The genes that encode factors VIII and IX are located on the long arm of the X chromosome. A genetic mutation in the factor VIII gene produces hemophilia A, occurring in about 1 in 5000 male births in the United States. A mutation in the factor IX gene causes hemophilia B, affecting approximately 1 in 25,000 male births in the United States. Together, these two forms of hemophilia make up about 99% of patients with inherited coagulation factor deficiencies. Hemophilia A and B are clinically indistinguishable from each other, and specific factor testing is required to identify the type.
Because hemophilia A and B are X-linked disorders, hemophilia is overwhelmingly a disease of men, with women typically being asymptomatic carriers. Only rarely do women have severe disease. While these disorders are genetic and usually inherited, a family history of bleeding may be absent because approximately one third of new cases of hemophilia arise from a spontaneous gene mutation.
Bleeding manifestations in patients with all forms of hemophilia are directly attribuTable to the decreased plasma activity levels of either factor VIII or IX (Table 235-1). Those with factor activity levels of 0.3 to 0.4 IU/mL (30% to 40% of normal) may never be aware that they have hemophilia, or they might manifest unusual bleeding only after major surgery or severe trauma. Unless there is another underlying disease, patients with hemophilia do not have problems with minor cuts and abrasions, as hemostasis from these injuries is achieved by platelet activation and the formation of the primary hemostatic plug (see chapter 232, "Tests of Hemostasis").
TABLE 235-1Hemophilia Severity ||Download (.pdf) TABLE 235-1 Hemophilia Severity
|Disease Severity ||Percentage of Factor VIII or IX Activity (% of Normal) ||Clinical Features |
|Severe ||<0.01 IU/mL (<1%) ||Severe spontaneous bleeding, difficult to control if trauma |
|Moderate ||0.01–0.05 IU/mL (1%–5%) ||Usually bleeding from trauma; may bleed spontaneously |
|Mild ||0.06–0.40 IU/mL (6%–40%) ||Bleeding after trauma |
Bleeding is the major complication of hemophilia, but as a result of frequent exposure to blood products, many hemophiliacs in the past were infected with viral hepatitis or human immunodeficiency virus, and had, in addition, complications related to these chronic infections; currently available factor replacement products have essentially eliminated the risk of seroconversion.
Depending on the severity of the disease, both hemophilia A and B are characterized by easy bruising and spontaneous recurrent bleeding into the joints and muscles.1,2 Although the joints and muscles are the most common areas into which bleeding occurs, hemorrhage may also occur in other areas (Table 235-2). Trauma or a surgical procedure can result in prolonged and difficult-to-control bleeding.
TABLE 235-2Hemophilia Bleeding Manifestations ||Download (.pdf) TABLE 235-2 Hemophilia Bleeding Manifestations
|Site ||Comments |
|Hemarthroses ||Most common site, more frequent in hinged joints (elbows, knees, ankles) than in multiaxial joints. |
|Soft tissue ||Bleeding into soft tissues or muscle; bleeding can dissect along fascial planes; most dangerous in the neck (airway compromise), limbs (compartment syndromes), eye (retro-orbital hematoma), spine (epidural hematoma), and retroperitoneum (circulatory shock). |
|Mucocutaneous bleeding ||Delayed bleeding after dental extractions; spontaneous bleeding from the nose, pharynx, GI tract, or lungs is uncommon. |
|CNS ||Intracranial bleeding is the most common cause of hemorrhagic death in hemophiliacs of all age groups; subdural hematomas occur spontaneously or with minimal trauma. |
|Hematuria ||Common, usually not serious, and a specific bleeding site is rarely found. |
|Hemophilic pseudotumor ||Unresolved or undertreated hematomas erode into adjacent bones resembling bone cysts or malignancy; may compress adjacent nerves and vessels. |
Although adults often know that they have hemophilia, young children may not have been diagnosed before they present to the ED with a bleeding episode. Family history may reveal a bleeding disorder on the mother's side. Hemophilia should be suspected in an infant or child who presents with excessive bruising or with bleeding into the joints, muscles, or CNS that is spontaneous or out of proportion to the history of trauma. Because factor level determines the severity of disease, those with mild hemophilia may come to medical attention only when they have a significant surgical procedure or trauma or have started a medication with antihemostatic effects.
