosis and can be used for short periods of time or to manage target joints. The consumption of factor concentrate is higher when patients are on prophylaxis when compared to on-demand but analysis of the economic impact of prophylactic therapy, weighing the benefits against the high costs of factor VIII concentrates, suggests the clinical benefit of prophylaxis is warranted, as evidenced by significant improvement in the clinical condition of patients and improvement in the quality of life.62,64
After the advent of factor VIII concentrates in the 1960s, the morbidity and mortality from bleeding in hemophilia were significantly reduced, and by the late 1970s the life expectancy of hemophilia A patients began to approach that of normal individuals in those populations. However, use of replacement therapy has not been without significant complications. Prior to 1985, common and serious adverse side effects of treatment included chronic liver disease resulting from hepatitides B and C and, from about 1978, infection with HIV.65 Factor VIII concentrates were prepared from many thousands of donors, making contamination of factor VIII concentrates by bloodborne viruses highly likely. With the introduction of heat- or solvent-detergent–treated concentrates in 1985, contamination of blood products with these viruses has been eliminated for all practical purposes. However, AIDS became a leading cause of death in older patients with hemophilia.65 Chronic liver disease in hemophilia A patients resulting from transfusion-related hepatitides B and C may be accelerated by HIV infection and by the associated hepatotoxicity of antiviral drug therapy.66 Fortunately, patients treated prophylactically after 1985 can expect almost normal life spans free of the complications of hepatitis, AIDS, and other currently recognized bloodborne viral diseases. However, the development of inhibitor antibodies against factor VIII has been, and continues to be, one of the more serious complications of replacement therapy.
Other than the transmission of viral diseases by factor VIII infusions, the main complication of hemophilia A replacement therapy is the development of specific inhibitor antibodies that neutralize factor VIII.67 The reported prevalence of anti–factor VIII inhibitors in severe hemophilia A patients is variable, ranging from 3.6 percent to 27 percent. In the white population the estimated prevalence is approximately 13 percent, compared to 27 percent and 25 percent in the black and Hispanic population, respectively.68 The risk of inhibitor development is higher in patients with large deletions and nonsense mutations when compared to small deletions/insertions and missense mutations. Frequent testing for inhibitors in previously untreated patients receiving newer highly purified factor VIII products from plasma or by recombinant technology revealed the frequent occurrence of transient inhibitors to factor VIII, many of which were of low titer and did not necessitate cessation of treatment with the same product. Although still controversial, some believe that the risk of inhibitors does not appear to be higher with the use of highly purified products than the risk reported in earlier studies using products of intermediate purity that contain VWF.69,70,71,72,73,74 Some studies have reported that VWF is immunomodulatory, so that products containing VWF may be less likely to induce inhibitors compared to highly purified products. One outbreak of inhibitors in Europe appeared to be related to the neoantigenicity of an intermediate-purity plasma-derived factor VIII concentrate. Fortunately, inhibitors disappeared from affected patients when use of the product was stopped.75
Table 123–4 lists the risk factors that have been associated with the development of inhibitors. They arise most frequently in severely affected patients, following treatment at an early age. Many have gross gene rearrangements or the intron 22 inversion abnormality of the factor VIII gene.
