Betsy Bickert Poon, Char Witmer, and Jane Pruemer
KEY CONCEPTS
Hemophilia is an inherited bleeding disorder resulting from a congenital deficiency in factor VIII or IX.
The goal of therapy for hemophilia is to prevent bleeding episodes and their long-term complications and to arrest bleeding if it occurs.
Recombinant factor concentrates usually are first-line treatment of hemophilia because they have the lowest risk of infection.
Inhibitor formation is the most significant treatment complication in hemophilia. It is associated with significant morbidity and decreased quality of life.
The goal of therapy for von Willebrand disease is to increase von Willebrand factor and factor VIII levels to prevent bleeding during surgery or arrest bleeding when it occurs.
Factor VIII concentrates that contain von Willebrand factor are the agents of choice for treatment of type 3 von Willebrand disease and some type 2 von Willebrand disease, and for serious bleeding in type 1 von Willebrand disease.
Desmopressin acetate often is effective for treatment of type 1 von Willebrand disease. It also may be effective for treatment of some forms of type 2 von Willebrand disease.
The coagulation system is intricately balanced and designed to stop bleeding at the site of vascular injury through complex interactions between the vascular endothelium, platelets, procoagulant proteins, anticoagulant proteins, and fibrinolytic proteins. Hemostasis stops bleeding at the site of vascular injury through the formation of an impermeable platelet and fibrin plug. Three key mechanisms facilitate hemostasis including vascular constriction, primary platelet plug formation (primary hemostasis), and clot propagation through fibrin formation (secondary hemostasis). Derangements in this finely tuned system can lead to either bleeding or thrombosis. Bleeding disorders are the result of either a coagulation factor defect, a quantitative or qualitative platelet defect, or enhanced fibrinolytic activity. The complex system regulating hemostasis is described in the pathophysiology section of Chapter 9.
COAGULATION FACTORS
Secondary hemostasis facilitates propagation and stabilization of the initial platelet plug formed in primary hemostasis through the formation of fibrin on the activated platelet surface. This step is initiated via the tissue factor pathway and is vital for adequate hemostasis. Coagulation factors circulate as inactive precursors (zymogens). Activation of these coagulation proteins entails a cascading series of proteolytic reactions (Fig. 9–2). At each step, a clotting factor undergoes limited proteolysis and becomes an active protease (designated by a lowercase “a,” as in Xa).
The coagulation factors can be divided into three groups on the basis of biochemical properties: vitamin K-dependent factors (II, VII, IX, and X), contact activation factors (XI and XII, prekallikrein, and high-molecular-weight kininogen), and thrombin-sensitive factors (V, VIII, XIII, and fibrinogen). Biologic half-life and blood product source varies by coagulation factor (Table 81–1).
TABLE 81-1 Blood Coagulation Factors
CLINICAL MANIFESTATIONS AND DIAGNOSIS
The diagnosis of coagulation disorders can be established from a detailed clinical history, physical examination, and laboratory test results. The clinical history should ascertain if there is a family history of bleeding or known bleeding disorders. Laboratory testing can distinguish bleeding disorders caused by defects in the coagulation pathways (Fig. 9–4), fibrinolytic pathways, or alterations in the number or function of platelets. Table 81–2 describes common coagulation tests.
TABLE 81-2 Laboratory Procedures
HEMOPHILIA
Hemophilia is a bleeding disorder that results from a congenital deficiency in a plasma coagulation protein. Hemophilia A (classic hemophilia) is caused by a deficiency of factor VIII, whereas hemophilia B (Christmas disease) is caused by a deficiency of factor IX. The incidence of hemophilia is about 1 in 5,000 male births, 80% to 85% hemophilia A and 15% to 20% hemophilia B.1,2 There are no significant racial differences in the incidence of hemophilia.
About one-third of patients with hemophilia have a negative family history, presumably representing a spontaneous mutation. Both hemophilia A and hemophilia B are recessive X-linked diseases, which mean that the defective gene is located on the X chromosome. The disease primarily affects only males while females are carriers. Affected males have the abnormal allele on their X chromosome and no matching allele on their Y chromosome, their sons would be normal (assuming the mother is not a carrier) and their daughters would be obligatory carriers. Female carriers have one normal allele and therefore do not usually have a bleeding tendency. Although female carriers have lower factor VIII levels than females who are not carriers.3 Sons of a female carrier and a normal male have a 50% chance of having hemophilia and daughters have a 50% chance of being carriers. Thus, there is a “skipped generation” mode of inheritance in which the female carriers do not express the disease but can pass it on to the next male generation.
Hemophilia has been observed in a small number of females. It can occur if both factor VIII and IX genes are defective,4,5 if a female patient has only one X chromosome as in Turner syndrome, or if the normal X chromosome is excessively inactivated through a process called lyonization or highly skewed X inactivation.6–8
In 1984, researchers isolated and cloned the human factor VIII gene.9,10 It is a large gene, consisting of 186 kilobases (kb).11 More than 900 unique mutations in the factor VIII gene, including point mutations, deletions, and insertions, have been reported (http://hadb.org.uk/). Deletions and nonsense mutations are often associated with the more severe forms of factor VIII deficiency because no functional factor VIII is produced. In 1993, researchers identified an inversion in the factor VIII gene at intron 22 that accounts for about 45% of severe hemophilia A gene abnormalities.12 That discovery has greatly simplified carrier detection and prenatal diagnosis in families with this gene mutation. A more recently discovered inversion mutation involving intron 1 of the factor VIII gene accounts for an additional 5% of severe hemophilia mutations.13
The factor IX gene, cloned and sequenced in 1982, consists of only 34 kb and thus is significantly smaller than the factor VIII gene.14 Unlike the factor VIII gene in patients with severe hemophilia A, the factor IX gene in patients with hemophilia B has no predominant mutation. Direct gene mutation analysis is simpler in hemophilia B because of the smaller gene size, and to date more than 900 different mutations have been reported (http://kcl.ac.uk/ip/petergreen/haemBdatabase.html). Most of these mutations are single base-pair substitutions. About 3% of factor IX gene mutations are deletions or complex rearrangements, and the presence of these mutations is associated with a severe phenotype.11
Hemophilia B Leyden is a rare variant in which factor IX levels initially are low but rise at puberty. The mechanism underlying the pathogenesis of this disorder has been controversial. Some propose that the binding of the androgen receptor and other transcription factors are responsible.15,16 Other molecular mechanisms for age-related gene regulation has been recently discovered and implicated in factor IX Leyden.17 Identification of this genotype is clinically important because it confers a better prognosis.
Clinical Presentation
The characteristic bleeding manifestations of hemophilia include palpable ecchymoses, bleeding into joint spaces (hemarthroses), muscle hemorrhages, and excessive bleeding after surgery or trauma. The severity of clinical bleeding generally correlates with the degree of deficiency of either factor VIII or factor IX. Factor VIII and factor IX activity levels are measured in units per milliliter, with 1 unit/mL representing 100% of the factor found in 1 mL of normal plasma.18 Normal plasma levels range from 0.5 to 1.5 units/mL. Patients with less than 0.01 units/mL (1%) of either factor are classified as having severe hemophilia, those with 0.01 to 0.05 units/mL (1% to 5%) are moderate, and those with greater than 0.05 units/mL (5%) have mild hemophilia (Table 81–3).
TABLE 81-3 Laboratory and Clinical Manifestations of Hemophilia
Patients with severe disease experience frequent spontaneous hemorrhages, whereas those with moderate disease have excessive bleeding following mild trauma and rarely experience spontaneous hemarthroses. Patients with mild hemophilia may have so few symptoms that their condition can be undiagnosed for many years, and they usually have excessive bleeding only after significant trauma or surgery. Disease severity does not always correlate with disease manifestations. Those with severe disease (less than 1% factor activity) may occasionally not display a severe phenotype, while some with milder forms of the disease may have more severe bleeding. Patients with hemophilia usually present with clinical manifestations after age 1 year, when they begin to walk and increase their risk of bleeding due to falling.
CLINICAL PRESENTATION Hemophilia
Signs and Symptoms
• Ecchymoses (palpable/raised)
• Hemarthrosis (especially knee, ankle, and elbow)
• Joint pain
• Joint swelling and erythema
• Decreased range of motion
• Muscle hemorrhage
• Swelling at the site of muscle bleeding
• Pain with motion of affected muscle
• Signs of nerve compression
• Significant anemia from an iliopsoas or thigh bleed
• Oral bleeding with dental extractions or trauma
• Hematuria
• Intracranial hemorrhage (spontaneous or following trauma)
• Excessive bleeding with surgery
Laboratory Testing
• Prolonged activated partial thromboplastin time (aPTT)
• Decreased factor VIII or factor IX level
• Normal prothrombin time (PT)
• Normal platelet count
• Normal von Willebrand factor antigen and activity
• Normal bleeding time
Diagnosis
The diagnosis of hemophilia should be considered in any male with unusual bleeding. A family history of bleeding is helpful in the diagnosis but is absent in up to 50% of patients with about one-third representing spontaneous mutations and the remaining secondary to an unrecognized family history.11 Brothers of patients with hemophilia should be screened; sisters should undergo carrier testing. Laboratory testing in patients with hemophilia will reveal an isolated prolonged partial thromboplastin time (PTT) and a decreased FVIII or FIX level.