Congenital hemophilia in neonates can be manifest as excess bleeding after circumcision or as intracranial hemorrhage, usually associated with traumatic delivery.4,5 In infants and mobile children, nonpatterned bruising can suggest hemophilia. An irriTable infant with hemophilia can be difficult to evaluate; if no other source is found, there should be a presumption of occult bleeding.
Hemophilia is diagnosed starting with the clinical suspicion of a bleeding disorder. Screening tests, such as the prothrombin time, which measures the extrinsic coagulation cascade, will be normal, whereas the activated partial thromboplastin time, which measures the intrinsic coagulation cascade, is usually abnormal. However, patients with mild hemophilia and factor levels above 0.3 to 0.4 IU/mL (30% to 40% of normal) may have an activated thromboplastin time within the test reference range. Bleeding time in both forms of hemophilia will be normal and therefore not helpful. The diagnosis is confirmed by quantitative measurement of factor VIII or IX levels below 0.50 IU/mL (<50% normal). If mild hemophilia A is suspected, a variant of von Willebrand's disease characterized by abnormal binding of factor VIII and von Willebrand factor should be excluded by special binding tests or genetic analysis.
For patients with established hemophilia, hemostatic testing (e.g., prothrombin time, activated partial thromboplastin time) is unlikely to yield new information and is not routinely indicated. Female carriers of a hemophilic gene can be suspected by family history and confirmed by DNA mutation analysis performed at specialized centers. Prenatal diagnosis is possible using chorionic villus sampling performed between 9 and 14 weeks of gestation or amniocentesis done at 15 to 17 weeks to detect the genetic mutation.
General Principles Treatment of patients with hemophilia relies on either the early replacement of missing factors or, for those who have mild factor VIII deficiency, stimulating the body to secrete clotting factor from intracellular stores. Begin replacement before or at the same time as other resuscitative and diagnostic maneuvers for intracranial, intrathoracic, intra-abdominal, retroperitoneal, ocular, or airway bleeding, as sustained bleeding raises the risk for morbidity and death (Table 235-2). Bleeding into the neck, tongue, or retropharynx can compromise the airway. Suspected intracranial hemorrhage, either spontaneous with an acute severe headache or following blunt head injury, should receive immediate factor replacement therapy followed by noncontrast head CT. Complaints of back, thigh, groin, or abdominal pain may be symptoms of retroperitoneal bleeding. Hemorrhage into the iliopsoas muscle is a common form of retroperitoneal bleeding seen in hemophiliacs, and patients may describe hip pain and have difficulty straightening their leg, preferring to keep it in a flexed, externally rotated position. An iliopsoas muscle bleed can compress and damage the femoral nerve, cause anemia of blood loss, or produce circulatory shock.
The initial manifestations of bleeding can be subtle. Simple injuries, such as ankle and wrist sprains, may at first appear benign, and several hours may pass before hemarthrosis is apparent. So, while there may not be physical signs of bleeding into a joint, patients reliably report when bleeding is occurring. Prompt treatment of hemarthroses can prevent or reduce the long-term sequelae of hemophilic arthropathy. If a large hemarthrosis is already present, consultation with an orthopedist for appropriate splinting and rehabilitation may improve the outcome once the bleeding has been controlled.6
Compartment syndromes can result from bleeds within the fascial compartments of the extremities. Compartment pressures can be safely measured after the patient has received factor replacement.
Many patients and their families administer factor concentrate therapy at home. Patients are taught to self-treat or seek care at the first symptom before little outward evidence develops. Take patient concerns seriously. Many patients will have an established management plan for acute bleeding episodes in the medical record. Regional hemophilia foundations, associations, and centers often maintain a database that can be contacted for patient-specific information.
Bleeding episodes are terribly painful, so provide adequate pain control whether or not there is a history of opiate abuse.
When treating patients with hemophilia for other reasons, some general principles apply. Do not place central venous access or arterial lines without factor replacement. Similar rules apply to arterial blood gases, lumbar puncture, and other invasive procedures. Do not give IM injections unless factor replacement is given and maintained for several days. As a general rule, do not give compounds that contain aspirin or nonsteroidal anti-inflammatory drugs for pain relief. If a hemophiliac patient requires interhospital transfer, initiate factor replacement before transfer, and do not delay factor replacement with attempts to obtain imaging. Most hemophilia centers prefer to be consulted anytime a patient with hemophilia presents to the ED, especially if there is an uncertainty about the need for factor replacement.
