AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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.^{1, 2, 3} See Image 1.

That the disorder was due to a deficiency of a factor (F) in the blood was proven in 1840 by correction of the bleeding defect by 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. Finally, 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 FVIII-C.

Further progress was achieved in the 1950s with the development of cryoprecipitate and plasma concentrates to treat hemophilia A. 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 FIX 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 FVIII molecule (FVIII-C, an X-linked gene product) noncovalently bound to von Willebrand factor (vWF, an autosomal 12p gene product) in plasma clarified the separate roles of FVIII-C and vWF proteins. This led to an understanding of the role of the different components of the FVIII molecule in the physiology of normal hemostasis and to a recognition that hemophilia A and von Willebrand (vW) disease were caused by a deficiency of different proteins in the FVIII complex.

An understanding of the reasons for the development of FVIII 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 FVIII molecule. Cloning of the FVIII gene was followed by the preparation of recombinantly derived FVIII (rFVIII) as replacement therapy for the missing factor. Several different vectors have now been used to correct FVIII deficiency in humans, with many questions still to be resolved.^{4, 5} The potential role of increased levels of FVIII in thrombophilic states is continuing to be explored.

Primary immunodeficiency diseases (PID) are associated with various autoimmune complications and several manifestations of autoimmunity. Acquired hemophilia is a rare in childhood even though autoantibodies may develop in various forms of PID. However, acquired hemophilia may rarely form FVIII inhibitors in patients with undefined PID features suggestive of autosomal recessive hyper-IgE syndrome.⁶

This article deals only with FVIII-C, the coagulant molecule, also referred to here as FVIII. For information about the vW portion of the molecule, see von Willebrand Disease.

Pathophysiology

FVIII-C 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 2). An isolated deficiency of FVIII-C is associated with a significant bleeding diathesis, demonstrating the importance of FVIII in hemostasis.

Production, processing, structure, and half-life

The liver and the reticuloendothelial system are thought to be primary sites of FVIII-C production. Liver transplant corrects FVIII deficiency in persons with hemophilia, and persons with mild hemophilia with progressive liver disease have a rise in FVIII levels, thus establishing the liver as the major site of FVIII synthesis.

FVIII mRNA has been detected in the liver, spleen, and other tissues.⁷ Studies of FVIII production in transfected cell lines have shown that following synthesis, FVIII moves to the lumen of the endoplasmic reticulum, where it is bound to several proteins that regulate secretion, particularly immunoglobulin binding protein, from which it has to dissociate in an energy-dependent process. Cleavage of its signal peptide and the addition of oligosaccharides also occur in the endoplasmic reticulum. The chaperone proteins, calnexin and calreticulin, enhance both FVIII secretion and degradation.

A part of the FVIII protein in the endoplasmic reticulum is degraded within the cell. The other part enters the Golgi apparatus, where several changes occur to produce the heavy and light chains and to modify the carbohydrates. The addition of sulfates to tyrosine residues of the heavy and light chains is necessary for full procoagulant activity, with the sulfated region playing a role in thrombin interaction. This posttranslational sulfation of tyrosine residues impacts the procoagulant activity of FVIII and its interaction with vWF. ERGIC-53 is a chaperone protein in the Golgi apparatus that facilitates secretion of both FVIII and FV; a single mutation in ERGIC-53 has been identified as a cause of combined deficiency of FVIII-C and FV.

The secreted FVIII-C glycoprotein in plasma is a heterodimer having a carboxy terminal–derived light chain (80,000 molecular weight) in a metal-dependent association with the amino terminal–derived heavy chain (90,000-200,000 molecular weight). See Image 3. The plasma concentration of FVIII-C is approximately 200 ng/mL, while that of vWF is approximately 10 mcg/mL. vWF appears to promote assembly of the heavy and light chains of FVIII and more efficient secretion of FVIII from the endoplasmic reticulum. It also directs FVIII into the Weibel-Palade bodies, which are the intracellular storage sites for vWF.

In plasma, FVIII is stabilized and protected from degradation because of its association with a 50-molar excess of vWF protein; the light chain of FVIII-C interacts noncovalently with the N-terminal region of the vWF protein. In the presence of normal vWF protein, the half-life of FVIII-C is approximately 12 hours, whereas in the absence of vWF, the half-life of FVIII-C is reduced to 2 hours.^{8, 9, 10}

Wide interindividual variations are found in the level of FVIII following FVIII infusions in patients with FVIII 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 FVIII was found to be significantly influenced by blood type and vWF level. Blood type O patients had a much shorter half-life of 15 ± 0.9 hours compared with type A patients, who had a longer half-life of 19.7 ± 0.9 hours (significant at P = .003). Older patients with higher vWF levels had longer half-lives.¹¹

Physiologically, factors such as estrogens, pregnancy, exercise, and epinephrine can raise FVIII levels. The extent of the exercise-induced rise in FVIII levels was recently shown in a study of experienced athletes after a 42-km marathon run on a relatively cool, cloudy day. A 3-fold increase in levels of FVIII-C and vWF antigen was found, along with a change in the vWF multimer pattern. Several drugs and progressive liver disease can induce a rise in FVIII 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 prior 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 TF becomes exposed to blood under altered normal or pathological states, it binds with a high affinity to both FVII and FVIIa (activated FVII); FVII bound to TF is rapidly activated to FVIIa. The TF-FVIIa complex (extrinsic pathway tenase) is regulated by TF and is the most potent activator of coagulation. TF-FVIIa activates FX to FXa and FIX to FIXa; FXIa activates FIX to FIXa at a slower rate than that achieved by the TF-FVIIa complex.

Under normal conditions, a small amount of free FVIIa (~4.34 ng/mL; ~1% of total FVII) circulates in plasma. The source of this small amount of free FVIIa (a serine protease) in normal circulation remains unclear.¹² The free FVIIa 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 FIX-to-FIXa activation by the TF-FVIIa complex is underscored by the fact that in patients with severely reduced levels of FIX (hemophilia B), only approximately 10% of normally expected FVIIa (~0.33 ng/mL) is spontaneously generated, whereas approximately half the normal amount of normal FVIIa (~2.69 ng/mL) is found in patients with severe FVIII-C deficiency (hemophilia A). The practical importance of this distinction is unclear because deficiency of FVIII or FIX is associated with a clinically indistinguishable bleeding disorder.

When FVIII is exposed to thrombin or FXa, 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 FVIIIa. This activation accompanies proteolysis of both heavy and light chains of FVIII 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 FVIIIa to bind specifically to the platelet membrane through its light chain, increasing FVIII activity and allowing assembly of the tenase complex to proceed.^{13, 14} 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 FIXa, and its cofactor FVIIIa, 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, FVIIIa increases the maximum velocity of FX activation by FIXa, 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 FVIII is followed by an immediate dissociation of the A2 subunit, leading to loss of activity of FVIIIa; prolonged reaction of FVIIIa with FIXa leads to proteolysis of the A1 subunit and subsequent loss of FVIIIa activity. Thus, the rapid decay of FVIIIa 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 FVIIIa 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 FVIIIa by APC occurs at sites on both the A2 and A1 subunits. The primary substrate of APC appears to be FVa rather than FVIIIa, and, under physiologic conditions, the major reason for loss of FVIIIa activity appears to be due to spontaneous dissociation of the A2 subunit of FVIIIa, rather than APC-induced proteolysis of FVIIIa.

