Hemophilia and von Willebrand Disease

The clinical and laboratory features of the three most common hereditary bleeding disorders—hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), and von Willebrand disease (VWD)—are discussed in this chapter. Hemophilia A and hemophilia B are both caused by a functional deficiency of a plasma protein inherited in an X-linked manner. Because these two proteins, factor VIII and factor IX, are part of the tenase complex that subsequently activates factor X (see Chapter 27 ), the clinical features and many of the diagnostic considerations for hemophilia A and B are similar. Thus these two types of hemophilia are discussed together, although the treatment of each is presented separately. The last part of this chapter is devoted to VWD. Because von Willebrand factor (VWF) and factor VIII exist as a circulating noncovalent complex in plasma, historically they copurified during plasma fractionation. In fact, for many years, severe VWD and hemophilia A were treated with the same plasma-derived therapeutic products. As the products to treat hemophilia A became more pure, factor VIII was subfractionated away from its carrier protein VWF, thereby making high-purity factor VIII products unsatisfactory for the treatment of VWD. The most commonly used products to treat hemophilia A contain recombinant factor VIII and do not contain VWF. To treat severe VWD, intermediate-purity plasma-derived concentrate containing both VWF and factor VIII or, in some regions of the world, purified plasma-derived VWF concentrates are available to treat deficiency of VWF when replacement therapy is indicated. Recombinant VWF is currently being investigated in clinical studies and will likely be available to patients in the near future.

Hemophilia A and Hemophilia B

Hemophilia A and hemophilia B are the most common severe inherited bleeding disorders. Historically, hemophilia has been recognized as an entity since biblical times. Use of the term hemophilia was ascribed to Schönlein in the 1820s. Progressive insight into the pathophysiologic course of the disease has led to the development of powerful tools for diagnosis and agents for improved therapy, as well as the need to minimize the primary and secondary complications of the disease and its therapy. The prolonged clotting time of hemophilic blood was first noted in 1893, and the associated decrease in factor VIII levels in hemophilia A was initially identified in 1947. In 1952 levels of factor IX were found to be decreased in Christmas disease , which was the early term used to denote hemophilia B because it was the surname of the first patient diagnosed with the disease.

Early therapy for hemophilia was primarily supportive, but after the observation in the 1930s that administration of plasma corrected the clotting time of hemophilic blood, treatment evolved to include transfusion with whole blood and plasma to achieve improved clotting function. The modern era of treatment began in 1964 with the discovery of cryoprecipitate and plasma fractions containing factor IX and their use to treat bleeding episodes in hemophilia. More purified products were introduced in 1965 and were referred to as factor VIII concentrates (containing both factor VIII and VWF). The next major improvements in replacement therapy were the result of attempts to limit transfusion-related viral infections during the 1980s, which included improved donor selection, heat treatment of the product, and further refined purification schemes.

In 1984 and 1985 the genes for factor VIII and factor IX were cloned, and in 1989, recombinant factor VIII was first used clinically. In recent years more highly purified factor IX and recombinant factor IX products have been developed. With the advent of recombinant products, patients with hemophilia could more readily and safely be treated with primary and secondary prophylactic therapy. Such vigorous treatment programs markedly reduce the likelihood of spontaneous bleeding episodes and the progression of hemophilic arthropathy. Thus prophylaxis continues to be the preferred approach to patients with severe hemophilia.

The landscape of hemophilia treatment is changing significantly. New progress has been made in the development of recombinant products based on the prolongation of the half-life of factors VIII and IX. Several clinical trials in adults and children are ongoing, and it is likely that some of these new products will be available to patients shortly. Additionally, a major breakthrough in hemophilia therapy was recently made with the report of a successful gene therapy clinical trial for hemophilia B with long-lasting, sustained coagulation factor IX levels.

Pathophysiology

The structure and function of factors VIII and IX in the coagulation pathway were outlined in Chapter 27 . Both factors are crucial for normal thrombin generation. The classic representation of hemostasis shows factor VII together with tissue factor activating factor X; however, subsequent studies suggested that the primary physiologic pathway of activation of factor X by tissue factor and factor VII is through the activation of factor IX. Activated factor IX complexes with factor VIIIa, calcium, and phosphatidylserine on physiologic membranes to generate factor Xa, which subsequently participates in formation of the prothrombinase complex. Thus, physiologically, the tissue factor pathway of factor X activation requires factor VIII and factor IX for normal thrombin generation, and the absence of either protein severely impairs the ability to generate thrombin and fibrin. This absence is not identified by use of the classic prothrombin time; the prothrombin time is normal in patients with hemophilia A or hemophilia B.

After injury the initial hemostatic event is formation of a platelet plug, and the subsequent generation of fibrin is crucial to prevent continued oozing. Because of the primary clotting factor deficiency in either hemophilia A or hemophilia B, the propagation phase of coagulation is impaired, and clot formation is delayed and is not robust. Thus patients with hemophilia do not bleed more rapidly; rather, there is delayed formation of an abnormal clot. Thrombin is crucial for platelet aggregation, fibrin generation, clot retraction, and activation of factor XIII. Because thrombin generation in hemophilia is markedly delayed, hemorrhage may occur after minimal or unknown trauma. Deep bleeding into joints and muscles is characteristic of hemophilia. In hemophilia the clot formed is often friable, and rebleeding is a common observation in inadequately treated patients. Medications such as aspirin and other nonsteroidal antiinflammatory drugs may alter platelet function and further impair hemostasis in affected individuals and are therefore contraindicated.

Demographics and Classification

Hemophilia occurs in approximately 1 in 5000 males. Of all patients with hemophilia, 80% to 85% have hemophilia A, and 10% to 15% have hemophilia B. Hemophilia shows no apparent racial predilection and appears in all ethnic groups.