Hemophilia Factor Replacement Therapy
For patients with hemophilia, there are two sources for factor replacement therapy: recombinant technology from hamster cell lines and purification from human plasma (Table 235-3).1,2,7,8 The highest level of purity and the lowest risk for human viral contamination are found with the recombinant factor concentrates: no transmission of human immunodeficiency virus, hepatitis B virus, or hepatitis C virus has been reported with the current products available in the United States. However, recombinant products may have a higher risk for the development of inhibitor antibodies than plasma-derived products.9,10,11 It remains possible for even the highly treated and purified plasma-derived products to potentially transmit viruses such as hepatitis A and the highly heat-resistant parvovirus B19.1,2,7,8 Opinions vary as to the preferred product,12,13 and current World Federation of Hemophilia guidelines do not express a preference.2 In the United States, the National Hemophilia Foundation position is that recombinant factor concentrates are the preferred treatment for hemophilia despite a cost higher than plasma-derived products.14 Where possible, the treating physician should use the product that the patient uses at home.
TABLE 235-3Hemophilia Replacement Factor Products ||Download (.pdf) TABLE 235-3 Hemophilia Replacement Factor Products
|Hemophilia Type ||Available Products* (Manufacturer/Distributor) |
|Hemophilia A || |
Recombinant Factor VIII Concentrates
Helixate FS® (Bayer/CSL Behring)
Kogenate FS® (Bayer)
Human Plasma-Derived Factor VIII Concentrates
Hemofil M® (Baxter)
Monoclate-P® (CSL Behring)
Human Plasma-Derived Factor VIII Concentrates That Contain von Willebrand Factor
Humate-P® (CSL Behring GmbH)
Koate-DVI® (Grifols/Kedrion Biopharma)
|Hemophilia B || |
Recombinant Factor IX Concentrate
Human Plasma-Derived Factor IX Concentrates
AlphaNine SD® (Grifols)
Mononine® (CSL Behring)
The dosing regimen used in the hemophilic patient is empiric based on the clotting factor volume of distribution, the half-life of the factor, and the hemostatic level of factor required to control the bleeding (Table 235-4).15,16 Clotting factor is dosed in units of activity; 1 IU of factor represents the amount present in 1 mL of normal plasma. In hemophilia A, 1 IU of factor VIII per kilogram of body weight raises the plasma level by approximately 0.02 IU/mL (2%). The half-life of factor VIII is approximately 8 to 12 hours. For hemophilia B, 1 IU of factor IX per kilogram of body weight will raise the plasma level by approximately 0.01 IU/mL (1%). The half-life of factor IX is approximately 16 to 24 hours.
TABLE 235-4Initial Factor Replacement Guidelines in Moderate and Severe Hemophilia ||Download (.pdf) TABLE 235-4 Initial Factor Replacement Guidelines in Moderate and Severe Hemophilia
|Severity and Site ||Desired Factor Level to Control Bleeding ||Hemophilia A Initial Dose (IU/kg) ||Hemophilia B Initial Dose (IU/kg) ||Comments |
|Minor: skin (deep laceration) ||— ||— ||— ||Abrasions and superficial lacerations usually do not require factor replacement. Treat with pressure and topical thrombin. |
|Minor: early hemarthrosis, mild muscle bleeding, mild oral bleeding ||0.2–0.4 IU/mL (20%–40%) ||10–20 ||20–30 ||Repeat dose every 12–24 h for 1–3 d until bleeding episode is resolved. Typical duration of replacement is 1–3 d. |
|Moderate: definite hemarthrosis, moderate muscle bleeding, moderate oral bleeding ||0.3–0.6 IU/mL (30%–60%) ||15–30 ||25–50 ||Orthopedic consult may be required for splinting, physical therapy, and follow-up. Typical duration of replacement is 3–5 d. |
|Major: retropharyngeal, GI, intra-abdominal, intrathoracic, retroperitoneal ||0.6–1.0 IU/mL (60%–100%) ||30–50 ||30–50 ||Repeat dose every 8–24 h until resolution of bleeding episode. May require replacement for up to 10 d. |
|CNS ||1.0 IU/mL (100%) ||50 ||50–100 ||Treat before CT. Early neurosurgical consultation. |
Factor concentrates are supplied as lyophilized powder in single-use glass vials containing a range of amounts, from 250 to 4000 IU per vial. Calculation of the amount of factor is done using the patient's weight, baseline factor level, the desired factor level, and, to avoid wasting factor, rounding up doses to the next vial. For patients with moderate and severe hemophilia and baseline factor levels below 0.05 IU/mL (5%), the presence of such low levels can be discounted when calculating initial dosing guided by these formulae:
For major bleeding, high levels of factor replacement are required and continued until bleeding stops (Table 235-4). Repeat doses are usually given as intermittent bolus therapy every 8 to 24 hours, or 6 to 12 hours in patients under 6 years of age.