In addition to APC, proteolysis of FVIIIa may also be mediated by FIXa, FXa, and thrombin; the relative importance of these pathways in vivo currently is unclear.

FV is another cofactor that has structural and functional similarities to FVIII. A single mutation in the FV gene leads to the production of an abnormal FV (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 FVIII gene might occur, leading to a thrombophilic state. However, analysis of mutant FVIII proteins created in the laboratory showed that mutations at both the Arg 336 and Arg 562 sites (sites of APC cleavage) of FVIII were necessary before the mutated FVIII was resistant to APC-induced proteolysis.^{15, 16}

FVIIIa is protected by vWF from inactivation by APC, but vWF is unable to prevent thrombin from activating FVIII to FVIIIa or prevent activation of FVIII by FXa. The inhibitory and protective actions of vWF probably result from the prevention by vWF of the interaction of FVIIIa with phospholipids and activated platelets. When thrombin cleaves FVIII, vWF is released and FVIIIa is freed and is capable of attaching to the platelet phospholipid, a site to which the FVIIIa is brought by the interaction of vWF with the platelet glycoprotein Ib receptor.

In the rare disorder of inherited combined deficiencies of FV and FVIII, the prothrombinase complex (extrinsic tenase) in which FVa participates is also deficient, in addition to the deficiency in the tenase complex caused by deficiency of FVIIIa.

Antigenic structure

Frequency

United States

The overall estimated frequency of hemophilia A 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 FVIII 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 FV and FVIII 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 FVIII (FVIII inhibitors) have been reported from many parts of the world. The inherited combined FV and FVIII deficiency has been reported in patients from Europe, Tunisia, the Middle East, Iran, and, more recently, India.

Mortality/Morbidity

Intracranial bleeding was the major cause of death in individuals with hemophilia until the AIDS epidemic, which, from the late 1970s into the 1990s, became the major cause of death in this population. Significant morbidity is experienced from frequent joint and other bleeding episodes. Hepatitis remains a major cause of morbidity and mortality because of its progression to chronic liver disease¹⁷; chronic fatigue is caused by the ongoing active viral illness and/or is related to antiviral therapy. Portal hypertension, variceal bleeding, ascites, and upper 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 FVIII 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, psychological, 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, HIV infection adds another layer of burden.¹⁸ 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 FV and FVIII 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 FV, such as purified FV concentrate, to correct the FV deficiency requires the repeated use of fresh frozen plasma (FFP), with its potential for transmitting illnesses.

Race

Hemophilia A has no ethnic predilection. Middle Eastern Jews and persons from Tunisia, Iran, India, Europe, and the United States have been reported with the combined deficiency of FV and FVIII.

Sex

Otherwise healthy males with a single copy of the abnormal gene in their only X chromosome have bleeding manifestations. The severity of bleeding generally depends on their basal level of FVIII-C but 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 FVIII-C than that expected with a carrier state have been found in such females (see Image 5). 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 FVIII-C. A combination of this unbalanced inactivation with a new FVIII gene mutation has been shown to result in severely reduced FVIII levels in a female (severe female hemophilia).¹⁹

Recent data cast doubt on a correlation between the pattern of X chromosome inactivation and the wide variation in levels of FVIII or FIX 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 FVIII or FIX.²⁰ Lower basal levels of FVIII-C in carriers is associated with a bleeding disorder, although less severe than that observed in the corresponding hemophilic male, due to the presence of higher basal levels of FVIII or FIX 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), X-autosome translocation involving a breakpoint in the FVIII 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 FVIII inhibitors develop in either sex.

Combined FV and FVIII deficiency is an autosomal recessive disorder with clinical manifestations in affected females and males.^{21, 22, 23, 5}

Age

Prenatal diagnosis of hemophilia A can be made 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.

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% bled within the first year, while 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; half the patients had their first bleeding episode by age 1.22 years, while 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.²⁴

Because of the increasing safety of recombinant FVIII concentrates, advances in therapy, home treatment, and the long-term physical and psychological benefits of being able to lead a normal life style, 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.^{25, 26}

Acquired FVIII deficiency is observed in older populations, generally those older than 60 years. Inhibitors that develop in patients with hemophilia now are likely to be found in a younger age group, due to the recent practice of starting prophylactic replacement therapy at a younger age.

Bleeding in patients with a combined deficiency of FV and FVIII starts in childhood as the child starts ambulating, with the earliest possible evidence at the time of circumcision after birth.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

Recurrent spontaneous or minor injury–induced episodes of joint bleeding are common in persons with severe and moderately severe hemophilia, causing severe pain and limitation of joint movement. The repeated presence of blood in the joint leads to synovial hypertrophy, with a tendency for recurrent joint bleeding, which finally results in a destructive chronic synovitis with destruction of synovium, cartilage, and bone. This leads to chronic pain, arthritis, joint stiffness, and limitation of movement due to progressive and permanent severe joint damage with progressive muscle wasting (see Images 6-13).