Patients with severe hemophilia A should be tested for the common factor VIII gene inversions. In patients with severe hemophilia A who lack an inversion mutation or patients with moderate or mild hemophilia A, the gene can be sequenced to determine the exact mutation.19 Techniques for determining the genetic mutation in patients with hemophilia B are similar, but no predominant mutation like the factor VIII inversion has been found. The smaller size of the factor IX gene facilitates direct DNA mutational analysis.19
Advances in molecular genetic analysis have greatly improved the accuracy of carrier status evaluation. Thus, female relatives of patients with hemophilia who are at risk of being carriers should be tested. Carrier testing is simplified if the familial mutation has already been identified. Additionally, the appropriate factor level should be measured in female carriers to identify those with levels less than 0.3 units/mL (30%) who themselves might be at risk for bleeding.
Hemophilia can be diagnosed prenatally by chorionic villus sampling in gestational weeks 11 to 14 or by amniocentesis after 15 weeks’ gestation.20 These are invasive procedures with a 0.5% to 1% chance for pregnancy loss.20A new noninvasive method uses cell-free fetal DNA that exists in maternal circulation to determine the sex of the fetus helping establish if more invasive testing is required for a male fetus.20 More recently this method was used to successfully identify hemophilia mutations in 12 subjects.21 At this time the method of using fetal DNA in maternal circulation to identify hemophilia mutations is still experimental and requires further validation.
TREATMENT
Hemophilia
Desired Outcomes
The comprehensive care of hemophilia requires a multidisciplinary approach. The patient is best managed in specialized centers with trained personnel and appropriate laboratory, radiologic, and pharmaceutical services. The healthcare team includes hematologists, orthopedic surgeons, nurses, physical therapists, dentists, genetic counselors, psychologists, pharmacists, case managers, and social workers. The goal for comprehensive hemophilia care is to preventing bleeding episodes and their long-term sequelae so that patients with hemophilia can live full, active, and productive lives.
IV factor replacement therapy for the treatment or prevention of bleeding is the mainstay of treatment for hemophilia. Parents usually learn how to infuse factor concentrate to facilitate home treatment. Older children and adult patients learn self-administration. Home healthcare nursing support may be helpful, particularly for the youngest patients in whom venous access may be difficult. In the setting of poor venous access, central line placement may be indicated. Administration of factor at home is more convenient for families and allows for earlier treatment of acute bleeding episodes. However, serious bleeding episodes always require medical evaluation.
Patients with hemophilia should receive routine immunizations, including immunization against hepatitis B. Hepatitis A vaccine is also recommended for patients with hemophilia because of the risk (albeit small) of transmitting the causative agent through factor concentrates.22 Use of a small-gauge needle can prevent excessive bleeding. Many healthcare providers advocate subcutaneous rather than intramuscular immunizations to decrease the risk of intramuscular bleeding or hematoma formation, but there is a lack of evidence to support this route of administration.
A few special considerations apply to the perinatal care of male infants of hemophilia carriers. Intracranial or extracranial hemorrhage has been estimated to occur in 1% to 4% of newborns with hemophilia.23Vacuum extraction and forceps delivery increase the risk of cranial bleeding. Elective cesarean section has not been shown to prevent intracranial bleeding. There is no clear consensus on the optimal mode of delivery or the use of prophylactic factor replacement in male infants of hemophilia carriers.23 Circumcision should be postponed until a diagnosis of hemophilia is excluded. Factor levels can be assayed from cord blood samples or from peripheral venipuncture. Arterial puncture should be avoided because of the risk of hematoma formation. If an infant has hemophilia, many clinicians recommend a screening head ultrasound to rule out an intracranial hemorrhage prior to discharge from the nursery.
History of Hemophilia Treatment
Therapy for hemophilia has undergone dramatic advances over the past few decades. Fifty years ago, administration of fresh-frozen plasma was the only available treatment. The introduction of cryoprecipitate in the early 1960s allowed more specific therapy for hemophilia A.24 Intermediate-purity factor VIII and IX plasma-derived concentrates became available in the 1970s.24 Plasma-derived factor concentrates are made from the donations of thousands of people. Contamination of plasma pools with hepatitis B, hepatitis C, and the human immunodeficiency virus (HIV) during the late 1970s and early 1980s resulted in transmission to a large portion of patients with hemophilia. Since the mid-1980s, plasma-derived concentrates have been manufactured with a variety of virus-inactivating techniques, including dry heat, pasteurization, and treatment with chemicals (e.g., solvent detergent mixtures).11 Since 1986, no transmission of HIV through factor concentrates to patients with hemophilia in the United States has been reported.11 Protein purification techniques, introduced in the 1990s, led to the production of high-purity plasma-derived concentrates with increased amounts of factor VIII or factor IX relative to the product’s total protein content. Recombinant factor VIII and then factor IX also became available in the 1990s.24 Significant improvements have also been made with recombinant products in limiting the risk of infectious transmission from albumin used to stabilize some of the products. Like plasma-derived products, these products use viral inactivation steps. With each subsequent generation of recombinant factor VIII products, the use of human proteins has been reduced.24
More recently, there has been significant progress in the development of long-acting factor VIII or IX products. Different methods have been utilized to prolong the half-life of either factor VIII or IX including pegylation, polysialic acid, albumin infusion, and Fc infusion.25 Clinical trials for factor VIII and FIX products that utilize either pegylation or fusion to an Fc receptor are ongoing.25
Hemophilia A
Table 81–4 summarizes the factor VIII products currently available in the United States. Most patients are treated with high-purity products. Products with the lowest risk of transmitting infectious disease should generally be used. Thus, recombinant products, when available, are generally used rather than plasma-derived products.
TABLE 81-4 Factor Concentrates
Recombinant Factor VIII
Recombinant factor VIII is produced with recombinant DNA technology and is derived from cultured Chinese hamster ovary cells or baby hamster kidney cells transfected with the human factor VIII gene.11 Because it is not derived from blood donations, the risk of transmitting infections through administration of recombinant factor VIII is low and recombinant products are generally favored over plasma-derived products. A small risk of viral infection of the cell lines used to produce the clotting factor remains.26 Furthermore, human and/or animal proteins are utilized in the production process of some recombinant products.24 Therefore, these products have a theoretical risk of transmitting infection, although hepatitis and HIV infection have never been reported with their use.11 The presence of parvovirus B19 DNA has been reported in recombinant factor VIII products.27 First-generation recombinant factor VIII products contain human albumin as a stabilizing protein.11 Second-generation recombinant factor VIII products add sugar instead of human albumin as a stabilizer, but human albumin is utilized in the culture process. One second-generation product (ReFacto®) has deletion of the B domain of the factor VIII gene, yielding a smaller protein product.11 This B domain does not appear to be necessary for coagulation function. Third-generation recombinant factor VIII products contain no human protein either in the culture or in the stabilization processes.24
Clinical trials have demonstrated that recombinant factor VIII products are comparable in effectiveness to plasma-derived products.11 The risk of patients with severe hemophilia A developing an inhibitory antibody to factor VIII with use of recombinant factor VIII is 25% to 32%.28 The risk of inhibitor formation has been reported to be higher in recombinant products as compared with plasma-derived products. In studies of previously untreated patients, the cumulative incidence of inhibitor formation was 10.3% for plasma-derived versus 28.7% for recombinant products.29 However, it is difficult to compare the cumulative incidence from different studies because of differences in patient population (e.g., heterogeneity in risk factors for inhibitor formation), study methodology, frequency of inhibitor testing, and length of follow-up.29 Two recent systematic reviews attempted to control for the heterogeneity in studies and were unable to demonstrate a difference in the risk of inhibitor formation.30,31 In the review by Iorio et al., most of the apparent difference in risk of inhibitor formation was explained by differences in study design, study period, testing frequency, and median follow-up. The source of factor concentrate (recombinant vs. plasma-derived) was not statistically significant.31 To address this very important clinical question, a prospective international randomized clinical trial (SIPPET—Survey of Inhibitors in Plasma Product Exposed Toddlers) is currently enrolling patients and is comparing inhibitor incidence in previously untreated patients exposed to either plasma or recombinant factor products.32
Plasma-Derived Factor VIII Products
Several different plasma-derived factor VIII products are available (Table 81–4). These products are derived from the pooled plasma of thousands of donors and therefore potentially can transmit infection. Donor screening, testing plasma pools for evidence of infection, viral reduction through purification steps, and viral inactivation procedures (e.g., dry heat, pasteurization, and solvent detergent treatment) have resulted in a safer product. No cases of HIV transmission from factor concentrates have been reported since 1986.11 However, isolated cases of hepatitis C infection with use of plasma-derived products have been reported.11 Additionally, outbreaks of hepatitis A viral infections associated with plasma-derived products, likely because solvent detergent treatment does not inactivate this nonenveloped virus, have been reported. Parvovirus has been reported to be present in both plasma-derived and recombinant factor VIII products.26,27 Finally, possible infection with as yet unidentified viruses that currently used methods would not inactivate remains a concern. In addition, Prion disease may be present in plasma-derived factor VIII products.26,33
Factor VIII concentrates can be classified according to their level of purity, which refers to the specific activity of factor VIII in the product. Cryoprecipitate is a low-purity product. Cryoprecipitate also contains von Willebrand factor, fibrinogen, and factor XIII. Current American Association of Blood Banks standards call for a minimum of 80 international units of factor VIII per cryoprecipitate pack.11 This product is no longer considered a primary treatment of factor VIII deficiency in countries where factor VIII concentrates are available because cryoprecipitate does not undergo a viral inactivation process. Intermediate-purity products have a specific factor VIII activity of 5 units/mg of protein and high-purity products have up to 2,000 units/mg of protein.11 Ultrahigh-purity plasma-derived products are prepared with monoclonal antibody purification steps and have a specific activity of 3,000 units/mg of protein prior to addition of albumin as a stabilizer.