Table 123–4.Risk Factors for Development of Anti–Factor VIII Antibodies in Hemophilia A Patients ||Download (.pdf) Table 123–4. Risk Factors for Development of Anti–Factor VIII Antibodies in Hemophilia A Patients
|Disease severity: 80% of hemophilia A patients with inhibitors have <1% factor VIII activity |
|Early exposure to factor VIII concentrates: majority of high-titer inhibitors develop after <90 days of exposure to factor VIII |
Family history of inhibitor development
Ethnic background: Blacks > Hispanics > whites
Molecular defects: inversion and crossing over defect in intron 22, gene deletions, and nonsense point mutations resulting in patients without factor VIII antigen
|Method of purification of factor VIII concentrate |
Factor VIII inhibitors are antibodies, most often of the immunoglobulin (Ig) G class and frequently restricted to the IgG4 subclass.67 Antibodies against the A2 and C domains of factor VIII are most common. These antibodies interfere with the interactions of factor VIII with other hemostatic components.67,76
Early diagnosis of factor VIII inhibitors is essential. Although the presence of an inhibitor can be suspected on clinical grounds, as when a patient does not respond to conventional doses of factor VIII, laboratory diagnosis is required for confirmation. Factor VIII inhibitors are time and temperature dependent in vitro. The prolonged aPTT of the plasma of a patient without an inhibitor is corrected when mixed 1:1 with normal plasma even after incubation at 37°C for 1 to 2 hours. In contrast, the aPTT of a 1:1 mixture of plasma from a patient with an inhibitor and normal plasma is significantly prolonged after incubation at 37°C for 1 to 2 hours. Specific diagnosis rests upon demonstrating that an appropriate dilution of the patient’s plasma, when added to normal plasma, specifically neutralizes factor VIII and not other blood clotting factors that influence the aPTT (i.e., factors IX, XI, XII, prekallikrein, high-molecular-weight kininogen). The demonstration that the inhibitor is specific for factor VIII distinguishes it from inhibitors of other clotting factors, for example, the lupus anticoagulant, and nonspecific inhibitors. A common assay used for inhibitor detection and quantification is the Bethesda assay.77 In the Bethesda assay, the patient’s plasma is diluted such that, when the plasma is mixed with an equal volume of normal pooled human plasma and incubated for 2 hours at 37°C, the factor VIII activity in the mixture is decreased by 50 percent. A modification of the Bethesda assay is the Nijmegen assay, in which buffer is used instead of factor VIII–deficient plasma. This method has shown to be more dependable at detecting low concentration of inhibitors.78
Several approaches to treatment of factor VIII inhibitors are available (Table 123–5). Use of these treatments requires knowledge of whether the patient with an inhibitor is a “high” or “low” responder and whether the bleeding episode requiring treatment is minor or major.67
Table 123–5.Treatment of Inhibitors in Hemophilia A Patients ||Download (.pdf) Table 123–5. Treatment of Inhibitors in Hemophilia A Patients
|Type of Patient ||Initial Titer ||Minor Hemorrhage* ||Major Hemorrhage* |
|High responder ||<5 BU ||Recombinant factor VIIa; FEIBA ||Factor VIII†; recombinant factor VIIa; FEIBA |
|High responder ||>5 BU ||Recombinant factor VIIa; FEIBA ||Recombinant factor VIIa; FEIBA; plasma exchange |
|Low responder ||<5 BU ||Recombinant factor VIIa; FEIBA ||High-dose factor VIII; recombinant factor VIIa; FEIBA |
High-Responder Patients Approximately 60 percent of patients who have inhibitors are high responders. High responders are defined as patients whose inhibitor titer is higher than 5 Bethesda units (BU) at baseline or whose initial inhibitor titer is less than 5 BU but rises to greater than 5 BU after administration of factor VIII. Thus, high responders who are not treated with factor VIII for long periods may have a sustained high level of inhibitor, or they may have a very low to undetectable level of inhibitor until they are challenged with factor VIII.
Major bleeding episodes in a high-responder patient whose initial inhibitor titer is less than 5 BU can be treated with human factor VIII concentrate (see Table 123–5). When the initial titer is low, sufficient factor VIII can be administered in high doses to neutralize the inhibitor and attain adequate factor VIII levels for hemostasis. Although factor VIII inhibitor bypassing agents can be used (see below), they are not as reliable as factor VIII in achieving hemostasis, and their effect cannot be adequately monitored with specific laboratory tests. If factor VIII is used, a loading dose of 10,000 to 15,000 U may be required, followed by up to 1000 U of factor VIII per hour, depending upon the factor VIII level. One can expect an anamnestic response approximately 5 days after administration of factor VIII.