• Intramuscular hemorrhage, the second most common bleeding event, also leads to acute severe and recurring pain, swelling, and limitation of movement. The hematoma may dissect down into the fascial planes and result in neuropathies due to nerve compression, such as with psoas bleeding; large retroperitoneal bleeding can lead to hypotension.
• Mucous membranes can be the site of bleeding, manifesting as epistaxis, oropharyngeal, or retropharyngeal bleeding, which can lead to acute respiratory obstruction. The GI tract may be a source of bleeding in approximately one fifth of patients, with an increasing frequency due to the consequences of cirrhosis and the use of readily available over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) for relief of arthritic pain. Peptic ulcer disease is approximately 5 times more common in individuals with hemophilia than in the general population.
• CNS hemorrhage (~3-14%) was the major cause of death in persons with hemophilia prior to the widespread availability and use of factor replacement to prevent bleeding and prior to the AIDS epidemic.²⁷ Approximately one third of CNS bleeding episodes lead to death, and at least half result in major, long-term sequelae. Bleeding is usually preceded by head trauma in children, whereas adults may develop CNS bleeding without obvious trauma. Symptoms are typical of any CNS event, with a variety of symptoms such as headaches, seizures, vomiting, and focal neurologic defects. Findings depend on the sites of bleeding.
• Spontaneous hematuria can be seen in those with severe hemophilia. The use of NSAIDs, protease inhibitors, or over-the-counter drugs; trauma; exercise; or exertion may precipitate genitourinary (GU) bleeding. Associated clots in the GU system causing acute hydronephrosis may be a complication of the use of fibrinolytic inhibitors concomitantly with factor replacement in patients with hematuria. Underlying pathology, such as nephrolithiasis, tumors, or infections, should be excluded when persistent bleeding is present. Indinavir (Crixivan) may be associated with crystalluria or calculi in HIV-infected patients.
• Acute and chronic viral illnesses have been transmitted by the less pure products, which were the only ones available to treat bleeding in the past. HIV-related illnesses and AIDS; repeated viral, fungal, and bacterial illnesses due to AIDS; malignancies, such as Kaposi sarcoma; and the aggressive AIDS-associated lymphomas are life-threatening complications.²⁸ Despite these problems, plasma-derived products remain a valuable resource without which many persons with hemophilia throughout the world would experience the painful consequences of recurrent bleeding. See Complications for further details.
• The availability of newer recombinant products (with no risk of transmission of HIV and hepatitis) for use in home care and in-hospital treatment means that those unexposed to plasma-derived products could conceivably achieve a normal life span.
• Pseudotumors are produced by a slow expansion of repeated hemorrhages in bone or soft tissues. They can be restricted by the fascial planes of a muscle, cause resorption of neighboring bone by pressure-induced ischemia, or develop under the periosteum, leading to erosion of the bony cortex. They develop slowly over months to years and often are asymptomatic, unless pressure on the nerves or vascular compromise occurs. Pseudotumors contain a brownish material and can become infected. The buttock, pelvis, and thighs are frequently involved locations for a pseudotumor (see Images 14-20).
• Delayed bleeding develops after dental extractions; therefore, patients require appropriate presurgical and postsurgical management. If not treated appropriately, dental bleeding can persist and expand to sublingual, pharyngeal, face, or dissecting neck hematomas or other serious bleeding.
• Co-inheritance of thrombophilic mutations has been suggested as a reason for reduction in the severity of bleeding in some individuals with severe hemophilia. A recent study of the correlation between concentrate utilization, incidence of bleeding episodes per year, and prevalence of hemophilic arthropathy in those with severe hemophilia with and without the FV Leiden mutation (a known thrombophilic mutation in the white population) showed that indeed FV Leiden carriers had fewer bleeding episodes, but the authors of this study do suggest, appropriately, the need to study this issue in a larger cohort with additional testing.^{29, 30, 31}
• The development of alloantibodies in persons with hemophilia is a serious complication that leads to increased bleeding and a lack of response to usual therapy, which can be fatal (see Images 21-22). See Complications for more information.
• Acquired FVIII inhibitors (ie, acquired hemophilia due to an autoantibody in previously hemostatically normal individuals) are a cause of significant morbidity and are associated with a mortality rate of at least 20% because they affect elderly people who have comorbid conditions. Patients present with extensive bleeding, often life-threatening, before it is recognized.
• • In contrast to persons with severe inherited FVIII deficiency (hemophilia A), in whom joint bleeding is common, patients with acquired hemophilia present with large intramuscular, retroperitoneal, limb, subcutaneous, GU, GI, or excessive postoperative or postpartum bleeding. Bleeding into an extremity can result in findings easily confused with deep vein thrombosis. Massive upper extremity bleeding can be precipitated by a simple venepuncture. Bleeding can develop at any site.
  • Postpartum inhibitors usually come to attention several months after delivery (2-5 mo), when bleeding symptoms supervene; rarely, the inhibitor may develop during pregnancy.
  • Because of the unusual characteristics of these autoantibodies, patients may present with significant bleeding despite the presence of detectable amounts of plasma FVIII-C activity in vitro; this residual FVIII activity in a patient with active bleeding can mislead the clinician about the seriousness of the FVIII deficiency.
• Bleeding manifestations in homozygous patients with the combined FV and FVIII deficiency include variable bleeding after circumcision, ranging from severe to less-than-severe. Epistaxis can occur, as can gingival bleeding and easy bruising, starting with mild trauma, as occurs during normal childhood activities. Menorrhagia can start at menarche. Hemarthrosis has been reported in approximately 20% of patients; therefore, joint bleeding is less common in this group than in patients with severe hemophilia A or B.
• • Confusion with joint bleeding may arise when bleeding occurs in a bursa surrounding a joint. For example, bleeding in the olecranon bursa may be misinterpreted as bleeding into the elbow joint.
  • In the absence of appropriate factor replacement, dental extractions or other surgeries precipitate bleeding. Intracranial bleeding can develop, even after minor trauma to the head.
  • Due to higher basal levels of FV and FVIII than those found in homozygotes with combined FV and FVIII deficiency, only a few heterozygotes manifest excessive bleeding.³²

Physical

• Severe pain in the target joint(s); bogginess around the involved joint(s) due to an inflamed synovium and the presence of blood and fluid; fullness of joint space and/or surrounding bursa; and varying degrees of limitation of joint mobility
• Deep muscle hematomas, with pain, tenderness, and limitation of movement
• Delayed onset of bleeding from sites of trauma and/or surgery
• Blood in the urine
• Blood in the stool or upper GI bleeding
• Changes in neurological function, eg, headache, focal neurologic deficits
• Signs of jaundice, spider angiomas, hepatomegaly accompanied by tenderness, and splenomegaly related to chronic hepatitis or cirrhosis
• Fatigue, poor appetite, and loss of energy with progression of chronic viral illnesses, including HIV and hepatitis C
• Weight loss, adenopathy, and opportunistic infections, particularly as a manifestation of AIDS syndrome
• Possible development of anaphylaxis after the start of FVIII infusions in severely deficient children (although frequency is greater in patients with severe FIX deficiency)

Causes

With the cloning of the FVIII gene in 1984, a new era began in the understanding of hemophilias. A large number of mutations have been documented in the FVIII gene and account for hemophilia A, and, in the early part of the 20th century, the prediction that approximately a third of these would have to be de novo mutations not present in the mother's X chromosome was correct. The functional defects of FVIII-C manifested as hemophilia A are due to structural defects in the FVIII gene (see Image 3 and Image 23).