Factor VIII Concentrate Replacement
Appropriate dosing of factor VIII concentrate depends on the half-life of the infused factor, the patient’s body weight, and the volume of distribution. The presence or absence of an inhibitory antibody to factor VIII and the titer of this antibody also influence treatment. Recovery studies, which measure the immediate postinfusion factor level, and survival studies, which assess the half-life of the factor, can establish patient-specific pharmacokinetics. The location and magnitude of the bleeding episode determine the percent correction to target as well as the duration of treatment. Serious or life-threatening bleeding requires peak factor levels of greater than 0.75 to 1 units/mL (75% to 100%); less severe bleeding may be treated with a goal of 0.3 to 0.5 units/mL (30% to 50%) peak plasma levels. Table 81–5provides general guidelines for the management of bleeding in different locations.
TABLE 81-5 Guidelines for Factor Replacement Therapy for Hemorrhage in Hemophilia A and B
Factor VIII is a large molecule that remains in the intravascular space. Therefore, the plasma volume (about 50 mL/kg) can be used to estimate the volume of distribution. In general, each unit of factor VIII concentrate infused per kilogram of actual body weight yields a 2% rise in plasma factor VIII levels. The following equation can be used to calculate an initial dose of factor VIII:
Factor VIII (units) = (Desired level – Baseline level) × 0.5 × (Weight [in kilograms])
The baseline level usually is omitted from the equation when it is negligible compared to the desired level. The half-life of factor VIII ranges from 8 to 15 hours. It is generally necessary to administer 50% of the initial dose about every 12 hours to sustain the desired level of factor VIII. A single treatment may be adequate for minor bleeding, such as oral bleeding or slight muscle hemorrhages. However, because of the potential for long-term joint damage with hemarthroses, 2 or 3 days of treatment is often recommended for these bleeds. Serious bleeding episodes may require maintenance of 70% to 100% factor activity for 1 week or longer. As previously mentioned, factor VIII dosing depends on several variables, and each case must be considered individually. Individual pharmacokinetics may help guide treatment, particularly for serious bleeding episodes.
Alternatively, factor VIII can be administered as a continuous infusion when prolonged treatment is required (e.g., in the perioperative period or for serious bleeding episodes). Infusion rates ranging from 2 to 4 units/kg per hour usually are given in fixed-dose continuous infusion protocols, with the aim of maintaining a steady-state level of 60% to 100%.34,35 Administration of factor concentrate via continuous infusion may reduce factor requirements by 20% to 50% because unnecessarily high peaks of factor VIII that occur with bolus injections are avoided.35 A gradual decrease in factor VIII clearance during the first 5 to 6 days of treatment contributes to the lower factor concentrate requirements.35 Daily monitoring of factor level can help determine the appropriate rate of infusion.
Administration of factor VIII concentrate via continuous infusion has been shown to be safe and effective, and it may be more convenient than bolus therapy for hospitalized patients.34,35 The advantages of continuous infusion include maintenance of a steady-state plasma level with avoidance of potentially subtherapeutic trough levels and reduced cost associated with decreased factor requirements. A potential side effect with continuous infusion is thrombophlebitis at the delivery site. Concomitant infusion of saline or the addition of heparin (2 to 5 units/mL) to the infusion bag can minimize this risk.35 Bacterial contamination of the concentrate is another theoretical concern and preparation of the infusion bag should occur under sterile conditions (i.e., under laminar flow).35 Finally, concerns about the stability of the formulations appear to be unwarranted, as most high-purity factor VIII concentrates have been shown to remain stable for at least 7 days after reconstitution.35 Exposure of factor VIII to light for 10 hours after reconstitution can decrease activity by 30%.35 Therefore, it would be prudent to shield the container with foil wrap or an appropriate bag.
Other Pharmacologic Therapy
Treatment with desmopressin acetate often is adequate for minor bleeding episodes in patients with mild hemophilia A. A synthetic analog of the antidiuretic hormone vasopressin, desmopressin, causes release of von Willebrand factor and factor VIII from endogenous endothelial storage sites. It appears to be most effective in patients with higher baseline factor VIII levels (0.1 to 0.15 units/mL).36 The recommended dose of desmopressin is 0.3 mcg/kg diluted in 50 mL of normal saline and infused IV over 15 to 30 minutes.36 Patients with mild or moderate hemophilia A should undergo a desmopressin trial to determine their response to this medication. At least a twofold rise in factor VIII to a minimal level of 0.3 units/mL within 60 minutes is considered an adequate response.37 In adults with mild hemophilia A, the response rate to desmopressin has been reported to be 80% to 90%.37 Pediatric studies have reported a lower rate of response ranging from 40% to 47%.37 Furthermore, the pediatric response rate was related to age; some nonresponding children became responders at an older age.37
Infusion of desmopressin can be repeated daily for up to 2 to 3 days. Tachyphylaxis, an attenuated response with repeated dosing, may develop after that time. The factor increase after the second dose of desmopressin is about 30% lower than after the initial dose.36 Factor concentrate therapy may be necessary if the patient requires additional treatment. Factor levels should be measured to ensure that an adequate response has been achieved. Treatment with desmopressin will not result in hemostasis in patients who have severe hemophilia and those who are only marginally responsive. Desmopressin should not be used as primary therapy for life-threatening bleeding episodes such as intracranial hemorrhage or for major surgical procedures when a minimum and sustained factor VIII concentration of 0.7 to 1 units/mL is required.
Desmopressin can be administered intranasally via a concentrated nasal spray.36 It elicits a slower and less marked response, with a peak effect in 60 to 90 minutes after administration, which is somewhat longer than with IV administration.36,37 The dosage is one spray (150 mcg) for patients who weigh less than 50 kg and two sprays (300 mcg) for those who weigh more than 50 kg.37 The nasal spray may serve as an alternative to the IV formulation, especially in patients with mild bleeding episodes.
Few adverse effects are associated with desmopressin. The most commonly observed side effect is facial flushing.36 Less frequently reported side effects include mild headaches, increased heart rate, and decreased blood pressure. Thrombosis is a rare complication associated with desmopressin.37 Because of its antidiuretic effects, desmopressin has the potential to cause water retention, which may lead to severe hyponatremia. This may be a particular problem in children younger than 2 years, in whom hyponatremic seizures have been reported.36 Therefore, desmopressin should be used with caution in this age group.37 Patients with congestive heart failure may be at increased risk for developing hyponatremia with use of desmopressin.37 Fluid restriction for 24 hours after the desmopressin dose and monitoring of urine output are recommended with desmopressin administration.37
Antifibrinolytic therapy inhibits clot lysis and therefore is a useful adjunctive therapy for the treatment of hemophilia. Antifibrinolytic agents are particularly beneficial for treatment of oral bleeding because of a high concentration of fibrinolytic enzymes in saliva. Antifibrinolytic therapy can also be helpful as adjuvant therapy in GI bleeding, epistaxis, or menorrhagia. The two currently available antifibrinolytics include aminocaproic acid and tranexamic acid. Aminocaproic acid is given at a dosage of 100 mg/kg (maximum 6 g) every 6 hours and can be administered orally or IV.11 The dosage of tranexamic acid is 25 mg/kg (maximum 1.5 g) orally every 6 to 8 hours.11
Hemophilia B
Therapeutic options for hemophilia B have improved greatly over the past several years, first with the development of monoclonal antibody-purified plasma-derived products and then with the licensure of recombinant factor IX. Products currently available in the United States for treatment of hemophilia B are listed in Table 81–4.