In high-responder patients whose initial inhibitor titer is less than 5 BU and who experience a minor bleeding episode, the agent of choice is a factor VIII inhibitor bypassing agent. Recombinant factor VIIa in doses of 90 to 120 mcg per kilogram of body weight or higher every 2 to 3 hours is safe and effective in most hemorrhagic episodes.79 The dosing frequency is based on a factor VIIa plasma half-life of approximately 2 to 3 hours. The mechanisms of action of factor VIIa have been investigated using in vitro techniques. After coagulation is initiated by the tissue factor–factor VIIa pathway, factor VIIa at recommended doses is hypothesized to activate factor X on the surface of activated platelets, even in the absence of additional tissue factor activity.80 Factor Xa then can associate with factor Va and convert prothrombin to thrombin. Because activated platelets are localized to the site of vessel injury, thrombin generation by factor VIIa is localized to the site of bleeding. This process may account for the reported safety of factor VIIa.80 Factor VIII inhibitor bypassing activity (FEIBA), a plasma-derived agent, has also been used successfully to treat bleeding episodes in inhibitor patients and is both safe and effective81 given at a recommended dose of 50 to 100 U per kilogram body weight every 8 to 12 hours (not to exceed 200 U per kilogram per day).
High-responder patients whose initial inhibitor titer is greater than 5 BU usually do not respond to even very high doses of human factor VIII. Thus, recombinant factor VIIa or FEIBA should be used.81 If these agents are not available, nonactivated prothrombin complex concentrates or plasma exchange with high dose replacement factor VIII can be considered.
Low-Responder Patients Low-responder patients are arbitrarily defined as patients whose inhibitor titer is less than 5 BU even after a challenge with factor VIII. For major bleeding episodes, high doses of human factor VIII can be used as recommended above. For minor bleeds, recombinant factor VIIa or FEIBA are recommended because some “low” responders may convert to high responders when they are challenged repeatedly with factor VIII.
Nonactivated or activated prothrombin complex concentrates both contain variable amounts of activated factors, including factors VIIa, IXa, and Xa. The activated products have higher concentrations of activated factors than do nonactivated products. FEIBA contains a complex of prothrombin and factor Xa that can bind to membrane surfaces and enhance thrombin generation in the absence of factors VIII or IX.80,81
Surgery in Inhibitor Patients The question of whether major surgery can be performed in patients with hemophilia A or B with inhibitors arises now that joint replacement is possible.82 Knee, ankle, hip, and elbow replacements have been carried out successfully in patients with inhibitor antibodies using bypassing agents. Basically, the patient is given a loading dose of factor VIIa followed by bolus doses of factor VIIa and use of fibrin sealant and antifibrinolytic therapy until healing is complete. FEIBA has also been successfully used in surgery in hemophilic patients with inhibitors.83
Immune Tolerance Removal of the antibody is the definitive goal of inhibitor management. Plasmapheresis, adsorption of the antibody on an affinity column during plasma exchange, and administration of intravenous γ-globulin have been used in patients with an inhibitor. The Malmö protocol uses nearly all of these approaches in combination, including extracorporeal adsorption of antibody to a Sepharose A column, administration of cyclophosphamide, daily administration of factor VIII, and intravenous γ-globulin.84
The most promising approach to eradication of an inhibitor is use of immune tolerance regimens. The basis of this approach is administration of frequent (daily or thrice weekly) doses of factor VIII until the inhibitor titer is undetectable.85 Low- and high-dose regimens have been described (Table 123–6). Predictors of success have been described in clinical studies in patients with high titer inhibitors and include young age at detection of inhibitor; inhibitor titer less than 10 BU before starting immune tolerance induction (ITI); peak titer less than 100 BU after starting ITI; historical peak titer less than 200 BU; age less than 5 years old between diagnosis and start of ITI; and genotype (small deletions and insertions, and missense mutations). Factor VIII inhibitor bypassing agents are used for prevention and treatment of acute bleeds that occur during immune tolerance induction.