The severity of hemophilia is classified on the basis of the patient's baseline level of factor VIII or factor IX. One unit of each factor is defined as the amount found in 1 mL of normal plasma. Factor levels are often expressed as a percentage of activity, with a 100% level (100 U/dL) being equal to the activity found in 1 mL of normal plasma. Severe hemophilia is characterized by a factor level of less than 1 U/dL (<1%). In moderate hemophilia the clotting factor level is between 1 and 5 U/dL, and in mild hemophilia factor VIII or IX levels are greater than 5 U/dL. This classification provides a rough guide for the patient's expected rate of occurrence of bleeding episodes. Although the correlation is not perfect, the clinical phenotype usually corresponds to the factor level. Patients with severe hemophilia often have bleeding episodes after minimal or unknown trauma, with children experiencing unprovoked muscle and joint bleeding between one and six times per month. With more aggressive prophylactic administration of factor VIII, instances of bleeding are markedly reduced. Patients with moderate hemophilia will have bleeding after mild to moderate injuries, whereas mild hemophilia may often be undiagnosed for many years, and these patients may have bleeding only after significant trauma or at the time of surgery.

Clinical Manifestations

Approximately 30% of male infants with hemophilia have bleeding with circumcision. In some reports as many as 2% to 3% of neonates with hemophilia may experience an intracranial hemorrhage. It is important to prevent head trauma during delivery. Forceps or vacuum extraction should be discouraged. In the majority of patients hemophilia is diagnosed at birth because of a family history, although in approximately a third of patients the occurrence of hemophilia represents a new mutation. In these latter patients the diagnosis is often made when the child begins to crawl and walk. The usual initial symptoms include easy bruising; oral bleeding, especially from a torn frenulum; hemarthrosis; and intramuscular hemorrhage. When the diagnosis of hemophilia is suspected on the basis of either clinical findings or a positive family history, the initial diagnostic studies should include determination of the prothrombin time, partial thromboplastin time (PTT), fibrinogen or thrombin time, platelet count, and studies to identify VWD (see Chapter 29 ). If the PTT is prolonged, assays for factor VIII and factor IX should be performed. The presence of an antibody inhibiting either factor VIII or IX can be ruled out by mixing normal plasma in equal volume with the test plasma, incubating the mixture for 30 to 60 minutes, and repeating the PTT to be sure that it has been normalized (mixing study). The specific assays for factor VIII and factor IX are not as easily affected by difficult venipuncture and are therefore more reliable. Factor VIII and VWF levels may be elevated by stress and inflammation, however, and repeated studies may be necessary to establish the diagnosis and the severity of the disorder.

Specific types of bleeding are described in the following paragraphs. In general, the clinical bleeding episodes associated with deficiency of factor VIII or factor IX are identical.

Musculoskeletal Bleeding

Although patients with hemophilia may bleed in any area of the body, the hallmark of hemophilia is deep bleeding into joints and muscles. The occurrence of such hemorrhage usually corresponds to the severity of the clotting factor deficiency in patients with either hemophilia A or hemophilia B. Without prophylactic factor treatment, patients with severe hemophilia may have a bleeding episode as often as once or twice per week. Bleeding occurs most commonly into the joint space, a condition referred to as hemarthrosis . These joint hemorrhages usually begin when the child reaches the toddler age. As the toddler attempts to maintain an upright position, the ankle becomes particularly prone to hemorrhage. Thus in toddlers the ankle is the most common site of hemorrhage, with the knee being the second most common. As the child grows older, the most frequent bleeding sites are the knees and elbows.

Patients who sustain hemarthrosis usually first note an aura of tingling or warmth, followed shortly thereafter by increasing pain and decreased range of motion of the joint as the joint capsule becomes progressively distended. As children get older, they are often able to tell their parents and the physician when a hemorrhage is beginning to occur, even in the absence of significant signs on physical examination. In young children who are unable to verbalize symptoms, severe pain and distention of the joint space often occur before the location of the hemorrhage can be easily determined. On examination pain and limitation of range of motion of the joint are obvious and followed by the development of warmth, swelling, and tenderness.

Prompt, early coagulation factor replacement therapy is the key to minimizing long-term complications of these hemorrhages. Patients with severe hemophilia are increasingly being treated prophylactically to prevent most bleeding episodes (discussed later). Prompt aspiration of hip hemarthrosis should be performed if joint distention is present to reduce the risk for avascular necrosis of the femoral head (a rare event). As children and their parents become familiar with the early symptoms of bleeding, aggressive early treatment can be given to reduce the degree of joint damage. If the child experiences repeated hemorrhage within a joint, chronic effusion and hyperemia often occur, and an aggressive secondary prophylactic therapy program may be needed to return the joint to a more normal state of recovery. Severe chronic arthropathy may develop in older children and adults who have not received aggressive early treatment. These individuals often experience pain very early with little swelling. The joints of younger children are usually more distensible, and massive joint swelling may be observed. Splinting and application of ice packs as auxiliary measures may provide a modicum of relief but are not substitutes for early coagulation factor replacement therapy. When the physician has doubts, treatment should be initiated; it is not appropriate to watch and wait because damage to the joint can start early in life.

The clinical diagnosis of intramuscular hematoma is often elusive. Such hemorrhage occurs deep within the body of the muscle and is associated with a vague feeling of pain on motion. Because the bleeding is not in a closed space, the mass may be difficult to palpate, although the circumference of the affected limb is generally increased. Muscle hemorrhage should be considered to be as severe as hemarthrosis because it may result in severe muscular contractures as a result of fibrosis and atrophy or even pseudotumor formation. Muscle weakness also predisposes patients to joint hemorrhage. Appropriate replacement therapy is critical for reducing the size of the hematoma, and physical therapy is important to restore normal range of motion and prevent fibrosis of the muscle.