Recombinant Factor IX
Recombinant factor IX was not available until 1998, which is 6 years after the first recombinant factor VIII product.38 Recombinant factor IX is produced in Chinese hamster ovary cells transfected with the factor IX gene. Blood and plasma products are not used to produce recombinant factor IX or to stabilize the final product; thus, recombinant factor IX has an excellent viral safety profile.11,38 Clinical trials have shown the product to be safe and efficacious in the treatment of acute bleeding episodes and in the management of bleeding associated with surgical procedures.11,38 Although the half-life of recombinant factor IX is similar to that of the plasma-derived products, recovery is about 30% lower.38 As a result, doses of recombinant factor IX concentrate must be higher than those of plasma-derived products to achieve equivalent plasma levels. Because individual pharmacokinetics may vary, recovery and survival studies should be performed to determine optimal treatment.11 Recombinant factor IX is considered the treatment of choice for hemophilia B.
Plasma-Derived Factor IX Products
High-purity factor IX plasma concentrates have been available in the United States since the early 1990s.11,38 These products are derived from plasma through biochemical purification and monoclonal immunoaffinity techniques. Other viral inactivation measures, such as solvent detergent or chemical treatment, are also used.
Before the high-purity products were approved for use, hemophilia B patients were treated with factor IX concentrates that also contained other vitamin K-dependent proteins (factors II, VII, and X), known as prothrombin complex concentrates (PCCs). These products contain small amounts of activated factors generated during processing, and their use has been associated with thrombotic complications, including deep-vein thrombosis, pulmonary embolism, myocardial infarction, and disseminated intravascular coagulation.11,38 The risk of such complications is highest in patients who are receiving high or repeated doses of PCCs, in those who have hepatic disease (the liver removes the activated factors from circulation), in neonates, and in patients who have experienced crush injuries or who are undergoing major surgery.11,38 Concomitant use of PCCs and antifibrinolytics should be avoided because of the risk for thrombosis.
Because of the lower purity of PCCs and their thrombogenic potential, these products are not first-line treatment of hemophilia B, although they are still used for treatment of patients with hemophilia A or B who have developed inhibitory antibodies against factor VIII or factor IX, respectively. High-purity factor IX concentrates have excellent efficacy in the treatment of bleeding episodes and in the control of bleeding associated with surgical procedures.38Their viral safety profile has been reported to be excellent, and the risk of thromboembolic complications is low.38
Factor IX Concentrate Replacement
Factor IX is a relatively small protein. Unlike factor VIII, it is not limited to the intravascular space; it also passes into the extravascular compartment.38 This results in a volume of distribution that is about twice that of factor VIII. For plasma-derived factor IX concentrates, each unit of factor IX infused per kilogram of actual body weight yields about a 1% rise in the plasma level of factor IX (range, 0.67% to 1.28%).11 The following equation can be used to calculate the initial dose:
As with the factor VIII dose calculation, the baseline level term can be omitted from the formula if it is negligible compared to the desired level. Because recovery of recombinant factor IX is lower than that of the plasma-derived products, the following adjustment is made:
Pediatric dosing:
Adult dosing:
A recovery study to determine optimal dosing is recommended for patients who receive recombinant factor IX because of the wide interpatient variability in pharmacokinetics.
Because the half-life of factor IX is about 24 hours, dosing can be less frequent than with factor VIII. Table 81–5 provides general guidelines for dosing factor IX based on the site and severity of the bleeding episode.
Prophylactic Replacement Therapy
Traditionally, factor concentrates for hemophilia patients have been given on demand, as the bleeding episode occurs. However, recurrent joint bleeding can damage the joint and lead to the development of severe physical disability. Thus, it would be preferable to prevent bleeding episodes and avoid the resultant damage. Known as prophylactic factor replacement therapy, this approach consists of regular infusion of concentrate to maintain the deficient factor at a minimum of 0.01 units/mL (1%). In developed countries, prophylaxis for patients with severe hemophilia is considered standard of care. Patients with moderate hemophilia may sometimes require prophylaxis and it is rarely used in patients with mild hemophilia.
In effect, prophylactic replacement therapy converts severe hemophilia into a milder form of the disease. The rationale for this approach is that patients with moderate hemophilia rarely experience spontaneous hemarthroses, and they have a much lower incidence of chronic arthropathy. Two recent pediatric clinical trials have demonstrated the efficacy of prophylaxis in pediatric patients.39,40 The first pediatric randomized clinical trial comparing prophylaxis to enhanced episodic treatment to prevent joint disease in boys (age <30 months) with severe hemophilia demonstrated that prophylaxis prevented joint damage and decreased the frequency of joint and other hemorrhages.41 More recently, a European randomized clinical trial of prophylaxis in pediatric patients with hemophilia A confirmed the efficacy of prophylaxis in preventing bleeds and arthropathy.39 The efficacy of prophylaxis in adult patients with hemophilia is unclear and is the focus of ongoing clinical trials.
At this time, no consensus exists regarding the timing for the initiation of prophylaxis or the dosing schedule.25 A common regimen for patients with hemophilia A is 25 to 40 units/kg of factor VIII given every other day or three times per week. For hemophilia B, the usual dosage is 30 to 40 units/kg of factor IX given twice weekly because of the longer half-life of factor IX.38
Controversy exists regarding the ideal timing for the initiation of prophylaxis. Primary prophylaxis is regular replacement therapy started at a young age (usually before age 2 years), prior to the onset of joint bleeding.41Secondary prophylaxis begins after significant joint bleeding has already occurred.41 In 2001, the Medical and Scientific Advisory Council of the National Hemophilia Foundation of the United States recommended primary prophylaxis beginning at age 1 to 2 years for children with severe hemophilia. The use of primary prophylaxis has many challenges and has not been widely accepted in the United States. Many institutions continue to use some form of secondary prophylaxis, in which prophylaxis is started after a pattern of bleeding has been established.
Several disadvantages are associated with primary prophylaxis. Perhaps most important is the high cost of prophylactic replacement therapy. Other issues to consider are the inconvenience to families and possible difficulties with compliance. Central venous lines may be necessary for frequent administration of factor concentrates, particularly in children younger than 2 years, who are at the age targeted for initiation of primary prophylaxis regimens. Potential complications of central venous access include surgical risks, infection, and catheter-related deep-vein thrombosis. Catheter-related infections are common in patients with hemophilia and have been reported to occur in up to 0.2 to 2/1,000 catheter days.42 Catheter-related infections appear to be even more common in hemophilia patients who have developed inhibitory antibodies.42 Finally, routine use of primary prophylaxis may initially overtreat some patients with severe hemophilia who do not have a severe clinical phenotype.
Clinical Controversy…
Hemophilia patients may receive prophylactic factor concentrate therapy to prevent or decrease bleeding episodes, or they may receive on-demand factor concentrate therapy in response to a bleeding episode. In addition, prophylaxis may be primary or secondary. Controversy exists over the benefits of prophylaxis in adult patients with hemophilia, appropriate time to initiate prophylaxis in children, and appropriate dosing for prophylaxis.
Treatment of Inhibitors in Hemophilia
Neutralizing antibodies to factor VIII and IX, known as inhibitors, develop in a subset of patients with hemophilia. 
The development of an inhibitor is the most serious complication of factor replacement therapy and is associated with considerable morbidity and a decreased quality of life. The incidence of new factor VIII inhibitors in patients with severe factor VIII deficiency is about 30%.43 Inhibitors are less common in patients with mild or moderate hemophilia occurring in about 3% to 13% of patients.44–46 The occurrence of inhibitors in patients with hemophilia B is much lower, occurring in only 1% to 3% of patients.11
Most inhibitors develop in childhood, after relatively few exposure days (median 10 to 15 days).47 Patients with severe hemophilia are much more likely to develop inhibitors than those with milder forms of the disease.47 It is possible that the low levels of factor produced in patients with mild or moderate hemophilia induce immune tolerance in these individuals. In contrast, factor levels are undetectable in patients with severe hemophilia, so infused factor VIII is regarded as a foreign protein, which may provoke an antibody response. The rate of inhibitor formation varies even among patients with identical mutations, which suggests that host factors modify the risk. The development of an inhibitor is the result of a complex interaction between a patient’s immune system and genetic and environmental risk factors.