Table 123–6.Examples of Tolerance Protocols for Hemophilia A Inhibitor Patients with Good-Risk Factors ||Download (.pdf) Table 123–6. Examples of Tolerance Protocols for Hemophilia A Inhibitor Patients with Good-Risk Factors
|Immune Tolerance Protocols ||Dose ||Time to Negative Inhibitor |
|High-dose regimen ||200 U/kg factor VIII per day ||4.6 months |
|Low-dose regimen ||50 U/kg factor VIII three times per week ||9.2 months |
Other approaches to treatment of factor VIII inhibitors include immunosuppressive drugs, like cyclosporine and rituximab.85,86,87 However, these drugs, although occasionally successful, seem to be more effective in patients with acquired hemophilia resulting from autoantibodies against factor VIII.
Hepatitis Almost all multitransfused patients with hemophilia treated before 1985 were infected with one or more viruses that caused hepatitis. Although many infected patients did not suffer acute symptoms, at least 50 percent developed chronic persistent or chronic active hepatitis that in many cases, resulted in cirrhosis. Hepatitis C and B viruses are commonly associated with chronic liver disease. Many adult hemophilia patients treated with concentrates before 1985 have circulating antibodies to hepatitis B surface antigen, and hepatitis C. Hepatitis C infection progresses more rapidly in the presence of HIV infection. Until recently, therapy with pegylated interferon, and ribavirin reduced viral load and improve survival of many affected patients; however, newer approaches using serine protease inhibitors and nucleotide polymerase inhibitors has led to a high rate of sustained virologic responses.88 All patients with hemophilia should be vaccinated against hepatitis A and hepatitis B.
Human Immunodeficiency Virus Many of the older, severely affected hemophilia A patients who were treated before 1985 have antibodies to HIV, indicating infection with the virus. The incidence of HIV antibodies in mildly affected patients is much lower and correlates with treatment with factor VIII concentrates before viral inactivation procedures were used. In one study, 14 percent of patients treated only with cryoprecipitate from 1979 to 1985 were infected with HIV, whereas 88 percent of patients treated with factor VIII concentrates became infected.89 Screening of donor populations and new techniques for preparing factor VIII concentrates since 1985 have eliminated the risk of HIV transmission.
Risk of Viral Disease Transmission By New Factor VIII Products All available factor VIII concentrates, both plasma-derived and recombinant products, are considered safe and effective with almost no risk of transmitting currently known viral diseases. However, occasional exceptions have been observed. For example, solvent-detergent treatment does not inactivate viruses without lipid envelopes, including the hepatitis A virus and parvovirus. As a result, outbreaks of hepatitis A have been reported in patients receiving some solvent detergent–treated products. These outbreaks of viral diseases usually have been related to breakdowns in the manufacturing process.
Prions Prions are infectious particles consisting of proteinaceous material devoid of a nucleic acid genome.90 They are thought to be variant forms of a normal protein with an altered conformation. The “infectious” nature of prions may result from their ability to bind to other proteins and induce similar conformational changes in them such that new “infectious” particles can be generated. Prions are responsible for several neurodegenerative disorders, including Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, and spongiform encephalopathy in cows. Prions are resistant to most currently available viral inactivation techniques. Removal of prion particles using iodine column chromatography has been claimed.91 Although prion diseases generally are transmitted by ingestion of infected neural tissues, a new variant of CJD appears to occur in people who have eaten beef from cows infected with a form of prion causing bovine spongiform encephalopathy. This form of CJD has been reported mainly in the United Kingdom and in certain other European countries and has been related to the bovine disease.92 For example, prions have been found in tonsillar tissue of patients with new-variant CJD, heightening concern about whether prions of this type might be transmitted by blood products.93 Conclusive data about possible prion infection of hemophilic patients are lacking, so continued vigilance is necessary.