• The gene for FVIII is located on 28q (the most distal arm of the X chromosome), is approximately 186 kilobases long, and comprises approximately 0.1% of the DNA in the X chromosome; it has 26 exons and 25 introns. The site for FVIII is linked to the locus for color-blindness and with polymorphisms at the glucose 6-phosphate dehydrogenase locus.
• Intron 22 of the FVIII gene, uniquely, contains 2 other genes. The first is called F8A, which is transcribed in a direction opposite to that of the FVIII gene itself. The second gene is F8B, which is transcribed in the 3' (normal) direction similar to the FVIII gene. Sequences called A2 and A3, homologous to the F8A sequence, are present on the X chromosome, 300 kb telomeric to the FVIII gene.
• Homologous recombination of the FVIII gene, with inversion and crossover involving the F8A sequence in intron 22 and the homologous distal sequence on the X chromosome, results in a split in the FVIII gene with the 2 parts aligned in opposite directions. This causes a disruption in the normal FVIII coding sequence, with an inability to transcribe the complete, normal FVIII protein, resulting in a loss of function. The mutation in intron 22 occurs during spermatogenesis and is a common cause of severe FVIII-C deficiency, being present in approximately 40% of patients. It is easily detected using a Southern blot analysis of the patient's DNA. These patients are more likely to develop an inhibitor to FVIII.
• In one study, all detected inversions originated in a maternal grandparent during male meiosis (spermatogenesis), supporting the hypothesis that an unpaired Xq, rather than a paired X chromosome, is more likely to undergo an intrachromosomal inversion. The majority of mothers of persons with the sporadic, inversion-related severe hemophilia are carriers.⁴ The knowledge of the parental origin of the inversion mutation has important implications for genetic counseling and should help alleviate the severe emotional burden carried by mothers of persons with hemophilia, who are blamed or blame themselves for being the cause of their son's devastating illness.
• Several other types of mutations have been described.
• • Point mutations can lead to mild, moderate, or severe deficiency of FVIII-C, depending on the effect of that mutation on FVIII gene function.
  • Missense mutations, such as the G-to-A single-base substitution, alter the amino acid composition of the molecule, producing a dysfunctional molecule (FVIII antigen, present with reduction in FVIII-C). These mutations are associated with mild, moderate, or severe FVIII-C reductions and are associated with the development of FVIII inhibitors. Intracellular accumulation of FVIII induced by Arg 593-->Cys and Asn 618-->Ser missense mutations also result in reduction of cross-reacting material in severe hemophilia A.
  • Gene deletions lead to FVIII-C deficiency, and large gene deletions result in severe hemophilia, with no detectable FVIII antigen; such patients are more susceptible to inhibitor development. Insertions apparently are uncommon in the FVIII gene but usually lead to severe hemophilia A (Roelse, 2000).³³
  • Non-sense mutations and abnormal splicing also may occur.
• Modification of the clinical severity of the bleeding disorder resulting from a specific FVIII mutation by co-inheritance of thrombophilic genes is increasingly recognized as a cause of the variability in bleeding manifestations within a single family with hemophilia A.^{29, 31, 34} Additionally, keep in mind that phenotypic variations can be found in patients with the same genotype in a variety of hematologic disorders (Beutler, 2001).³⁵ The case-control design has been suggested as an appropriate type of clinical study to elucidate genetic-environmental interactions (Clayton, 2001).³⁶
• The role of genetic polymorphisms, particularly intragenic polymorphisms, should be recognized when providing genetic counseling for families with unknown mutations. Some polymorphisms are universal, whereas others appear to be restricted to particular ethnic groups; the latter situation will change as ethnic intermarriages increase with increased globalization of populations.
• Recent studies of a heterogeneous population in India have identified a higher heterozygosity index of polymorphic variants of 2 new variants of the multiallelic locus DXS52(St14) of the human X chromosome;^{37, 38} other intragenic polymorphisms have also been reported in this population and are of obvious use in prenatal diagnosis.³⁹ Data published for a Korean population showed a higher occurrence of low molecular weight alleles in Korean persons than in white persons.⁴⁰
• Some cases of the combined deficiency of FV and FVIII are caused by mutations in the ERGIC53 gene, with loss of splicing or insertion of a nucleotide leading to a frameshift; both mutations identified to date result in an altered ERGIC-53 protein in the endoplasmic reticulum–Golgi apparatus. ERGIC53 has an affinity for the glycosylated B domains of both FV and FVIII, and the ERGIC-53 protein transports FV and FVIII through the secretory processes in cells. In families with known mutations, allele-specific hybridization studies show the difference between homozygotes and heterozygotes. Because of a single error in a common processing mechanism affecting both FVIII and FV, a similar degree of reduction in plasma levels of FV and FVIII occurs in homozygotes, with levels varying 5-30%.^{21, 4, 5, 16}
• Other causes of this disorder remain to be identified. The Haemostasis Research Group Web site has a continually updated database of genetic defects related to hemophilia A.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Acquired FVIII inhibitors
Hemophilia B
Other acquired hemorrhagic disorders

Rare combined FV and FVIII deficiency

The rare association of a true hemophilic FVIII deficiency with hereditary FV deficiency should be kept in mind when making a diagnosis of combined FV and FVIII deficiencies. A similarly reduced level of FV and FVIII clotting activities in plasma, independent segregation of FV and FVIII deficiency in the family, and finding other members in the same family with combined FV and FVIII deficiency all are clues to the presence or absence of a single defect leading to combined or individual deficiencies of FV and FVIII. Most difficult to detect based on history findings alone is the presence or absence of consanguinity (a feature of recessive disorders requiring 2 doses of the gene for clinical manifestations). In families with known mutations, allele-specific hybridization studies show the difference between homozygotes and heterozygotes.

Acquired multiple-factor coagulopathies due to liver disease, diffuse intravascular coagulation (DIC), warfarin excess, or coagulopathy of dysproteinemias should also be considered.

See Complications for a discussion of FVIII inhibitors.