An inhibitor is a polyclonal high-affinity immunoglobulin G (IgG), directed against the factor VIII or IX protein.48,49 Inhibitors interfere with infused factor concentrate rendering them ineffective. The presence of an inhibitor is suspected when a decreased clinical response to factor replacement is observed, or it may be discovered incidentally on routine laboratory screening. Inhibitors are measured with the Bethesda assay, and titers are reported in Bethesda units (BUs). One BU is the amount of inhibitor needed to inactivate half of the factor VIII or factor IX in a mixture of inhibitor-containing plasma and pooled normal plasma.11 Patients with inhibitors to factor VIII or factor IX are divided into two groups: low responders, who have low levels of inhibitors (<5 BU/mL) and generally have little or no rise in antibody titers after exposure to the factor; and high responders (>5 BU/mL), who have higher inhibitor levels and develop an increase in antibody titer after exposure (anamnestic response).50
Therapy for patients with inhibitors involves treatment of acute bleeding episodes and treatment directed at eradicating the inhibitor. The inhibitor titer, the site and magnitude of bleeding, and the patient’s past response to bypassing therapy determine the approach to the treatment of acute bleeding. For patients with a low inhibitor titer, administration of high doses of the specific factor often can control bleeding episodes. Two to three times the usual replacement dose and more frequent dosing intervals are often necessary to overcome the antibody. Factor-level monitoring and clinical assessments help to evaluate the adequacy of treatment. Additional supportive measures, such as immobilization and administration of antifibrinolytic agents, should be used, where appropriate.
In the presence of a high-titer inhibitor, it is impossible to administer enough factor VIII or factor IX to neutralize the antibody and achieve a hemostatic plasma level. Therefore, the treatment of bleeding episodes consists of using agents that bypass the factor to which the antibody is directed. These bypassing agents include prothrombin complex concentrates (PCCs), activated prothrombin complex concentrates (aPCCs), and recombinant factor VIIa.
PCCs contain the vitamin K-dependent factors II, VII, IX, and X. Small quantities of activated factors are present in these products. Activated aPCCs contain greater quantities of the activated factors primarily factor X and prothrombin.51 The recommended dosage for aPCCs is 50 to 100 units/kg administered every 8 to 12 hours, depending on the severity of the bleeding episode and the maximum dose should not exceed 200 units/kg/day.51 Activated PCCs appear to be more effective than PCCs and are preferred in patients with inhibitors. As previously mentioned, there is a risk of serious thrombotic complications, including pulmonary emboli, deep-vein thrombosis, and myocardial infarction associated with use of PCCs and aPCCs.51 Additionally, because these products contain trace amounts of factor VIII and larger amounts of factor IX, they can stimulate an anamnestic response in patients with hemophilia A and, more commonly, in those with hemophilia B.51 Other minor side effects include dizziness, nausea, hives, flushing, and headaches. Patients with factor IX inhibitors occasionally develop severe allergic reactions in response to infusion of factor IX-containing products, so these patients should be monitored closely.38
Recombinant factor VIIa, a bypassing agent, is thought to be hemostatically active only at the site of tissue injury where the tissue factor is present.52 Recombinant factor VIIa is not a plasma-derived product, so both viral transmission and anamnestic responses to factor VIII or factor IX are unlikely.51 The initial recommended dose for bleeding episodes is 90 mcg/kg.51 However, depending on a patient’s response to recombinant factor VIIa, higher doses up to 300 mcg/kg are used. A drawback is the product’s short half-life, which necessitates dosing every 2 hours. Continuous infusion of recombinant factor VIIa, which may be more convenient and cost-effective, has been reported, although studies are limited. Patients treated with bypassing agents must be monitored clinically because no laboratory test directly measures the effectiveness of treatment.
Both recombinant factor VIIa and aPCCs have been demonstrated to be effective in the treatment of bleeding for patients with inhibitors.53–58 A randomized crossover trial of recombinant factor VIIa versus an aPCC (FEIBA) assessed patient-reported efficacy 6 hours after treatment and did not demonstrate statistical equivalence between the two products.59 However, the confidence interval of the difference only slightly exceeded the 15% boundary (–11.4% to 15.7%, P = 0.59).59 The efficacy between products was rated quite differently by many of the subjects, which shows significant variability in their individual hemostatic response to bypassing agents.
In determining which bypassing product to use in an individual patient, the clinician must consider multiple factors. In a patient with a newly diagnosed inhibitor where the inhibitor titer needs to fall before initiating immune tolerance induction (ITI), it is prudent to use recombinant factor VIIa because aPCCs contain a small amount of factor VIII or IX and have been shown to increase the inhibitor titer. It is also important to consider an individual’s response to specific bypassing agents because of the significant variability in response between individuals. In some patients, bleeding can be unresponsive to monotherapy and may require alternating products.60 Due to the risk of developing thrombosis or disseminated intravascular coagulation from alternating bypassing agents, this therapy should be used with caution and only in an inpatient setting.61
In the past, porcine factor VIII was an alternative therapeutic option for patients who have hemophilia A and inhibitors. Porcine factor VIII is not currently available, although a recombinant version is in development.62 It was removed from the market secondary to contamination with porcine parvovirus.51 The rationale is that porcine factor VIII is enough like human factor VIII to participate in the coagulation cascade, yet most factor VIII inhibitors have absent or only weak neutralizing activity against nonhuman factor VIII. However cross-reactivity with porcine factor VIII does occur, and a high titer of antibody against porcine factor VIII can develop.
The current hemostatic therapies for patients with an inhibitor have limited effectiveness leading to significant morbidity and a decreased quality of life. The ideal therapy for patients with an inhibitor is total eradication so that optimal hemostatic treatment with either factor VIII or IX is possible. At this time, the only proven method for inhibitor eradication is ITI, which involves the regular infusion of high doses of the factor to induce antigen-specific tolerance.
The majority of ITI data are from patients with hemophilia A. Multiple immune tolerance registries were established to help determine patient- and treatment-related factors associated with immune tolerance outcome.63–67Across these registries, a patient’s peak historical FVIII inhibitor titer (<200 BU) and the inhibitor titer at the time of ITI induction (<10 BU) were associated with successful immune tolerance. The overall ITI success rate from these registries ranged from 51% to 79%.63–67 This wide range is likely related to a lack of standardization in study methodologies, treatment protocols, and eradication definitions.
There are conflicting data regarding the ITI factor VIII dose and success of ITI. A variety of different dosing regimens, ranging from 25 units/kg every other day to more than 200 units/kg every day, have been used. The International Immune Tolerance Registry demonstrated improved ITI success with high doses (200 IU/kg), while the North American and Spanish Immune Tolerance Registries demonstrated improved success with lower dosing strategies.64,65,67 The International Immune Tolerance Study is a multicenter randomized clinical trial that compared high-dose (200 units/kg/day) to low-dose (50 units/kg three times/week) regimens in patients with severe hemophilia A and high titer inhibitors (>5 BU).68 This study was stopped early due an increased risk of bleeding events in the low-dose arm. At the stopping point, the proportion of ITI success was not significantly different between the two arms, but the time to achieve ITI success was shorter in the high-dose arm. Because the study was stopped early, it lacked statistical power to demonstrate therapeutic equivalence below the 30% boundary of equivalence. It appears that a high-dose strategy achieves tolerance at a faster rate, which explains the lower bleeding rate.
Although not commonly used in ITI protocols, immune modulation has been reported as a method to improve tolerance success. In Sweden, the Malmo protocol uses a combination of immunoabsorption (to acutely decrease the factor VIII inhibitor titer), cyclophosphamide, IV immunoglobulin, and daily high dose factor VIII.69 The benefit appears to be decreased time to tolerance, but the overall success rate is comparable to other ITI protocols without the risks associated with immune modulation.70 Rituximab, an anti-CD20 monoclonal antibody that inhibits B-cells and interferes with IgG production, has been used with some success. A phase II single-arm clinical trial used rituximab as a single agent in patients with high titer inhibitors. Only 3 out of 16 subjects (18.8%) had a major response (decline in the inhibitor to <5 BU without an increase in the inhibitor titer after re-challenge to factor VIII).71 It appears that as a single agent in previously treated patients with inhibitors, rituximab had a small effect but further studies are needed to determine if rituximab could be more effective if used with ITI.
Figure 81–1 summarizes the therapeutic options in the management of hemophilia A patients with inhibitors. The same algorithm can be applied to the management of hemophilia B patients, except that factor IX should be substituted for factor VIII.
FIGURE 81-1 Treatment algorithm for the management of patients with hemophilia A and factor VIII antibodies. (aPCC, activated prothrombin complex concentrate; BU, Bethesda unit; PCC, prothrombin complex concentrate.)