Iliopsoas bleeding is a particularly troublesome form of intramuscular hemorrhage. A patient with an iliopsoas hemorrhage is generally seen with vague symptoms of lower abdominal or upper thigh discomfort. The patient may have a characteristic gait; the hip is flexed and inwardly rotated. On examination the patient is unable to extend the hip, but usually both internal and external rotation of the hip joint is normal; the latter finding often distinguishes an iliopsoas hemorrhage from a true hemarthrosis of the hip joint. The diagnosis is made clinically by these findings and should be confirmed by either ultrasonography or computed tomography (CT). Appropriate treatment is crucial; iliopsoas hemorrhages may be life threatening because large volumes of blood can be lost into the retroperitoneal space. Physical examination demonstrates loss of hyperextension of the hip. If an iliopsoas hemorrhage is identified, an aggressive infusion program should be initiated and maintained for 10 to 14 days or longer, followed by at least several months of prophylactic therapy until clinical and radiographic evidence demonstrates resolution.

Life-Threatening Hemorrhages

Bleeding episodes of the central nervous system (CNS), bleeding into and around the airway, and exsanguinating hemorrhage are the most common causes of life-threatening hemorrhage in hemophilia. The first element of treatment is prompt therapy with clotting factor concentrate to bring the plasma clotting factor level to normal. CNS hemorrhage may occur without known trauma, and early symptoms may be minimal. Thus therapy should be initiated before radiologic evaluation or lumbar puncture; when there is any doubt, it is better to treat immediately. Rapid performance of CT is often critical in the early diagnosis of intracranial bleeding, although an astonishingly large volume of blood can be present within the cranium in infants with relatively few neurologic findings. Treatment of life-threatening hemorrhage involves replacement therapy to achieve a level of 100 U/dL for factor VIII and factor IX, maintenance of adequate hemostatic levels (>50 to 60 U/dL) for a minimum of 14 days, and a more prolonged period of prophylactic therapy for an additional 2 to 3 weeks or longer to ensure resolution of the underlying event ( Table 31-1 ). Patients with intracranial hemorrhage should receive prophylaxis for at least 6 months after the more intense initial therapy and may benefit from lifelong prophylaxis.

TABLE 31-1

Treatment of Specific Hemorrhages in Hemophilia

Type of Hemorrhage	Hemophilia A	Hemophilia B *
Hemarthrosis ^†	50 U/kg factor VIII concentrate initially, ^‡ 20 U/kg the following day; consider additional treatment every other day, depending on response	80 U/kg factor IX concentrate initially, 40 U/kg the following day; consider additional treatment every other day, depending on response
Muscle or significant subcutaneous hematoma	50 U/kg factor VIII concentrate; may need 20 U/kg every other day until well resolved	80 U/kg factor IX concentrate; may need 40 U/kg every other day until well resolved
Mouth, deciduous tooth, or tooth extraction	20 U/kg factor VIII concentrate (40 U/kg if molar extraction), antifibrinolytic therapy; remove loose deciduous tooth	40 U/kg factor IX concentrate (80 U/kg if molar extraction), antifibrinolytic therapy; remove loose deciduous tooth
Epistaxis	Apply pressure for 15-20 min, nosebleed QR, pack with petrolatum gauze, antifibrinolytic therapy; 20 U/kg factor VIII concentrate if preceding measure fails	Apply pressure for 15-20 min, nosebleed QR, pack with petrolatum gauze, antifibrinolytic therapy ^§ ; 30 U/kg factor IX concentrate if preceding measure fails
Major surgery, life-threatening hemorrhage (e.g., central nervous system, gastrointestinal, airway)	50-75 U/kg factor VIII concentrate, then initiate continuous infusion of 3 U/kg/hr to maintain factor VIIII > 100 U/dL for 24 hr, and then give 2-3 U/kg/hr for 5-7 days to maintain the level greater than 50 U/dL and an additional 5-7 days at a level >30 U/dL (bolus dosing to maintain these levels is acceptable); monitor factor VIII levels	80-100 U/kg factor IX concentrate, then 20-40 U/kg every 12-24 hr to maintain factor IX >40 U/dL for 5-7 days, and then >30 U/dL for 5-7 days ^‖ ; monitor factor IX levels
Iliopsoas hemorrhage	50 U/kg factor VIII concentrate, then 25 U/kg every 12 hr until asymptomatic, and then 20 U/kg every other day for a total of 10-14 days ^¶	80 U/kg factor IX concentrate, then 20-40 U/kg every 12-24 hr to maintain factor IX > 40 IU/dL until asymptomatic, and then 30 U/kg every other day for a total of 10-14 days ^‖ ^, ^¶
Hematuria	Bed rest, 1.5 × maintenance fluids; if not controlled in 1-2 days, 20 U/kg factor VIII concentrate; if not controlled, prednisone if human immunodeficiency virus negative	Bed rest , 1.5 × maintenance fluids; if not controlled in 1-2 days, 30 U/kg factor IX concentrate; if not controlled, prednisone if human immunodeficiency virus negative

* Dosing of recombinant factor IX should be increased to 1.3 to 1.5 times the recommended doses or, preferably, be based on an individual in vivo recovery study.

† For hip hemarthrosis, orthopedic evaluation for possible aspiration is advisable.

‡ For mild or moderate hemophilia, desmopressin, 0.3 µg/kg, should be used instead of factor VIII concentrate if patient is known to respond with a hemostatic level of factor VIII; if repeated doses are given, monitor factor VIII levels for tachyphylaxis.