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Preliminary identification of the coagulation disorder: Tests include activated partial thromboplastin time (aPTT), prothrombin time (PT), platelet count, and bleeding time
• • A prolonged aPTT and a normal PT indicate an abnormality in the early part of the intrinsic coagulation pathway. However, a normal aPTT does not exclude mild hemophilia A because the aPTT may not be sufficiently sensitive to detect slightly reduced levels of FVIII-C in the approximate 20-30% range, as occurs in persons with mild hemophilia or in carriers. If the clinical history warrants it, then a specific FVIII-C level should be obtained.
  • Prolongation of the PT alone, or both the PT and aPTT, is not consistent with hemophilia A alone; this kind of coagulopathy may be due to the superimposition of other causes, such as liver disease, overdose of heparin or warfarin sodium, or DIC.
  • Thrombocytopenia or platelet dysfunction is not consistent with hemophilia A alone.
  • The nature and severity of bleeding are assessed using a CBC count with differential, stool analysis for blood, and urinalysis for hematuria.
• Confirmatory tests and specific coagulation factor assays
• • A mixing test in which the patient's plasma is mixed with normal pooled plasma, incubated at 37°C, and then tested for an aPTT is performed.
  • Correction of the aPTT in this test implies a deficiency, whereas persistence of an abnormally prolonged aPTT suggests the presence of an inhibitor.
  • Most clinical laboratories only perform a single-stage FVIII-C assay.
  • The importance of maintaining expertise in performing 2-stage assays was reiterated by a study from the Oxford Hemophilia Centre, showing a significantly reduced FVIII-C activity of 18% and 35% by the 2-stage and chromogenic assays, respectively, in contrast with a normal 106% activity obtained by a single-stage assay on plasma from a patient with mild hemophilia A. This patient with mild hemophilia had a mutation in the A3 domain; patients with mutations in the A1 and A2 domains also have been described with a similar discrepancy. The lesson here is that the diagnosis of hemophilia will be missed in patients with a history of a bleeding disorder unless the 2-stage or chromogenic assay is performed to exclude a reduction in the level of FVIII-C.^{41, 42} The lower activity found in chromogenic substrate assays, as opposed to the misleading normal value found in routine single-stage clotting assays in such patients, has been confirmed by others.
  • Both the aPTT and PT are prolonged in patients with a combined deficiency of FV and FVIII, which is detected by specific factor assays in appropriate factor-deficient plasmas and corrected by the addition of or incubation with pooled normal plasma. Patients with an inhibitor to FV developing after exposure to bovine thrombin have a prolonged aPTT, PT, and thrombin time; the thrombin time corrects if human thrombin is used to perform the test instead of bovine thrombin, showing the specificity of the antibodies to bovine thrombin.
• Determination of the specific titer of an inhibitor to FVIII: The Bethesda inhibitor assay has been widely used to assess the titer of an inhibitor directed against a coagulation factor. Ideally, the Nijmegen modification of the Bethesda inhibitor assay should be used to detect the presence of an inhibitor if the mixing test result is positive.^{43, 44}
• • The improved Nijmegen modification for more accurately assaying inhibitor titer uses immunodepleted FVIII-deficient plasma instead of an imidazole saline buffer, to ensure pH control to prevent non–antibody-mediated loss of FVIII-C activity during the prolonged 2-hour incubation period.⁴³ The Bethesda assay tends to underestimate the titer of the autoantibody because of its characteristics, in contrast with a hemophilic antibody. The Oxford assay is another modification of the Bethesda inhibitor test.
  • Confirmation of the specificity of an inhibitor requires a 2-hour incubation of an equal part of the patient's and pooled normal plasma at 37°C, along with separate assays of the patient's fresh plasma for FVIII-C, FIX, FXI, and FXII activities to prove that there is demonstrable specificity of the inhibitor against a single coagulation factor, such as against FVIII-C in this case. Reduction of a single-factor level, as opposed to multiple-factor reductions, is expected with a specific alloantibody or autoantibody. Use of an aPTT-type system, rather than a factor-deficient assay system, detects very low-titer inhibitors of less than O.4 Bethesda units (BU). However, the presence of clinically important bleeding must be pursued even if the inhibitor titer appears low initially; this scenario is more likely with autoantibodies.
  • Specific antibodies to FVIII are usually immunoglobulin G (IgG), subclass 4, or a mixture of IgG classes 1 and 4.
  • These tests must be performed in a laboratory staffed by personnel who are highly experienced in performing these assays.
  • Separate alloantibodies to FVIII and FV could develop in the rare patient who may have inherited separate mutations for both factor deficiencies.
• Identification of carriers: Carriers can be detected by linkage studies using restriction fragment length polymorphism analysis.
• • This test can be used only if the precise genetic defect is known.
  • If the mutation in the family is known, molecular biological methods can be used to diagnose hemophilia A prenatally by analysis of fetal cells in amniotic fluid.
  • Caution is warranted when obtaining blood samples for coagulation assays from heparinized central lines because of the effect of heparin contamination on all coagulation test results. A recent study suggests that all blood samples obtained from vascular access devices, which are usually flushed with heparin, should be treated with heparinase before performing an inhibitor assay because significant heparin contamination has been found in 45% of all specimens obtained through such access catheters.⁴⁵ The excess heparin causes false-positive and/or higher inhibitor titer values compared with those actually present in the patient because heparin is also an inhibitor of coagulation. False-positive or higher inhibitor titers than actually present in the patient could lead to unnecessary use or the use of larger doses of expensive concentrates in patients with hemophilia.
• Other laboratory studies: These may include liver function tests, kidney function tests, HIV-1 and HIV-2 antigen and antibody tests, and tests for hepatitis A, B, C, D, and E antigen/antibody.
• Alpha-fetoprotein and other tumor markers (as needed)
• Other laboratory tests or new tests: These are performed as needed or as newer tests are introduced into routine testing protocols.

Imaging Studies

• MRI, CT scan, and ultrasound have all been used to localize, quantify, and serially follow the response of bleeding to specific therapy. The depth, location, and size of the hematoma guide the choice of diagnostic test. A simple test, if adequate, is more appropriate for serial follow-up of the size of the hematoma during therapy. MRI and CT scan are better for diagnosing and localizing pseudotumors. Other tests should be performed as needed to diagnose renal calculi and tumors.

Other Tests

• ECG may be useful as a general test.

Procedures

• Arthrocentesis must not be performed, either for diagnostic or therapeutic purposes, for a routine joint bleed in a known hemophilic patient because it increases the risk of exacerbating the joint bleed (see Image 8). Diagnostic arthrocentesis should only be performed when an infection is suggested.
• Routine dental care is of the utmost importance in maintaining dental hygiene and preventing gingival bleeding.
• Other procedures, such as colonoscopy, should be performed as in patients without hemophilia, when indicated. Persistent GI bleeding without an apparent cause should be evaluated using endoscopy and colonoscopy to rule out underlying lesions.
• Persistent GU bleeding requires evaluation for nephrolithiasis, tumors, or obstruction. If a biopsy is needed, patients require replacement therapy prior to any invasive procedure.
• Surgical excision of any pseudotumor in toto is necessary, often requiring laborious, long, and extensive dissections; partial removal leads to recurrence of the pseudotumor caused by repeated bleeding. Avoid aspirating a pseudotumor because of the risk of exacerbation of already existing, slowly progressive bleeding.
• Prenatal diagnosis
• • Carriers who have been diagnosed with a specific mutation can have chorionic villous sampling at approximately 10-12 weeks' gestation or amniocentesis at 16-20 weeks' gestation to obtain fetal cells for DNA analysis or for linkage studies. If DNA analysis cannot be performed, then fetal blood obtained by fetoscopy at approximately 20 weeks' gestation can be assayed for FVIII-C level. All of these procedures carry a risk ranging from a low of 0.5% for maternal-fetal complications to a high of 1-6% for fetal death from fetoscopy. These procedures should be undertaken only after patients receive intense genetic and obstetric counseling. If the fetus is a female, the couple may elect to carry the pregnancy to term because carriers rarely have bleeding problems. If the fetus is a severely affected male, the couple must make a decision about continuing the pregnancy to term.
  • Prenatal diagnosis is useful in that it allows trauma (eg, that caused by forceps or prolonged labor) to be avoided and helps minimize the risk of intracranial hemorrhage.
  • Concerns regarding the consequences of vaginal delivery to a hemophilic infant and the lack of data regarding outcomes of pregnancy/delivery for carriers has led to the recommendation that vacuum devices and scalp monitors not be used in delivering carriers. Issues related to vaginal delivery currently require individualized management.^{25, 26} See Pathophysiology for additional information on this subject.
  • Genetic counseling before the woman becomes pregnant is ideal and may help couples make informed decisions before conception.
  • The same techniques discussed above can be used in patients with known ERGIC53 gene mutations for prenatal diagnosis in families with a combined deficiency of FV and FVIII.

Histologic Findings

Synovial proliferation is caused by repeated bleeding into the joint. This results in damage to joint structures, leading to limitation of movement and deformity. The presence of excess iron in these tissues is evident microscopically. See Image 13 for histologic features.

The gross and microscopic findings of a pseudocyst with chocolate-colored inspissated material are shown in Images 14-17.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

FVIII replacement is used for acute bleeding, perioperatively for prevention of bleeding during planned surgical procedures, for prophylaxis to prevent recurrent bleeding of target joints, in early institution of childhood prophylactic therapy to preserve long-term joint function, or for immune tolerance induction (ITI) regimens. Prompt and adequate therapy for bleeding is essential to avoid the long-term destructive consequences of joint bleeding.