Gene Therapy in Hemophilia
Hemophilia is an excellent candidate for gene therapy because tight control of gene expression is not required. Even low levels of factor expression can reduce bleeding episodes in patients with severe hemophilia, which is similar to the rationale of prophylactic factor replacement. Gene therapy for the treatment of hemophilia remains in the early clinical stages. Advances at this time are most apparent in hemophilia B. Recently, a landmark clinical trial reporting the results of a single peripheral venous infusion of an adenovirus associated factor IX transgene vector under the control of a liver-restricted promoter in six patients with severe hemophilia B was published.72 All of the study subjects demonstrated long-term (over 2 years) expression of the factor IX transgene with therapeutic levels of factor IX (plateau factor IX levels from 1% to 6%).72,73 At this time, gene therapy for factor VIII deficiency has not progressed to human clinical trials. Potential benefits to gene therapy include patient convenience, viral safety, and decreased cost. Possible drawbacks to gene therapy include a risk of inhibitor formation, tumorigenesis related to possible integration of the viral vector, possible germ-line transmission of the viral vector, and concerns about long-term gene expression.
Pain Management in Hemophilia
Pain, both acute and chronic, can be a common occurrence in patients with hemophilia. The most likely cause of acute pain is bleeding, and treatment should include factor replacement to stop the bleeding, and RICE (Rest, Ice, Compression, Elevation).74 Acetaminophen can be used for mild pain, although narcotic analgesia may be required for more severe pain. Nonsteroidal antiinflammatory drugs impair platelet function and may increase bleeding and should not be used during acute bleeding episodes. Cyclooxygenase-2 inhibitors have less antiplatelet activity and are an option for acute pain management.74
Chronic pain in patients with hemophilia is typically secondary to hemophilic arthropathy. Hemophilic arthropathy is the direct result of recurrent hemarthrosis. Persistent blood in the joint leads to inflammation, synovial hypertrophy and inflammation, cartilage destruction, and finally bony erosion.75 Cyclooxygenase-2 inhibitors can also be helpful in managing chronic pain. Surgical interventions may help to alleviate chronic pain. Synovectomy (removal of the hypertrophied synovium) can reduce chronic pain from recurrent bleeding. Patients with more advanced joint disease could benefit from joint replacement.
Surgery in Hemophilia
In the patient with hemophilia undergoing a surgical procedure, the goal of treatment is maintaining factor levels of at least 0.5 to 0.7 units/mL (50% to 70%) during surgery and in the postoperative period in order to prevent excessive bleeding. Intermittent dosing or continuous infusion factor replacement may accomplish this goal. Before surgery, factor concentrate usually is infused to obtain a plasma level of 1 unit/mL (100%). Replacement therapy is continued to maintain plasma levels greater than 0.5 units/mL (50%) for 5 to 7 days or longer, depending on the type of surgery. Preoperative evaluation for elective procedures should include measurement of an inhibitor titer and assessment of the recovery and half-life of infused factor in the patient.
Personalized Pharmacotherapy
The newest approach in hemophilia treatment is “personalized” prophylaxis.76 Traditionally, standard prophylaxis is prescribed based on a weight-based calculation to increase a patient’s trough factor level to greater than 0.01 units/mL (1%). While this approach is successful for many patients, some may still experience breakthrough bleeding. Demonstrating that a single prophylactic regimen is unlikely to be optimal for all patients and that prophylactic dosing and timing may need to be altered to optimally prevent bleeding. Many factors can contribute to breakthrough bleeding including the patient’s activity level, individual pharmacokinetics, the presence of a target joint, synovial hypertrophy, and the degree of hemophilic arthropathy present.76 The prophylaxis regimen should take into account these factors and be adjusted accordingly.
With inhibitor formation as the most significant treatment complication in hemophilia, targeted pharmacotherapy is being evaluated to decrease a patient’s risk of inhibitor formation. For example, researchers are working to identify immunodominant epitopes in FVIII that could lead to the creation of new therapeutic FVIII products for high-risk individuals.77
Evaluation of Therapeutic Outcomes
The main goal in the treatment of hemophilia is to control and prevent bleeding episodes and their long-term sequelae, such as chronic arthropathies. Pharmacologic and nonpharmacologic interventions should be aimed at achieving this goal. Treatment response can be monitored through clinical parameters, such as cessation of bleeding and resolution of symptoms. Monitoring plasma factor levels also may be helpful, particularly for severe bleeding episodes. Home therapy for administration of factor concentrates is common among patients with hemophilia because this approach can lead to earlier treatment and more independence for the patient. Diaries in which the patient documents symptoms, the dose of factor replacement, adjuvant therapies used, and treatment response can help the caregiver evaluate the success of home therapy. Monitoring the number and type of bleeding episodes and trough plasma factor levels makes it possible to evaluate the adequacy of prophylactic regimens. Physical examination with evaluation of joint range of motion and radiographic imaging of target joints indicates the long-term success of preventing and treating arthropathies.
Clinicians should check for the development of inhibitors, especially in patients with severe disease and exposure to factor concentrates, at least yearly and with any suspicion of poor treatment response. The development of inhibitors challenges the management and control of bleeding episodes. A full understanding of the clinical situation and the titer of the inhibitor are mandatory to address all treatment options for each patient. Because no laboratory test measures the effectiveness of bypassing therapy in patients with inhibitors, close clinical monitoring for worsening or resolution of symptoms is essential for optimizing the outcome.
VON WILLEBRAND DISEASE
The most common congenital bleeding disorder in the United States and in the world, von Willebrand disease, has a prevalence of 1% to 2%.78,79 von Willebrand disease refers to a family of disorders caused by a quantitative and/or qualitative defect of von Willebrand factor, a glycoprotein that plays a role in both platelet aggregation and coagulation (Table 81–6). von Willebrand factor mediates platelet adhesion to injured blood vessel sites and promotes platelet aggregation. It binds factor VIII and protects it from degradation by plasma proteases, thus prolonging its half-life. Unlike hemophilia, von Willebrand disease has an autosomal inheritance pattern, resulting in an equal frequency of disease in males and females.
TABLE 81-6 von Willebrand Disease
The gene for von Willebrand factor is located on chromosome 12 and is 178 kb in length.80,81 Transcription and translation produce a large primary product that subsequently undergoes complex modifications, resulting in von Willebrand factor multimers of various sizes with molecular weights ranging from 500 to 20,000 kDa.82 von Willebrand factor is synthesized in endothelial cells, where it is either stored in Weibel–Palade bodies or secreted constitutively.83 It also is synthesized in megakaryocytes and stored in α-granules, from which it is released following platelet activation.
von Willebrand factor is important for both primary and secondary hemostasis. In response to vascular injury, it promotes platelet adhesion by interacting with the glycoprotein Ib receptor on platelets.80,83 It can facilitate platelet aggregation by binding to the platelet glycoprotein IIb/IIIa receptor, although fibrinogen is the main ligand for this receptor.80 The highest-molecular-weight von Willebrand factor multimers appear to be the most important in platelet adhesion because their large surface area contains numerous binding sites for various ligands and receptors. An additional function of von Willebrand factor is that it is the carrier molecule for circulating factor VIII, protecting it from premature degradation and removal.84 A deficiency of von Willebrand factor reduces the half-life of factor VIII and decreases plasma factor VIII levels. Therefore, von Willebrand factor plays a dual role in hemostasis, affecting both platelet function and coagulation.
Classification of von Willebrand Disease
von Willebrand disease consists of a heterogeneous group of disorders that can be classified into three major subtypes. The National Institutes of Health has developed a classification scheme that characterizes von Willebrand disease according to both the quantity of the von Willebrand clotting factors and their functionality (Table 81–7). Types 1 and 3 are associated with quantitative defects in von Willebrand factor; type 2 mutations refer to functional abnormalities in von Willebrand factor.85 Determination of the disease subtype is important because it influences treatment.