§ Do not give antifibrinolytic therapy until 4 to 6 hours after a dose of prothrombin complex concentrate.

‖ If repeated doses of factor IX concentrate are required, use highly purified, specific factor IX concentrate.

¶ Repeat radiologic assessment should be performed before discontinuation of therapy.

Preparation for Surgery

Preparation of a hemophilic patient for surgery includes a careful history and physical examination, measurement of inhibitor titer, careful determination of the incremental recovery and half-life after infusion of the appropriate clotting factor (VIII or IX), and assurance that adequate amounts of coagulation factor replacement material are available, as well as red cells if a transfusion is needed. Before surgery the replacement materials should be infused to achieve a level of 80 to 100 U/dL for factor IX and 100 to 150 U/dL for factor VIII; levels should be maintained at greater than 50 to 60 U/dL for 7 to 10 days postoperatively. Lower doses to maintain levels at greater than 20 to 30 U/dL for an additional 1 to 2 weeks may then be used and continued until healing has occurred (see Table 31-1 ). Because recovery of recombinant factor IX activity is less than that of therapeutic plasma-derived factor IX, 1.2 to 1.5 times the dose should be administered if using recombinant factor IX.

Miscellaneous Hemorrhages

A common manifestation of hemophilia is oral bleeding, whether from a torn frenulum in a young child or after tooth extraction in an older patient. Replacement therapy to achieve a factor level of 30 to 40 U/dL is adequate for initial therapy. Because the mucosae of the oral cavity contains abundant fibrinolytic activity, therapy with antifibrinolytic agents (aminocaproic acid [Amicar] or tranexamic acid [Cyklokapron and Lysteda]) is useful to stabilize the clot until the wound has healed.

Hematuria can be a particularly troublesome problem. Blood in the urine may arise spontaneously, and determination of an actual bleeding site is often difficult. Therapy is also controversial. Replacement therapy with 40 to 50 U/kg of factor VIII or IX followed by bed rest is generally advisable after other common causes of hematuria have been ruled out. Treatment with corticosteroids may be helpful. Sudden abdominal or flank pain should be investigated for the possibility of ureteral obstruction and hydronephrosis secondary to bleeding. Antifibrinolytic agents are not recommended in hematuria because of the risk they present for ureteral obstruction.

Gastrointestinal bleeding is an occasional complication of hemophilia. All the common causes of gastrointestinal bleeding can occur in patients with hemophilia, as well as spontaneous hemorrhage after no known insult. An initial episode of gastrointestinal hemorrhage requires that the patient receive a thorough gastrointestinal evaluation after the acute bleeding is controlled with replacement therapy. If substantial blood loss has occurred, patients should be treated with high doses of concentrate as though they were at risk for life-threatening hemorrhage.

Long-Term Complications of Joint Bleeding

Chronic arthropathy is the major long-term disabling complication of hemophilia. The articular surface of a normal joint is lined with cartilage that is lubricated by synovial fluid produced by the synovial lining of the joint. A thick fibrous capsule protects the joint. The natural history of hemophilic arthropathy is one of a cycle of recurrent hemorrhage into a “target” joint leading to synovial thickening and friability, followed by additional hemorrhage into the joint. After a joint hemorrhage, proteolytic enzymes are released by granulocytes into the joint space. In addition, heme iron is ingested by macrophages and may contribute to inflammation by the release of oxidative products. The synovium of the joint, originally the width of a single cell, proliferates in response to inflammation and develops frondlike projections into the joint.

These projections are by nature friable and bleed with minimal trauma, thus setting up a vicious cycle of recurrent hemorrhage. With recurrence of hemorrhage there is further release of substances injurious to the joint cartilage, which causes it to develop a roughened, lunar landscape–like surface. As the cartilage erodes, the joint space becomes narrowed. In recent years the pathophysiology of hemophilia arthropathy has been better characterized at a molecular level; not surprisingly, it shows some similarities with other inflammatory processes that are associated with joint diseases such as rheumatoid arthritis.

On examination, the clinical findings depend on the stage of arthropathy that has developed. The early stages are characterized by synovial thickening with little evidence of joint damage. With synovitis alone, the range of motion of the joint is nearly normal, although recurrent bleeding episodes usually result in weakness of the proximal muscles. With time, however, proliferative changes become associated with erosion of the cartilage. The patient at this stage may note the development of arthritic symptoms that are often difficult to distinguish from joint bleeding. Crepitus and decreased range of motion are prominent findings on physical examination. At this stage proximal muscle weakness is accentuated because of the inability of the joint to attain full range of motion. Finally, with progressive bleeding and further narrowing of the joint space, the joint fuses.

This progression of joint disease was once commonly seen in hemophilia centers throughout the United States and other countries. The most commonly affected joints were the knees, ankles, and elbows. With the development of modern concentrates for replacement therapy, home therapy, and prophylactic therapy, this cycle has now been disrupted in the vast majority of children with severe hemophilia. Primary prophylactic therapy and early diagnosis and treatment of joint hemorrhage have limited the number of “target joints” that develop. When a joint becomes a target, hemorrhage into that joint must be treated vigorously and the joint must be carefully watched for the cycle of rebleeding every 1 to 2 weeks that is characteristic of incompletely treated hemarthrosis. If evidence of early synovitis or loss of range of motion is present, a secondary prophylactic therapy program of every-other-day treatment for 30 to 90 days is often helpful for “cooling down” the affected joint and allowing healing to occur.