Home-care programs have made patients self-sufficient in infusing product, with guidance and supervision from personnel at a hemophilia center or a knowledgeable physician in the local community. This has also improved quality of life by minimizing the time spent in hospital emergency departments, providing rapid and early therapy for acute bleeding, achieving a prompt reduction in pain due to early specific correction of the factor deficiency and joint immobilization, and allowing concomitant provision of appropriate narcotic and nonnarcotic analgesics. Joint integrity can be preserved with the start of early prophylactic home-care programs in childhood (maintain a minimum of 1-2% FVIII-C at all times by infusing replacement product at home 3 times per week).

All of these allow a patient to participate in more of life's activities. The specific dose and duration of factor replacement therapy is determined by the location of the bleeding, severity of the bleeding, and known actual response to prior therapy.

Intermediate- or high-purity plasma-derived products are still available for use in patients who have previously used such products. Monoclonal antibody purified plasma–derived products are usually free of some viral contaminants. In children who are starting therapy for the first time or in persons with hemophilia who are negative for HIV, recombinant products are used whenever possible because of their presumed higher viral safety. Importantly, be aware that approximately 25% of the lots of human albumin containing first-generation recombinant FVIII concentrates have been found to be positive for transfusion-transmitted (TT) virus from contaminated human serum albumin. All second-generation recombinant FVIII preparations (free from human albumin) have been negative for the virus.⁴⁶

See the table in Medication and related material for a general dosing guide for replacement therapy and for target FVIII levels for acute bleeding. The duration of therapy depends on the site and cause of bleeding and response to therapy. Bolus dosing is still the most often used method of replacement, but a continuous infusion regimen generally reduces total administered doses by approximately 30%. Data on the lowest necessary dose for adequate therapy, a consideration because of the enormous cost of products, are being obtained.⁴⁷

Monitoring actual levels of FVIII-C is necessary to confirm the presence of adequate amounts of FVIII in vivo to correct hemostasis when (1) a patient is first treated, (2) a new product is being used, (2) the onset of an inhibitor is suggested, (4) active ongoing bleeding is present, or (5) persistence or inadequate correction of bleeding has been encountered with previously adequate doses.

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

Epistaxis and moderately severe hematuria may be adequately treated by achieving and maintaining FVIII levels in the range of 30-50%. Use higher dosing initially, followed by a gradual lowering of the dose after bleeding is under control, and then continue FVIII replacement until clinical and objective evidence indicates resolution of the bleeding. Acute joint bleeding and expanding, large hematomas require adequate replacement for a prolonged period until the bleed begins to resolve, as evidenced by clinical and/or objective methods. Relief of the intense pain with joint bleeding frequently requires the use of narcotic analgesics; relief of pain also accompanies cessation of bleeding after adequate factor replacement.

Life-threatening bleeding episodes are generally initially treated with FVIII levels of approximately 100%, until the clinical situation warrants a gradual reduction in dosage. Continuous intravenous infusions avoid the low troughs and excesses of intermittent bolus dosing, maintain adequate levels at all times, and save approximately 30% of expensive product usage.^{48, 49}

For serious bleeding events, continue replacement for at least 7-10 days because of the potential risk of recurrent bleeding. A multiple-bolus drug dosing regimen model has been developed to better estimate loading and maintenance dose requirements to allow maintenance of a minimum trough level of FVIII at all times.⁵⁰ In patients who may have an intracranial hemorrhage, administer a full dose of factor concentrate before the patient is sent for any diagnostic radiologic procedures in order to avoid delays in bleeding control. Surgically drain intracranial bleeding promptly, as clinically dictated, following replacement therapy.

Patients with combined FV and FVIII deficiency require combined replacement with FVIII concentrates and FFP for FV, which also supplies a small amount of FVIII. Deamino-8-D-arginine vasopressin (DDAVP) to raise FVIII (without concomitant FVIII concentrate) in combination with FFP as a source of FV has been used successfully in the perioperative management of an older Italian man who was undergoing surgical repair of massive bilateral inguinal hernias.⁵¹ In current practice, pooled solvent-detergent–treated plasma (PLAS⁺ SD) is safer than standard FFP because the lipid enveloped viruses are removed. See Medication for further details of PLAS⁺ SD.

Collaboration with an infectious disease consultant is a major need in caring for patients with HIV/AIDS or hepatitis. The serious psychiatric issues present in the management of patients infected with HIV may require the assistance of a psychiatrist.¹⁸

Simple immediate ancillary measures of ice, pressure, elastic bandage (ACE) wrap, immobilization of the affected joint, and avoidance of NSAIDs must not be forgotten.

The benefits of prophylaxis in the management of hemophilia A should be emphasized.⁵² There are clear advantages of prophylaxis for patients with hemophilia A compared to on-demand treatment, including a reduction in the number of bleeding episodes, improved joint function, and greater patient well-being. Sadly, there is a heavier economic burden with increased factor use.