TABLE 81-7 von Willebrand Disease Classification and Laboratory Values (Modified from Nichols 2009)
Type 1 von Willebrand disease is the most common type, accounting for 60% to 70% of cases.78,86 It is characterized by a mild-to-moderate reduction in the level of von Willebrand factor (although its multimeric structure is normal) and a similar reduction in the level of factor VIII. It usually is inherited in an autosomal-dominant fashion with variable penetrance and expression.87 Bleeding symptoms often are very mild to moderate.84 Patients with von Willebrand disease can experience easy bruising, nosebleeds, or other mucosal bleeding such as GI or heavy menstrual bleeding. Subjects may be at risk of bleeding following surgery, traumatic injury, or childbirth.78
Type 2 von Willebrand disease, diagnosed in 9% to 30% of affected patients, is characterized by a qualitative abnormality of von Willebrand factor.84 Bleeding manifestations may be more severe than with type 1 disease. Inheritance most often is autosomal dominant but may be recessive.87 Type 2 von Willebrand disease can be subdivided into four variants. Type 2A is the most frequent subtype and is characterized by a reduced von Willebrand factor–platelet interaction and an absence of high- and intermediate-molecular-weight factor multimers. Type 2B is a less common variant characterized by an abnormal von Willebrand factor that has an increased affinity for the platelet glycoprotein Ib receptor. This subtype is associated with thrombocytopenia, which usually is mild. In addition, there usually is an absence of high-molecular-weight forms of von Willebrand factor. Type 2M arises from a qualitative defect in von Willebrand factor that impairs its binding to platelets; it is similar to type 2A, except that there is no measurable reduction in the high-molecular-weight multimers.87 Finally, type 2N von Willebrand disease (Normandy) is a rare form of the disease in which von Willebrand factor has a markedly reduced affinity for factor VIII. This subtype leads to a moderate-to-severe reduction of factor VIII plasma levels with normal von Willebrand factor levels.87
Type 3 von Willebrand disease refers to a severe quantitative variant of the disease in which von Willebrand factor is nearly undetectable and factor VIII levels are very low (<20 IU/dL). It often is inherited in an autosomal recessive fashion.84,86 Type 3 von Willebrand disease is rare, affecting only about 1 person in 1,000,000.78 The clinical phenotype is severe, reflecting major deficits in primary hemostasis and coagulation.
There is a platelet-type pseudo-von Willebrand disease in which von Willebrand factor is normal but a defect in the platelet glycoprotein Ib receptor causes an increased affinity for normal von Willebrand factor.84 As a result, platelet-type pseudo-von Willebrand disease is phenotypically similar to type 2B disease but should be distinguished from it because the treatment is different.
Acquired von Willebrand disease is a rare bleeding disorder that is similar to the congenital form of the disease. It has been reported primarily in association with autoimmune disorders, such as systemic lupus erythematosus, lymphoproliferative disorders, myeloproliferative disorders, hypothyroidism, and certain neoplastic diseases such as Wilms’ tumor and lymphoma.84,88 It has been reported in situations of high shear stress, such as aortic stenosis. Certain medications have been associated with acquired von Willebrand disease, including valproic acid, griseofulvin, hydroxyethyl starch, and ciprofloxacin.88 Bleeding manifestations vary from mild to severe, and the condition often resolves with treatment of the underlying disease. Various mechanisms have been proposed, including autoantibodies to von Willebrand factor resulting in rapid removal from the plasma, adsorption to tumor cells or activated platelets, increased proteolysis, or mechanical destruction.88
CLINICAL PRESENTATION von Willebrand Disease
• Clinical manifestations are variable; some patients are asymptomatic
• Mucocutaneous bleeding: epistaxis, gingival bleeding with minor manipulation, menorrhagia
• Easy bruising
• Postoperative bleeding
Diagnosis
When a patient has a lifelong history of mucocutaneous bleeding and a family history of abnormal bleeding, the clinician should suspect von Willebrand disease. For a review of clinical questions to ask the patient, refer to the National Heart, Lung, and Blood Institute guidelines (Table 81–8).78 Several different laboratory tests are helpful in the diagnosis of this hemostatic abnormality. Initial screening tests include determinations of PT, activated partial thromboplastin time (aPTT), and platelet count. PT is normal, whereas aPTT may be normal or prolonged in relation to the reduction in plasma factor VIII levels. A normal aPTT does not rule out von Willebrand disease; specific laboratory assessment of the von Willebrand factor is required. The platelet count usually is normal, although thrombocytopenia is common in type 2B and platelet-type pseudo-von Willebrand disease. The bleeding time or PFA-100 may be prolonged but can be normal in patients with milder forms of the disease.
TABLE 81-8 Replacement Therapy in von Willebrand Disease a
Specific laboratory tests for the diagnosis of von Willebrand disease include measurement of von Willebrand factor antigen (vWF:Ag) level, factor VIII assay, determination of von Willebrand factor (ristocetin cofactor) activity, and von Willebrand factor multimer analysis (Table 81–6). Plasma concentrations of von Willebrand factor increase with age, cigarette smoking, exercise, pregnancy starting in the second trimester, and infection, and with the use of certain medications, such as corticosteroids, high-dose estrogen birth control pills, and desmopressin.89 Repeated test measurements may be necessary to make the diagnosis because of physiologic variations in plasma levels.
Electroimmunoassay, immunoradiometric assay, or enzyme-linked immunosorbent assay can be used to quantify vWF:Ag.84 vWF:Ag levels are known to vary with different ABO blood types.90 The vWF:Ag level is usually low in types 1 and 2 von Willebrand disease and virtually absent in type 3 disease. Factor VIII levels are normal or mildly decreased in patients with type 1 or 2 disease and very low (<10%) in those with type 3 disease.84 Ristocetin, an antibiotic that causes platelet aggregation in the presence of functional von Willebrand factor, is used to measure von Willebrand factor activity. The assay is performed by mixing platelet-free patient plasma, normal formalin-fixed platelets, and ristocetin and then quantitating the extent of platelet agglutination.82 Ristocetin cofactor activity usually is reduced in parallel to vWF:Ag levels in types 1 and 3 disease and decreased to a greater extent than vWF:Ag in type 2 disease (except type 2B).87 Ristocetin-induced platelet agglutination is useful for further distinguishing type 2B disease, as a low concentration of ristocetin induces excessive aggregation in type 2B disease. The reader is referred to Table 81–7 for a summary of the various types of von Willebrand disease.
von Willebrand factor multimers can be analyzed by separating them by size on an agarose gel. All multimer sizes are present in type 1 disease, whereas reduced levels of intermediate- and high-molecular-weight multimers are characteristic of type 2 disease. Type 3 patients lack all types of von Willebrand factor multimers.
The von Willebrand factor gene was cloned in the mid-1980s, and now the role of molecular genetics is coming into play in the diagnosing of von Willebrand disease. Molecular genetic testing for vWD is now a feasible option in some instances.91 Genetic testing may be used to clarify diagnostic uncertainty that may remain after coagulation testing and clinical evaluation.
TREATMENT
von Willebrand Disease
Desired Outcomes
The specific type of von Willebrand disease and the location and severity of bleeding determine the approach to treatment. The comprehensive care of patients with von Willebrand disease requires a team approach. The desired outcome is to prevent bleeding episodes and their short-term and long-term consequences so that patients with von Willebrand disease can live active and productive lives. Local measures, including pressure, ice, and topical thrombin, often can control superficial bleeding. Systemic treatment is used for bleeding that cannot be controlled in this manner and for prevention of bleeding with surgery. The goal of systemic therapy is to correct platelet adhesion and coagulation defects by stimulating the release of endogenous von Willebrand factor or by administering products that contain von Willebrand factor and factor VIII.83,92 General guidelines for treatment of von Willebrand disease are shown in Figure 81–2. The von Willebrand disease guidelines are available at the National Heart, Lung, and Blood Institute Web site (http://www.nhlbi.nih.gov/guidelines/vwd/index.htm). In addition, a consensus guideline for the treatment of von Willebrand disease and other bleeding disorders in women was published in 2009.93
FIGURE 81-2 Guidelines for treatment of von Willebrand disease.
Replacement Therapy
The treatment of choice for patients with types 2B, 2M, and 3 von Willebrand disease and for patients with type 1 or 2A von Willebrand disease who are unresponsive to desmopressin (which is discussed in the next section) is replacement therapy with plasma-derived von Willebrand factor-containing products.86,94 Several virus-inactivated, intermediate- or high-purity factor VIII concentrates contain sufficient amounts of functional von Willebrand factor.94 Four factor-replacement products, all of them plasma-derived, are available in the United States for the treatment of patients with von Willebrand disease (Table 81–4). Two vWF/FVIII complex (human) products that contain high-molecular-weight multimers of vWF are commercially available. Ultrahigh-purity (monoclonal antibody-derived) plasma-derived products and recombinant factor VIII products contain only negligible amounts of von Willebrand factor and are inadequate for treatment of von Willebrand disease. A very high-purity plasma-derived von Willebrand factor concentrate and a recombinant von Willebrand factor product (does not contain blood-based additives) are currently in clinical trials.95 Data from the Phase I study of the recombinant vWF have been presented at the 2011 International Society on Thrombosis and Haemostasis meeting. Pharmacokinetics of the recombinant factor were found to be similar to that of endogenous vWF. Because these von Willebrand factor concentrates do not contain appreciable factor VIII, concomitant administration of a factor VIII-containing product may be necessary for patients with severe disease and low levels of factor VIII.96 Cryoprecipitate contains about 80 to 100 units of von Willebrand factor per unit (5 to 10 times more von Willebrand factor and factor VIII than fresh-frozen plasma), and in the past it was the mainstay of therapy for von Willebrand disease.84 However, because cryoprecipitate is not virally inactivated, it should not be used as first-line treatment. General guidelines for the dosing of replacement therapy in patients with von Willebrand disease unresponsive to desmopressin are provided in Table 81–9.