Alternatively, a lifelong prophylactic therapy program to prevent spontaneous, severe joint bleeding may be started in young infants (discussed later), a modality that is currently widely used in the United States and other developed nations. If medical therapy fails, synovectomy frequently reduces the occurrence of bleeding and may prevent progression of the joint disease. With the advent of arthroscopic means to perform synovectomy, this procedure has been more readily performed with reduced morbidity; equally important, early mobilization of the affected joint allows more rapid return of range of motion. Another procedure in which various radioisotopes are used to reduce the mass of inflamed synovium is termed radioactive synovectomy . This approach is recommended for patients with inhibitors. Fewer radioactive synovectomies are now performed because of the development of acute lymphoblastic leukemia in two children who underwent this procedure. When aggressive medical and less invasive surgical management fails to halt progression of the joint disease, some adults have benefited from joint replacement.

If pain and bleeding are severe in a joint with minimal range of motion, joint fusion may provide a significant decrease in pain and rebleeding. A critical element in the care of patients with chronic joint disease is the need for a team approach to the problem because the care of these children requires the combined expertise of an orthopedic surgeon, physical therapist, nurse, social worker, and hematologist to achieve optimal results.

Symptomatic Carriers

Although the usual patient with hemophilia A or hemophilia B is a male, carriers of a factor VIII or factor IX gene mutation may also be symptomatic. Known carriers should have their levels of clotting factor measured at least once to determine whether they are at increased risk for clinical bleeding episodes. There are several possible explanations for the observation of a female patient with moderate or severe deficiency of factor VIII or factor IX. Skewed lyonization of a carrier female is the most commonly accepted explanation. As predicted by the Lyon hypothesis, the X chromosome in each female cell is randomly inactivated early in embryonic development; by chance, some carriers of hemophilia will have a high percentage of inactivated normal X chromosomes. The active abnormal X chromosome will result in deficient synthesis of factor VIII or factor IX. Other explanations for the presence of hemophilia A or B in a phenotypic female include testicular feminization of a genotypic male, Turner syndrome with the genotype XO, an X autosomal translocation with skewed X inactivation, and a daughter of a maternal carrier and a father with hemophilia A. Factor VIII deficiency is also found in type 2N VWD as a result of mutations in the factor VIII–binding region of the VWF protein.

Laboratory Evaluation

Severe hemophilia A or hemophilia B is easily identified by a markedly prolonged PTT and the absence of either factor VIII or factor IX. The diagnosis of mild hemophilia A or hemophilia B may be more difficult to make because the newborn has a slightly prolonged PTT secondary to a physiologic reduction in vitamin K–dependent factors such as factor IX. In addition, the stress of delivery and other neonatal problems may transiently elevate factor VIII levels into the normal or nearly normal range. Thus in the absence of clinical bleeding, mild deficiencies may be identified only after repeated testing in the weeks or months after birth (see Chapter 29 ). VWF testing must be done to distinguish mild or moderate factor VIII deficiency secondary to hemophilia from deficiencies of factor VIII secondary to VWD.

Partial Thromboplastin Time

The PTT measures all the procoagulant clotting factors except factor VII and factor XIII (see Chapters 27 and 29 ). In general, the PTT is most sensitive for deficiencies of the “intrinsic” pathway. In general, commercial PTT reagents have good sensitivity for factor VIII deficiency, but their sensitivity for factor IX deficiency is more variable. Use of some of these reagents will give normal PTTs even with factor IX levels of 15 to 20 U/dL. Because the hemostatic level of factor IX is approximately 30 U/dL, mild or moderate factor IX deficiency may be missed. Thus if hemophilia is suspected, a factor IX assay should be performed even if the PTT is normal. The clinical laboratory technician should study the sensitivity of each lot of PTT reagent to be able to advise the clinician about the likelihood that a normal PTT implies normal clotting factor levels. In patients with severe hemophilia A or hemophilia B, the PTT is generally prolonged to two to three times the upper limit of the normal range. The prolonged PTT will correct to within the normal range when the reagent is mixed 1 : 1 with normal plasma. Failure of the PTT to correct on 1 : 1 mixing of the reagent with normal plasma implies the presence of an anticoagulant (e.g., lupus inhibitor, antibody to factor VIII or IX, or heparin). The presence of a specific anti–factor VIII or anti–factor IX inhibitory antibody is described in more detail later.

Specific Assays for Factor VIII and Factor IX

Functional assays for factor VIII and factor IX are performed on plasma samples that contain no factor VIII or factor IX, respectively (either hemophilia A or hemophilia B plasma); alternatively, normal plasma from which the respective clotting factor is selectively removed by a monoclonal antibody can be used. If adsorbed plasma is used for factor VIII–deficient plasma, the VWF content of that plasma should be normal. A standard curve is constructed with the use of normal plasma, with the 100% point being a 1 : 10 dilution of normal plasma. Serial dilutions of this normal plasma should usually be linear through a dilution of 1 : 640 or 1 : 1280 when plotted semilogarithmically versus the clotting time. Serial dilutions of the patient's plasma are compared with this normal curve and expressed in units per deciliter. One unit is the amount of factor VIII or factor IX present in 1mL of normal plasma.

Immunoassays for factor VIII and factor IX are sometimes performed to identify dysfunctional proteins, also known as cross-reacting material (CRM) positive (+) variants. The majority of patients with severe hemophilia A have undetectable levels of factor VIII protein, but some patients with mild or moderate hemophilia A possess levels of factor VIII protein that are detectable with an immunoassay. In hemophilia B approximately 50% of patients will have detectable or even normal levels of factor IX antigen and therefore have true CRM + variants. Immunoassays are not usually required for the clinical management of these disorders because the coagulant-based assays predict the functional concentration of these clotting factors.