• Prophylactic factor replacement
  • Secondary prophylaxis thus far has been undertaken mainly in patients with target joint–related recurrent bleeding in a biweekly or triweekly intravenous dose of FVIII of 25-40 U/kg to maintain trough FVIII-C levels in the range of 3-5%. Recent data clearly show that in order to preserve joint function, primary prophylaxis must be started early in childhood, after the child experiences the first few episodes of bleeding into a joint.
  • This may appear to be an expensive proposition, but this approach has been shown to be good for the patient's joints and quality of life, and, over the long-term, it reduces costs by reducing the number of in-hospital days and outpatient and day care visits when compared with on-demand therapy.^{53, 54, 55, 56, 57} Moreover, on-demand and secondary prophylaxis do not prevent hemophilic arthropathy, which better preserves normal joint structure and function and a normal quality of life while presumably delaying or even reducing the need for early joint replacement.
  • As early as 1994, the Medical Advisory and Safety Committee recognized the long-term physical and psychosocial benefits of early prophylaxis in allowing the hemophiliac patient to lead a normal life style, and it endorsed the principle of prophylactic therapy as the optimal approach to hemophilic care. However, venous access problems do arise, especially in children, and indwelling lines invariably lead to recurrent infections and thrombotic complications. Subclavian, brachiocephalic, jugular, and superior venocaval thrombi have been objectively documented in hemophilic children with long-term (>1 y) central venous catheters for access. Approximately 50% of patients with central venous catheters for more than 1 year have deep vein thrombosis.^{58, 34}
  • An intriguing new concept is the development of an oral peptide, peptidomimetic, or other compound that may activate the coagulation mechanism, with an ability to control the extent of activation. This is the reverse side of the coin of controlled anticoagulant use to treat thrombotic diseases.
• Home therapy
• • In the last few decades of the 20th century, home therapy has revolutionized the type of care provided to individuals with hemophilia. New products have resulted in improved patient outcomes, which considerably improves the quality of patients' lives.
  • The typical picture of a wheelchair-bound, disabled adult with hemophilia of earlier times has been replaced by that of an ambulating patient with a lesser degree of joint damage. However, the fact remains that many require joint replacements at a younger age than persons without hemophilia but with osteoarthritis.
  • Patients and families have become self-sufficient with the application of sterile home infusion techniques, with prompt replacement of the missing factor at the earliest evidence of pain and/or possible bleeding rather than having to spend hours waiting for care in crowded emergency departments. Distant travel and summer camp experiences have also become feasible (see Image 24).
  • The availability of lyophilized product, the equipment and teaching needed for intravenous self-infusion, and security to infuse the product have helped release patients from the necessity of remaining in the vicinity of a hospital for emergent care (see Images 25-26). This aspect is also extremely important from the psychological standpoint of allowing parents and other family members to become actively involved in the care of their loved one.
  • The subsequent increase in product usage has led to an increasing risk of exposure to virally transmitted illnesses and led to the AIDS and hepatitis epidemics. Patient who are negative for HIV and hepatitis C virus and those who have not undergone treatment as yet are now being treated exclusively with the more expensive recombinant products.
  • With the availability of concentrates of FVIII and developments in the field of joint replacement, previously disabled patients can ambulate and become self-sufficient in their daily lives. There are advantages and disadvantages in using the albumin-free recombinant factor VIII concentrates in the treatment of hemophilia A.⁵⁹ The third-generation recombinant factor VIII product Advate is safe and effective in treating bleeding associated with hemophilia A. Controversy remains with regard to a higher risk of inhibitor development with recombinant products, and the higher cost may play a role in product choice. Each patient and family should be educated about the advantages and disadvantages of all factor VIII concentrates, and be allowed to make an informed decision about which product to use.
• Other therapeutic measures
  • DDAVP, or desmopressin acetate (Stimate), is an arginine vasopressin analogue, which, when given intravenously in a dose of 0.3 mcg/kg over 15-20 minutes, causes a transient 2- to 4-fold rise in FVIII and vWF levels by inducing release of FVIII and vWF from storage sites. Doses are usually repeated 8-12 hours later, but an approximate 30% lower response may be expected after the second dose.
  • Repeated administration results in a markedly reduced response (tachyphylaxis). FXI levels also rise in response to this drug. The rise in FVIII level is accompanied by an increase in fibrinolytic activity due to the simultaneous release of tissue plasminogen activator.
  • DDAVP can also be given by intranasal spray (150 mcg in each nostril), but the time to maximal rise in FVIII levels is delayed (unlike the response to an intravenous dose); therefore, extra time is required for response. This approach may be inadequate under some clinical circumstances.
  • DDAVP is a good drug to use in patients with mild hemophilia (who have been proven to respond to the drug) to prevent bleeding associated with minor procedures or surgeries expected to be associated with very little bleeding.
  • Patients must be tested and proven to have a good response to DDAVP before the use of DDAVP in a patient who has been scheduled for surgery. If an appropriate rise in FVIII level is obtained in response to the test dose of DDAVP, then at least a week should elapse between the date of the test dose of DDAVP and surgery. This allows time for replenishment of endogenous stores of FVIII-C prior to surgery, so that an adequate DDAVP-induced rise in FVIII is again obtained perioperatively.
  • Patients with severe hemophilia are not proper candidates for this therapy because they do not have intravascular stores of FVIII available for release.
  • Hyponatremia due to water retention is a potentially serious adverse effect; a patient's oral or intravenous intake of fluids must be curtailed for approximately 12-18 hours after the administration of DDAVP, until the antidiuretic effect passes. Importantly, alert the patient to this effect, so that the patient will be aware of the distinct drop in urine volume following DDAVP administration, with an increase in urinary output when the antidiuretic effect of DDAVP wanes. (There were instances in which this author's patients who had been educated about this antidiuretic effect pointed out the lack of antidiuretic effect and the lack of the flushing that accompanies DDAVP administration, thus alerting the physician to the possible lack of DDAVP in the bag provided by the pharmacy.)
• Antifibrinolytic agents
• • Preservation of the hemostatic plug formed in the presence of adequate levels of FVIII at the time of surgical trauma (as with dental procedures or with mucosal bleeding) can be achieved by inhibiting fibrinolysis with EACA (Amicar) or tranexamic acid (AMCA, Cyklokapron) given orally or, if needed, intravenously.
  • The first dose of EACA (5 g PO/IV slowly) is administered prior to the surgical procedure, along with a dose of FVIII sufficient to raise the level, followed by a maintenance dose of EACA of 1 g/h postoperatively for several hours until it is clinically appropriate to start tapering the dose over the next several days.
  • An intriguing in vitro observation is the finding that EACA in a final concentration of 1.25-5 mg/mL (concentrations achievable with a large loading dose) inhibits FVIII inhibitor activity without affecting other immunological reactions.³⁷
  • In vivo confirmation of this phenomenon was obtained in plasma from 2 patients with inhibitors who received EACA in a dose of 100 mg/kg over 10 minutes; the lysine-binding sites did not appear to mediate this effect.³⁷
  • AMCA is given in a dose of 1.5 g intravenously every 6-8 hours and then tapered, as needed; this drug is not available in the United States.
  • These drugs can also be used as a mouthwash for oral bleeding and have been used to stop local intracavitary oozing.
  • Antifibrinolytic agents are contraindicated in patients with hematuria because of the risk of developing a firm, occluding clot in the ureters when given simultaneously with factor replacement. These drugs are not useful in the management of joint bleeding.
  • In recent years, the use of NSAIDs by individuals with hemophilia has increased, in an effort to ease the pain of chronic, disabling, and frequently crippling joint disease. Although they allow improved joint function, because of the impact of NSAIDs on primary hemostasis, their use comes at a price of increased bleeding episodes and increased incidence of GI and other bleeding, all requiring more use of concentrate. COX-2 inhibitors have been tried with caution, but they are likely to increase the bleeding risk. Alternates to NSAIDs, such as acetaminophen and codeine-type analgesics, are much less effective because they lack an anti-inflammatory effect; additionally, some of these drugs are addictive.
• Fibrin glue
• • This product is very useful for controlling bleeding at surgical sites. It consists of a mixture of fibrinogen, thrombin, and FXIII to cross-link freshly formed fibrin. Cryoprecipitate has also been used as a source of fibrinogen and FXIII, with bovine thrombin being used to start the clotting process. Some preparations also incorporate antifibrinolytic agents to inhibit clot lysis.
  • Fibrin glue has been particularly useful in orthopedic and pseudotumor-related surgical procedures and to achieve adequate hemostasis at operative sites in patients with an inhibitor to FVIII.
  • Bovine thrombin present in fibrin glue can elicit an antibody, as it has in other postoperative states.⁶⁰
• Gene therapy: Several ideal characteristics have been proposed for a DNA delivery system, including that is (1) is produced in concentrated form, (2) is targeted to specific cell types, (3) results in long-term gene expression with stable levels for years, (4) is nontoxic, and (5) is nonimmunogenic.^{61, 62} Several studies have been undertaken in humans using different approaches to introducing the FVIII gene into a patient so that higher FVIII levels can be maintained in persons with severe hemophilia; maintenance of basal levels of 3-10% significantly ameliorate bleeding in patients with severe hemophilia. The most successful and least toxic method of introducing the gene remains to be determined. Some of the problems with gene therapy are as follows:
• • Despite a high level of short-term expression of FVIII in a canine model of hemophilia A by the use of an attenuated adenoviral vector, liver toxicity, thrombocytopenia, and the development of an anticanine FVIII antibody occurred as a result of the immunologic response to the vector.
  • Another issue is a question of the appropriate in vivo vector dose, with evidence for a threshold dose requirement. Short-term correction of FVIII levels due to high gene expression in the neonatal period following injection of an adenoviral murine vector in utero has also been accomplished. An adenoviral vector encoding a human B-domain–deleted FVIII complementary DNA–corrected bleeding in hemophilic mice and dogs, suggesting that this is another viable approach. Successful production of significant amounts of FVIII by a parvovirus-based vector in immunocompetent mice in the absence of significant hepatotoxicity suggests a promising new vector for use in gene therapy.
  • An interesting approach consists of transducing human umbilical vein endothelial cells with a retroviral construct to create a store of FVIII-C and vWF in the Weibel-Palade bodies, which can then be released in a functional state. Thus, the vascular endothelium could also be an appropriate target of gene therapy.⁶³ Transgenic mice with expression of FVIII in the epidermis support the possibility of cutaneous gene therapy for a systemic bleeding disorder.
  • The development of antibodies to replaced proteins is another major disadvantage of human gene therapy. In a gene knockout mice model of hemophilia A, the immune system was shown to be capable of recognizing a species-specific transgene protein as a neoantigen and produced cytotoxic T cells despite a temporary rise in FVIII levels. An approach to preventing this problem was suggested by the success of the injection of murine CTLA4-immunoglobulin to block T-cell function, which completely blocked the primary response to FVIII in hemophilic mice.
  • Several possible approaches to gene therapy include ex vivo gene therapy, in which cells to be transplanted are modified to secrete FVIII or FIX and then reimplanted into the recipient; in vivo gene therapy, in which the vector is directly injected into the patient; and nonautologous gene therapy, in which cells modified to secrete the missing factor are packaged in immunoprotected devices and implanted into recipients. Several trials using different vectors were underway until the death of a patient treated for a metabolic disorder led to a halt in clinical trials, with reevaluation of the type of vector, dose, route, and toxicity of the different approaches to gene therapy.^{64, 65, 66, 67, 68, 69, 70, 71, 72, 62, 73}
• Management of inhibitors: See Medication.