TABLE 81-9 Questions to Ask Patients
Other Pharmacologic Therapy
Desmopressin stimulates the endothelial cell release of von Willebrand factor and factor VIII. It is effective for patients with von Willebrand disease who have adequate endogenous stores of functional von Willebrand factor. This group includes most patients with type 1 disease and some patients with type 2A disease. Conversely, desmopressin is not appropriate for patients with type 3 disease, who lack stores of von Willebrand factor.
Desmopressin usually is not recommended for treatment of type 2B disease because the release of additional abnormal von Willebrand factor may exacerbate thrombocytopenia, but it has been reported to be beneficial in some patients with type 2B disease.84 If desmopressin is used for treatment of type 2B disease, close monitoring is necessary.
Clinical Controversy…
Some hematologists find desmopressin beneficial in treating patients with type 2B von Willebrand disease, whereas others believe that it may exacerbate thrombocytopenia.
The dose of desmopressin used for treatment of von Willebrand disease is identical to that used for treatment of mild factor VIII deficiency, 0.3 mcg/kg given IV over 15 to 30 minutes. Patients with von Willebrand disease generally have a better response to desmopressin than those with hemophilia, with an average three- to fivefold increase in von Willebrand factor and factor VIII levels.84 These levels remain elevated for about 6 to 8 hours. The response to desmopressin in a given patient usually is consistent, and a trial of desmopressin should determine if the medication likely will be effective for the individual. Desmopressin is preferable to use of plasma-derived products for patients who have an adequate response because desmopressin does not carry a risk of viral transmission. An added benefit is the substantially lower cost of desmopressin compared to the plasma-derived products. (For a discussion of the side effects of desmopressin, see Treatment of Hemophilia A above.)
Desmopressin can be administered every 12 to 24 hours, but the response diminishes with repeated treatment. After three to four doses, desmopressin often is no longer effective, and alternative replacement therapy may be necessary if prolonged treatment is required. Laboratory monitoring, including vWF:Ag measurements, factor VIII assays, vWF:activity assessments, and clinical examinations, will determine the adequacy of treatment.
Intranasal administration of desmopressin, at the same dosage as that used for mild factor VIII deficiency, can be useful for treatment of mild bleeding episodes. One or two doses administered at the start of menses may be helpful in controlling menorrhagia.97 Oral contraceptives may also be very effective in controlling this symptom. Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, may be of special value in tissues rich in plasminogen activators, such as the mouth, especially with tooth extractions.84 They can also be used in the management of epistaxis, GI bleeding, and menorrhagia. However, these agents should be avoided in urinary tract bleeding because of the risk of thrombosis and obstruction.
In acquired von Willebrand disease, low levels of plasma vWF are the result of accelerated removal of protein from plasma through the action of different pathogenic mechanisms. Acquired von Willebrand disease may be associated with monoclonal gammopathy, lymphoproliferative or myeloproliferative syndromes, or cardiovascular disease. The treatment of the underlying lymphoproliferative disease with rituximab, a monoclonal antibody against CD20 on lymphocytes, has been reported to be relatively ineffective in the management of the acquired von Willebrand disease.98 IV immune globulin remains an additional therapy in acquired von Willebrand disease, along with vWF concentrate and/or desmopressin.
Gene Therapy
Patients with the most severe bleeding phenotypes of von Willebrand disease (type 3 and some severe cases of types 1 and 2) may be the most likely candidates for gene therapy, which may offer the potential of a long-term, if not lifelong, correction of vWF deficiency. Studies placing vWF cDNA into a lentiviral vector are currently ongoing.81 Preclinical trials are being conducted to test the feasibility of gene transfer in the management of von Willebrand disease.
Personalized Pharmacotherapy
Current treatment of individual patients with von Willebrand disease is personalized. While the general goal of systemic therapy to correct platelet adhesion and coagulation defects by stimulating the release of vWF or administering products that contain vWF, a single guideline that works for every patient with von Willebrand disease would not be plausible. Each patient’s bleeding risk factors must be taken into consideration, and therapy tailored to the individual. The proposed regimen should take into account these risk factors and the most appropriate individualized therapy should be provided.
Evaluation of Therapeutic Outcomes
Since the main goal in the treatment of patients with von Willebrand disease is to prevent or control bleeding and the consequences of such bleeding, assessment of bleeding episodes can be monitored via clinical and laboratory parameters. Monitoring the number and types of bleeding episodes and measurement of plasma concentrations of vWF and Factor VIII make it possible to evaluate the effectiveness of specific prophylactic and treatment regimens. As with hemophilia patients, assessment of patients’ activities of daily living gives clinicians a better appreciation of the success of the treatment plan.
OTHER CONGENITAL FACTOR DEFICIENCIES
In addition to deficiencies in factors VIII and IX, congenital deficiencies in fibrinogen, in factors II, V, VII, X, XI, and XIII, and in combinations of factor deficiencies have been reported.99 Contact factor abnormalities, including deficiencies in factor XII, high-molecular-weight kininogen, and prekallikrein, prolong the aPTT but do not lead to any bleeding diathesis. Identification of these disorders is important so that inappropriate treatment is not given. The only contact factor deficiency associated with bleeding symptoms is factor XI deficiency. Also known as hemophilia C, this deficiency is particularly common in people of Ashkenazi Jewish descent.99 Bleeding manifestations are variable. Bleeding usually does not occur spontaneously, but excessive bleeding may occur after trauma or surgery. Most other deficiencies are inherited as autosomal recessive disorders and are rare. Some patients with abnormal molecules, such as a dysfibrinogenemia, may have an increased tendency to develop thromboembolic disease. Most of these deficiencies are treated with fresh-frozen plasma. Newer specific concentrates are becoming available. For example, a factor XIII plasma-derived concentrate is available, and recombinant factor VIIa is approved for use in patients with congenital VII deficiency. Cryoprecipitate, which is rich in fibrinogen, can be used to treat patients with fibrinogen deficiency or dysfunctional fibrinogen (dysfibrinogenemia).
COMPLICATIONS OF REPLACEMENT THERAPY
Transmission of bloodborne infectious diseases is always a concern when blood and blood-derived products are used. Most patients with hemophilia who received plasma-derived products were infected with hepatitis viruses and HIV during the 1980s prompting the development of viral inactivation methods for use during the manufacturing of factor concentrates.26 All currently available plasma-derived factor concentrates come from screened donors and undergo viral inactivation procedures in an effort to reduce the risk of viral transmission. Heat treatment, which includes dry and wet heat, is one method of viral inactivation. Wet heat is applied while the concentrate is in suspension or in solution (pasteurization) and appears to be more effective than dry heat. Other methods of viral inactivation include chemical (solvent detergent) and affinity chromatography with monoclonal antibodies. Solvent detergent treatment inactivates lipid-coated viruses such as HIV and hepatitis B and C, but it is not effective against parvovirus B19, transfusion transmitted virus, hepatitis A, or prions.26 Parvovirus B19 has been found in both plasma-derived and recombinant factor VIII concentrates (due to the use of albumin as a stabilizer in some recombinant products).26,27 Parvovirus B19 may be particularly important for patients with hemophilia and HIV infection because it can cause chronic anemia in patients with immune deficiency.100Prions are not inactivated by either solvent detergent treatment or by heat, so there is a risk of transmission.26
Other complications associated with factor administration include allergic reactions, fever, chills, urticaria, and nausea. PCCs and aPCCs also have the potential to cause thromboembolic complications, including deep-vein thrombosis, pulmonary embolism, myocardial infarction, and DIC, likely related to the presence of activated factors.101 Antifibrinolytic agents should not be given to patients receiving PCCs or aPCCs to avoid thrombotic complications.
Porcine factor VIII, used in the treatment of patients with inhibitors to factor VIII, is not known to transmit human viruses. However, allergic-type reactions (e.g., fever, chills, skin rashes, nausea, and headaches) have been reported.102 Patients who experience these reactions can be treated with steroids and/or diphenhydramine. Thrombocytopenia is another potential complication of porcine factor VIII use.102
Recombinant factor VIII or IX has a low risk of viral transmission. Adverse effects of these products include metallic taste, mild dizziness, mild rash, burning at the infusion site, and a small drop in blood pressure.
ABBREVIATIONS
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