Inhibitory Antibodies to Factor VIII or Factor IX

Inhibitor development is one of the most feared complications of hemophilia. The presence of a factor VIII or factor IX inhibitory antibody is usually suspected when the PTT does not correct to normal after being mixed 1 : 1 with normal plasma. Because of the kinetics of the inhibitory antibody, this mixture should be incubated 60 minutes before the PTT is performed. When a low-titer inhibitory antibody is identified, the PTT performed on a 1 : 1 mixture with normal plasma may initially be prolonged only by several seconds, but when the mixture is incubated for 1 hour, the PTT may be as long as or even longer than the PTT when it was originally performed on the patient's plasma.

Specific assays for factor VIII or factor IX antibodies are performed with the Bethesda assay. Dilutions of the test plasma are mixed with normal plasma and incubated for 120 minutes. A standard factor VIII or factor IX assay is then performed. One Bethesda unit is defined as the amount of antibody that will inactivate 50% of the normal factor VIII or factor IX in 2 hours when the residual factor VIII or factor IX level is between 25 and 75 U/dL. The dilution of the test plasma that inhibits this amount of factor VIII is determined. If a 1 : 10 dilution of test plasma has this effect, the inhibitor plasma is said to contain 10 Bethesda units.

Genetic Testing

The genes encoding factors VIII and IX ( F8 and F9, respectively) map to the distal portion of the long arm of the X chromosome. Therefore both hemophilia A and B are inherited as X-linked traits. Approximately two thirds of patients have a family history, while the rate of de novo mutations is approximately one in three. Genetic testing for hemophilia A and hemophilia B is now widely available. Such testing is usually performed on the proband first, and once the mutation is identified the potential carriers of hemophilia in the family can be then tested. Prenatal testing for hemophilia is performed by amniocentesis or chorionic villus biopsy and may be useful for the perinatologist and neonatologist in the management of pregnancy, delivery, and immediate neonatal care. Databases of the known mutations causing hemophilia A are available ( http://hadb.org.uk ). The most common genetic alteration is inversion. Gene inversion occurs in approximately 45% of patients with severe hemophilia A, with most inversions originating in male germ cells. The most common inversion occurs in intron 22 of F8; this inversion accounts for approximately half of the cases of severe hemophilia A. In families in which the propositus has a known molecular abnormality, genetic screening and carrier detection are highly accurate. Direct DNA sequence analysis is available for families in which the results of testing for the factor VIII gene inversion are negative. Additionally, molecular genetic diagnosis can also be done by performing linkage for the affected allele if an appropriate number of family members are available. This test is clinically available ( www.genetest.org ). If genetic testing is uninformative or unavailable, a coagulation-based assay to detect the carrier state may also be useful and is approximately 90% accurate.

In contrast to the complexity of the factor VIII gene, the factor IX gene is considerably smaller (33 versus 187 kilobases [kb]). More than 60% of factor IX gene defects are due to missense point mutations, and an identifiable defect in the gene can be found in nearly all patients ( http://www.factorix.org ). In approximately 50% of patients with hemophilia B, a factor IX protein that is nonfunctional is produced, whereas in the other patients no factor IX protein is produced.

Fundamentals of Treatment

Knowledge of the half-life, volume of distribution, patient's inhibitor status, and appropriate replacement material is necessary to make intelligent decisions for the treatment of bleeding episodes. Prompt and appropriate treatment of hemorrhage and prophylactic therapy are the key to excellent care of patients with hemophilia. Home therapy and prophylactic therapy have revolutionized the care of children and adults with hemophilia. Early or prophylactic treatment prevents the long-term morbidity of hemophilia. For adequate treatment of mild to moderate hemorrhage, it is necessary that factor VIII levels of 30 to 50 U/dL or factor IX levels of 30 U/dL be achieved.

For patients with mild hemophilia A who have previously shown a satisfactory response to desmopressin acetate (DDAVP, 1-deamino-8-d-arginine vasopressin), this drug is the treatment of choice for bleeding episodes of mild to moderate severity. For life-threatening hemorrhage, the immediate aim is to correct the patient's clotting factor level to normal (100 to 150bU/dL) and to maintain a nadir level between 50 and 60 U/dL for 5 to 7 days, followed by a vigorous maintenance treatment program.

Table 31-1 summarizes the treatment of specific types of hemorrhage in hemophilia A and hemophilia B. Calculation of the dose, recommendations concerning prophylaxis, and the specific treatment products for hemophilia A and hemophilia B are reviewed later.

Hemophilia A

Calculation of Dose.

Calculation of the dose required to achieve a desired hemostatic level is based on a convenient formula derived from the work of Abildgaard and colleagues :

\begin{matrix} Dose factor VIII (units) = U/dL desired rise in plasma \\ factor VIII \times Body weight (kg) \times 0.5 \end{matrix}

$\begin{matrix} Dose factor VIII (units) = U/dL desired rise in plasma \\ factor VIII \times Body weight (kg) \times 0.5 \end{matrix}$

Thus for treatment of hemarthrosis in a 20-kg child with severe hemophilia A, to achieve a plasma level of 60 U/dL, the dose would be 60 U/dL × 20 kg × 0.5 = 600 units of factor VIII.

For patients undergoing major surgery or with serious hemorrhage, the plasma factor VIII level should be initially corrected to 100 to 150 U/dL (immediately before the procedure if given for surgery) and maintained at greater than 50 to 60 U/dL for 5 to 7 days and then at greater than 30 U/dL for an additional 5 to 7 days. This can be accomplished by infusion of intermittent doses of factor VIII based on a half-life of 12 hours (e.g., administration of 30 U/kg [60-U/dL correction] every 12 hours).