For less severe bleeding in soft tissue, muscle, or joints, a lesser amount of factor replacement is necessary; usually three doses over 1 to 2 days are sufficient to control bleeding. In addition to factor replacement, extremity and joint bleeding may benefit from splinting followed by physical therapy.6 Cryotherapy has no proven benefit in hemarthroses.17
There may be rare instances in which a patient presents with what appears to be a previously undiagnosed bleeding disorder. In these cases, treatment with fresh frozen plasma is appropriate to control bleeding until definitive studies can be done. Fresh frozen plasma contains all of the plasma clotting factors, with an average concentration of 1 IU/mL. However, one bag (about 200 mL) of fresh frozen plasma will only raise the factor levels by 3% to 5% in an average adult, so volume overload can complicate extensive factor replacement using this product.
Oral and Mucosal Bleeding Oral bleeding from hemophilia is more common in children than in adults. For an oral bleed, the area should be identified, cleaned of inadequate clot, and solution of topical bovine thrombin sprayed on to the site or applied in conjunction with a saturated absorbable gelatin sponge. Repeat doses should be limited because repetitive application of topical bovine thrombin can induce antibodies to factor V, resulting in a syndrome of severe bleeding and thrombosis, which can rarely be fatal. Factor replacement may be required, dosed according to the severity of bleeding. Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, are useful adjunctive therapies with a low rate of adverse effects.2 For very superficial mucosal injuries, it may be possible to manage the bleeding with antifibrinolytic therapy alone. The dose of aminocaproic acid is 75 to 100 milligrams/kg every 6 hours for children, and 6 grams every 6 hours for adults, given PO or IV. The dose of tranexamic acid is 10 milligrams/kg IV three times per day for 1 to 7 days. Tranexamic acid should be used with caution if hematuria is present because ureteral obstruction due to clot formation has been reported.7
Mild Hemophilia A Patients with mild hemophilia A (factor levels of 5% of normal or greater) who have mild bleeding may not always require factor replacement.1,2,18 Rather, they may be treated with desmopressin, which stimulates the release of von Willebrand factor from endothelial storage sites promoting an increase of factor VIII in the plasma (Table 235-5).19,20 A concentrated intranasal preparation is available and can be used at home.21 IV or intranasal desmopressin will increase the factor VIII level by two to four times. Desmopressin treatment can be repeated in 24 hours, but with repetitive use, the patient's stores of factor VIII will become depleted, and subsequently, the effect will be less. Desmopressin is an antidiuretic agent, and fluid restriction may be needed during use.19
TABLE 235-5Desmopressin Treatment of Mild Hemophilia A and von Willebrand Disease ||Download (.pdf) TABLE 235-5 Desmopressin Treatment of Mild Hemophilia A and von Willebrand Disease
|Patient ||IV Preparation ||Nasal Preparation |
|<2 y ||Not recommended ||Not recommended |
|<50 kg weight ||0.3 micrograms/kg IV over 30 min ||Single spray 150 micrograms in one nostril |
|>50 kg weight ||0.3 micrograms/kg IV over 30 min; maximum dose, 20 micrograms ||One spray 150 micrograms in each nostril (total dose, 300 micrograms) |
Hematuria Hematuria is common in hemophilia but is typically not severe.22 Rest and hydration are important to ameliorate the degree of bleeding. Factor replacement is indicated for gross hematuria. There is evidence that hemophiliacs are at increased risk for nephrolithiasis, suggesting that renal imaging is indicated for patients with symptoms of renal colic or new-onset hematuria.23
Factor Inhibitors Factor inhibitors, antibodies against replacement factors, tend to occur most commonly in severe hemophiliacs.2 Inhibitors not only interfere with the effectiveness of factor replacement therapy, but also can cause anaphylaxis during factor administration in patients with hemophilia B.24 The use of factor replacement in hemophilic patients with inhibitors is guided by the concentration of inhibitor (measured in Bethesda inhibitor assay units) and the type of response the patient has to factor concentrates. ED physicians should query hemophiliacs about whether they have known inhibitors.
