Hemophilias are bleeding disorders due to deficiency in one of the factors present in the clotting cascade.^1,2 The most common factor abnormalities are of factor VIII (hemophilia A) or factor IX (hemophilia B). von Willebrand’s disease is a related defect of the von Willebrand factor.³

These hereditary bleeding disorders typically appear early in life, and adult patients will usually be able to relate a history of a bleeding problem. However, patients with mild forms of inherited disease may be unaware of a bleeding disorder until stressed by significant trauma or development of another hemostatic problem.

Systemic bleeding disorders should be suspected in patients with severe bleeding related to trivial trauma or minor surgery, or spontaneous bleeding, particularly when the bleeding occurs in joints or muscle. Unusual bleeding or bruising at multiple areas should also raise concern about a coagulopathy. Medications can be responsible for unmasking a mild bleeding diathesis.

The pattern of bleeding can suggest a likely cause. Patients with easy bruising, gingival bleeding, epistaxis, hematuria, GI bleeding, or heavy menses are more likely to have a deficiency or dysfunction of the platelets. Conversely, patients with spontaneous deep bruises, hemarthrosis, retroperitoneal bleeding, or intracranial bleeding are more likely to have a coagulation factor deficiency. In factor-deficient patients, bleeding associated with trauma may be delayed, due to inadequate fibrin clot formation that inadequately stabilizes the initial platelet thrombus. Patients with von Willebrand’s disease may present with features of both platelet and clotting factor problems.

EPIDEMIOLOGY

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.

PATHOPHYSIOLOGY

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”).

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.

CLINICAL FEATURES

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.

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.

DIAGNOSIS

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.

HEMOPHILIA TREATMENT

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.