Alternatively, a level of 50 to 60 U/dL can be maintained by continuous infusion of factor VIII at a rate of 2 to 3 U/kg/hr. The level of factor VIII should be monitored periodically to ensure that the expected levels are attained. Immediately after surgery, it is advisable to administer 25 U/kg of factor VIII concentrate to compensate for the loss of factor VIII by increased consumption and blood loss during the surgical procedure. For surgical procedures and limb- or life-threatening hemorrhage, factor VIII levels should be monitored at least every 24 hours. CNS bleeding should be treated for a 2- to 3-week course of therapy. Such patients have a risk of recurrence of CNS bleeding for approximately 6 months after an episode, and these patients often continue to receive prophylactic therapy. At the conclusion of therapy for CNS hemorrhage, CT should be performed to provide a baseline scan for comparison if any subsequent CNS symptoms appear and to demonstrate resolution of the previous hemorrhage.

For treatment of more routine bleeding episodes, such as hemarthrosis, often only one to two doses of clotting factor replacement (plasma factor VIII level of 80 to 100 U/dL), initially followed by infusions as recommended in Table 31-1 , are required to produce significant clinical improvement. Nevertheless, many centers are now using a more aggressive approach to managing severe joint hemorrhage by administering follow-up infusions daily until the signs and symptoms have resolved and then every other day for 7 to 10 days to limit the potential development of chronic joint disease. For dental extractions, mouth lacerations, or recurrent epistaxis, adjuvant antifibrinolytic therapy should be used (discussed later).

Prophylactic Factor VIII Therapy.

Most centers in the United States and other developed countries are now routinely giving individuals factor VIII prophylactic replacement therapy with recombinant factor VIII. Most centers initiate prophylactic therapy as soon as joint bleeding occurs while others start in early life even before the first bleed occurs. This therapy is usually administered through a subcutaneous access port after the insertion of a central venous line. Insertion of such lines is often associated with catheter infections or thrombosis (or both), so patients and family members must be aware of the signs and symptoms. In general, a dose of 20 to 40 U/kg of factor VIII is administered every other day or three times a week. The dose and rate are adjusted to ensure that the nadir before the next infusion is greater than 1 U/dL. The levels attained by use of this regimen usually prevent spontaneous bleeding, although hemorrhage caused by trauma may still require additional replacement therapy. The goal is to prevent recurrent hemarthrosis and associated chronic hemophilic arthropathy and thereby promote a normal lifestyle. A number of centers throughout the world have initiated prophylactic therapy programs and have demonstrated their cost-effectiveness when productivity and lifestyle are used as indicators of success. However, this long-term vision is not always shared by administrators of managed health care systems, and the most successful programs have been carried out in countries with nationalized health care.

Factor VIII Treatment Products.

Clotting factor replacement products should be rendered as free as possible of transfusion-transmissible agents, but vigilance is still necessary. As a result, recombinant products are generally considered to be preferable to plasma-derived products. Because even recombinant products may contain human albumin added as a stabilizer, products have recently been developed that contain no human plasma–derived protein. The question of which product to use, the rate of administration, and the potential use of prophylaxis are decisions that need to be made by the health care provider, the family, and the patient.

Recombinant Factor VIII Concentrates.

The factor VIII gene has been cloned, sequenced, and used to successfully transfect mammalian cells to produce recombinant factor VIII, and several recombinant factor VIII products have been licensed. Clinical trials have documented that the half-life, recovery, and efficacy of these recombinant factor VIII products are similar to those for plasma-derived factor VIII. Advantages of these recombinant factor VIII products are their freedom from human viral contamination and their production by methods that do not require human blood or plasma donors. There was initial concern that there may be an increase in the incidence of inhibitor development in previously untreated patients, but this appears not to be warranted. Careful study of patients receiving recombinant products identified inhibitors in 20% to 25%, as opposed to the previously reported 14% prevalence of inhibitors. The difference is now thought to be due to detection of transient inhibitors that subsequently disappear and not due to differences between the immunogenicity of recombinant factor VIII and plasma-derived factor VIII. More recent studies have revived interest in this issue, and a number of studies are re-evaluating whether factor VIII in the presence of VWF might be less immunogenic. A recombinant factor VIII product missing the B domain has been licensed, which may require a different approach to laboratory monitoring because its activity differs between one- and two-stage factor VIII assays. More recently developed products are formulated so that other human proteins are removed.

Plasma-Derived Factor VIII Concentrates.

Several commercial plasma-derived factor VIII concentrates are available. Intermediate-purity concentrates are produced from large pools of donor plasma by a combination of cryoprecipitation or precipitation with glycine, polyethylene glycol, or ethanol. These intermediate-purity products contain 2 to 5 units of factor VIII per milligram of protein. Products of higher purity have also been developed and are produced by immunopurification of factor VIII with the use of monoclonal antibodies to factor VIII or VWF. All these products undergo multiple purification steps that involve heat treatment, as well as other modalities, to reduce the risk of viral transmission. As a result, the risk of human immunodeficiency virus (HIV) infection; hepatitis B; hepatitis C; and, more recently, transmission of hepatitis A and parvovirus B19 has been markedly reduced or eliminated.

With the improved purity of plasma-derived products, the incidence of complications has greatly diminished. Allergic reactions, isohemagglutinin-induced hemolytic anemia, immune complex–mediated hematuria, and granulocyte antibody–induced lung injury are rarely seen. The use of immunoaffinity-purified factor VIII concentrates and recombinant factor VIII concentrates appears to stabilize CD4 ⁺ counts in HIV-infected patients with hemophilia.

To minimize the risk for hepatitis B and hepatitis A, unimmunized patients should be immunized at the time of diagnosis.

Cryoprecipitate.