The overriding principle in treating patients with inhibitors is close consultation with a hematologist. In patients with an inhibitor titer <5 Bethesda inhibitor assay units and who are not vigorous antibody responders, some hematologists may recommend giving an increased dose of factor in an attempt to overwhelm the existing antibody. Alternative therapies include human plasma-derived activated prothrombin complex concentrates and recombinant activated factor VII (Table 235-6).25,26,27 Activated prothrombin complex concentrate contains factors II, IX, and X, mostly nonactivated, and factor VII, primarily in the activated form. Activated factor VII, either from human plasma or recombinant, when complexed with tissue factor, activates factor X. Factor Xa, in concert with factor Va, calcium, and phospholipid, promotes the conversion of prothrombin to thrombin, which ultimately leads to the formation of a hemostatic plug composed of cross-linked fibrin. Even without tissue factor, activated factor VII can bind to the surface of activated platelets stimulating the conversion of factor X to factor Xa.
TABLE 235-6Replacement Therapy for Hemophilia A and B in Patients With Inhibitors ||Download (.pdf) TABLE 235-6 Replacement Therapy for Hemophilia A and B in Patients With Inhibitors
|Type of Product* ||Initial Dose ||Dosing Interval ||Comments |
Human plasma-derived activated prothrombin complex concentrate
FEIBA NF® (Baxter)
|50–100 units/kg ||6–12 h ||Total daily doses should not normally exceed 200 units/kg |
Recombinant activated factor VII
NovoSeven RT® (Novo Nordisk)
|90 micrograms/kg ||2 h ||Repeat until hemostasis achieved or therapy judged ineffective |
Acquired Hemophilia Acquired hemophilia occurs when autoantibodies are created against factor VIII, resulting in inactivation of this factor and a hemorrhagic tendency.28,29 This rare disorder is associated other conditions in about 40% of reported cases, such as autoimmune diseases, cancer, drugs (e.g., penicillin, sulfonamides, ciprofloxacin, phenytoin, clopidogrel), or the postpartum period. Acquired hemophilia occurs equally in both genders with a median age of 60 to 70 years. The bleeding pattern in acquired hemophilia is usually widespread cutaneous purpura and internal bleeding, with hemarthroses being less common, a difference from congenital hemophilia.
The autoantibodies are typically polyclonal IgG4 antibodies that form complexes with factor VIII in a manner that enables some residual factor VIII activity, causing a poor correlation between measured factor activity and bleeding severity. The laboratory findings include a prolonged activated partial thromboplastin time and a low factor VII level.30 The autoantibody of acquired hemophilia has different kinetics of interaction with factor VII, enabling a differentiation between the inhibitor antibody sometimes seen in congenital hemophilia and antiphospholipid antibodies by mixing studies (see chapter 232).
Treatment of acute bleeding is with activated prothrombin complex concentrates or recombinant activated factor VII (Table 235-6).30,31 Suppression of antibody formation is initiated with prednisone plus either cyclophosphamide or azathioprine. Most patients respond and maintain remission after the immunosuppressives are tapered and discontinued; relapse occurs in about 20%.32
Postpartum Acquired Hemophilia Postpartum acquired hemophilia is a rare condition with severe hemorrhagic potential.33 The risk is highest with the first pregnancy, and presentation is typically 2 months after delivery with persistent vaginal bleeding being the most common presenting symptom. Treatment for hemorrhage is with activated prothrombin complex concentrates or recombinant activated factor VII (Table 235-6). Production of the autoantibodies will spontaneously cease over many months, achieving complete remission. Immunosuppressants will reduce time to remission. Recurrence with subsequent pregnancies is uncommon.
DISPOSITION AND FOLLOW-UP
Many hemophilic patients are able to judge the severity of bleeding, self-administer replacement therapy, and monitor the response at home.1,2 Such patients may likely be discharged after initial treatment in the ED for typical joint, soft tissue, or nasal hemorrhage. Relative indications for hospital admission include treatment requiring multiple factor replacement doses or necessity for parenteral pain management. Patients with bleeding in the CNS, neck, pharynx, retropharynx, or retroperitoneum, or those with a potential compartment syndrome should be admitted. Given the complexity of treatment, consultation or transfer to a hemophilia treatment center is recommended.