Surgical Care

• Preoperative evaluation of the aPTT, along with a mixing test that includes prolonged incubation of a patient's plasma with normal pooled plasma to exclude an inhibitor, is very important. Most individuals with hemophilia are routinely tested when examined by a physician with expertise in this area. The patient must receive the proper dose of FVIII before and serially after surgery to achieve and maintain an adequate level of FVIII-C to permit maintenance of good hemostasis. Following bone and joint surgery, prolonged replacement for several weeks is necessary not only to allow healing at the surgical site but also to prevent bleeding during the necessary intensive postoperative physical therapy, which allows for maximum joint mobility to develop.⁷⁴
• Procedures such as endoscopies, although considered routine for unaffected people, require preprocedural product replacement in persons with hemophilia so that they do not bleed either during or following a needed biopsy. Postbiopsy replacement with FVIII must continue until the biopsy site has healed.
• Dental extractions or mucosal procedures can be handled with a single preprocedure dose of FVIII, along with Amicar. A standard approach to dental extractions has been proposed based on a case-control study, which proved the validity of the tested approach.⁷⁵ In this study, patients received a single dose of AMCA of 20 mg/kg, along with a single infusion of FVIII, to achieve a peak level of approximately 30% prior to dental extraction. No significant differences in bleeding rates occurred when compared with controls, with a cost reduction due to outpatient management. Routine practice is to continue therapy with antifibrinolytics in an outpatient setting for several days after the dental extraction, with a gradual tapering of the dosage over 5-7 days.
• The use of ancillary measures, such as fibrin glue and antifibrinolytics, is very valuable in surgical procedures in which excessive bleeding is anticipated or encountered.
• • Fibrin glue consists of a mixture of fibrinogen, thrombin, and FXIII used to cross-link the freshly formed fibrin clot. Cryoprecipitate has also been used as a source of fibrinogen and FXIII, with the use of bovine thrombin to clot fibrinogen. Some preparations also incorporate antifibrinolytic drugs to inhibit premature lysis of the fibrin clot.
  • Fibrin glue has been particularly useful in orthopedic surgery and with surgical procedures in patients with inhibitors. Bovine thrombin may elicit antibodies. Bleeding from suture holes is a complication of a variety of invasive vascular procedures (eg, surgery, radiography, coronary angiography).
  • In an experimental porcine vascular graft model, fibrin sealant containing FXIII effectively reduced blood loss and reduced the time to achieve adequate hemostasis when compared with fibrin alone or with thrombin-coated gelatin sponges.⁷⁶
  • Avoidance of NSAIDs and other known platelet-inhibiting drugs, including herbal remedies, perioperatively is essential to minimize the bleeding risk. Ice packs and pressure are always useful wherever feasible.
• Orthotopic liver transplantation for hepatic failure corrects FVIII levels in patients with hemophilia. Interestingly, FVIII-C levels in persons with mild hemophilia rise to normal levels as their chronic liver disease advances (author's observations).
• When treating patients with combined FVIII and FV deficiency, an FV level of approximately 25% is sufficient for major surgery. Maintain FVIII levels as for patients with hemophilia A. FFP in a loading dose of approximately 20 U/kg preoperatively or emergently for a bleeding episode, followed by FFP in a dose of 5-10 U/kg every 12 hours to maintain a minimal hemostatic level of FV, may be required. PLAS⁺ SD is safer than FFP and may be substituted for FFP whenever it is available (see Medication). Use antifibrinolytics and other ancillary measures as discussed in the management of patients with hemophilia A.

Consultations

Hematologist, orthopedist, physical therapist, dentist, social worker, psychologist, infectious disease specialist, gastroenterologist/hepatologist, geneticist, and an appropriately equipped special laboratory all play important roles in providing optimal care for patients and their families. The efforts of the National Hemophilia Foundation and its regional chapters must be recognized in helping with education, facilitating home care programs and summer camps, improving financial support for health care through legislation, assisting service providers, and fostering dialogue among affected individuals to exchange problems and ideas for new solutions.

Diet

A healthy, nutritional, normal diet is encouraged. Avoidance of unproven health remedies is necessary because several of these agents have now been shown to potentiate bleeding. Caution is warranted when taking any natural supplement.

Activity

Activity restrictions depend on the condition of the joints; appropriate physical activity and physical therapy must be encouraged to maintain and preserve muscle function. Studies have shown that compared with age-matched controls, children with hemophilia have poorer muscle mass and function.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Prompt and early therapy for acute bleeding episodes, with appropriate replacement with factor concentrate to achieve adequate levels of FVIII, immobilization of acutely affected joints, and adequate pain relief with narcotic analgesics is essential. A variety of intermediate and high-purity FVIII-containing products are commercially available.

Increasing product purity (high specific activity) and improved protection from viral contaminants result in increased costs because of the different methodologies used to purify FVIII obtained from pooled human plasma and because o