The first widely used preparation of factor VIII was made by Judith Graham Poole in 1965 by a method called cryoprecipitation. Each bag of cryoprecipitate contains only 100 units of factor VIII, and thus 10 to 20 donor units are required for the treatment of joint hemorrhage in an adult. Because cryoprecipitate lacks any active method of viral inactivation, possesses significant amounts of other human proteins, and is inconvenient to administer, it is no longer considered a viable alternative to purified factor VIII products, except in areas of the world where other forms of therapy are unavailable or in short supply.

Desmopressin.

Desmopressin is a synthetic vasopressin analogue that increases plasma factor VIII and VWF levels, thereby allowing successful treatment of bleeding episodes associated with dental and surgical procedures in patients with mild and moderate hemophilia A and VWD. Desmopressin is now considered the treatment of choice in patients with mild and moderate hemophilia A who have shown a response to the drug during a therapeutic trial. It is not effective in the treatment of severe hemophilia A, severe VWD, or any form of hemophilia B.

The individual response to desmopressin is varied, with the range of increase in factor VIII level being between twofold and fifteenfold over baseline in patients with mild or moderate hemophilia A. It is therefore recommended that patients undergo a therapeutic trial of desmopressin with laboratory measurement of response to factor VIII before it is used for the treatment of bleeding episodes or as prophylactic therapy before dental and other surgical procedures. A similar degree of response is generally seen in an individual patient with subsequent doses, and thus the factor VIII level attained after a trial dose can be used to predict the response to future therapy. The level of response to factor VIII is not usually sufficient to treat life- or limb-threatening hemorrhage. Tachyphylaxis may occur with repeated doses of desmopressin, but this varies from patient to patient. Consequently, if repeated doses of desmopressin are to be administered, factor VIII levels should be monitored, and if necessary, exogenous factor VIII should be administered. In general, if several days have elapsed between doses, a response similar to that for the baseline infusion can be expected. Side effects from the administration of desmopressin are minimal and include headache; flushing; a slight change in pulse rate or blood pressure; and, rarely, hyponatremia. Because hyponatremia after the administration of desmopressin may cause a seizure in rare instances, particularly in young children, fluid intake should be restricted to maintenance levels for at least 24 hours. If repeated doses of the drug are given, serum sodium levels should be monitored. Because of rare reports of thrombosis after the use of desmopressin, the drug should be used with caution in patients with an increased risk for thrombosis.

The recommended intravenous dose of desmopressin is 0.3 µg/kg, and it is administered in 25 to 50 mL of normal saline over a period of 20 to 30 minutes. If desmopressin is being given before a procedure such as a dental extraction, it should be administered as close to the procedure as possible because the maximal response occurs 30 to 60 minutes after administration. A concentrated form of desmopressin (Stimate) is available for intranasal administration to treat bleeding disorders. This preparation should not be confused with the far less concentrated formulation (brand name DDAVP) that is used to treat enuresis; the latter formulation is ineffective for the treatment of hemophilia and VWD. The appropriate dose of intranasal Stimate is 150 µg (1 puff) for persons weighing less than 50 kg and 300 µg (1 puff in each nostril) for persons weighing more than 50 kg. It is particularly important to document the response to intranasal desmopressin before it is used for the treatment of bleeding.

Antifibrinolytic Therapy.

Bleeding from mucosal surfaces in patients with hemophilia is often problematic because of the increased fibrinolytic activity associated with the mucosa. Antifibrinolytic therapy has been found to be effective in controlling mucosal bleeding, especially from the oral mucosa. Although hemostasis is generally achieved with either factor VIII replacement or desmopressin, the risk of recurrent bleeding from oral mucosal surfaces is dramatically reduced with the administration of antifibrinolytic agents. Use of these agents for nasal bleeding or for bleeding from the urinary tract or gastrointestinal surfaces has not been studied extensively. The clearest demonstration of their efficacy is with dental extractions, for which transfusion therapy was previously required for 10 to 12 days. With the use of antifibrinolytic therapy, a single infusion of factor VIII and 7 to 10 days of antifibrinolytic therapy are usually sufficient to prevent recurrent hemorrhage after dental extractions. In addition, tranexamic acid has been shown to be effective when used topically as a mouthwash.

Two antifibrinolytic agents, aminocaproic acid and tranexamic acid, are available. Aminocaproic acid (Amicar) is formulated in an intravenous form, oral tablets, and an elixir. The tablet contains 500 or 1000 mg, and the elixir contains 250 mg/mL. Because the tablets are large and the usual dose is 5 g (5 to 10 tablets), most adult patients prefer taking the elixir. The oral dose of ε-aminocaproic acid is 100 to 200 mg/kg initially (maximum dose, 10 g), followed by 50 to 100 mg/kg per dose every 6 hours (maximum dose, 5 g). The second agent, tranexamic acid, is available in 650-mg capsules (Lysteda). The dose of tranexamic acid is 25 mg/kg every 6 to 8 hours. No elixir is available for tranexamic acid. Both tranexamic acid (Cyklokapron) and aminocaproic acid are available in intravenous forms.

Treatment of Patients with Hemophilia A Who Have Inhibitory Antibodies to Factor VIII

In 14% to 25% of patients with severe hemophilia A, antibodies develop that inactivate the procoagulant activity of factor VIII; these antibodies are referred to as factor VIII inhibitors. The clinical hallmark of inhibitor development is failure to respond to routine replacement therapy. Patients with factor VIII inhibitors can be divided into two general categories: high responders and low responders. High responders are those in whom high-titer antibody develops with exposure to factor VIII and in whom an anamnestic response usually occurs with subsequent exposure. The titer of their antibody is in excess of 5 Bethesda units and may increase to hundreds or thousands of Bethesda units after repeat exposure. In low responders a titer of inhibitory antibody is maintained at less than 5 Bethesda units, even when they are exposed to repeated doses of factor VIII. The clinical approach is different for these two groups.

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