History
Hemophilia is suggested by a history of hemorrhage disproportionate to trauma or of spontaneous hemorrhage, or a family history of bleeding problems. Concomitant illness may include chronic inflammatory disorders, autoimmune diseases, hematologic malignancies (in acquired hemophilia), and allergic drug reactions.
For individuals with documented hemophilia, inquire regarding the type of deficiency (eg, VIII, IX, von Willebrand), percent factor deficiency, known presence of inhibitors, and HIV/hepatitis status.
Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. Other neonates may present with severe hematoma and prolonged bleeding from the cord or umbilical area or at sites of blood draws or immunizations.
After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers, when trauma-related soft-tissue hemorrhage occurs. Young children may also have oral bleeding when their teeth are erupting. Bleeding from gum and tongue lacerations is often troublesome because the oozing of blood may continue for a long time despite local measures.
As physical activity increases in children, hemarthrosis and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a serious life-threatening complication that requires urgent diagnosis and intervention.
With mild disease, hemorrhage is most likely to occur with trauma or surgery. A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is suspected.
Signs of hemorrhage include the following:
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General - Weakness and orthostasis
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Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)
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CNS - Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes
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GI - Hematemesis, melena, frank red blood per rectum, and abdominal pain
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Genitourinary - Hematuria, renal colic, and postcircumcision bleeding
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Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, and contusions
Joint and muscle hemorrhage are the most common manifestations of moderate and severe hemophilia. Petechiae usually do not occur in patients with hemophilia because they are manifestations of capillary blood leaking, which is typically the result of vasculitis or abnormalities in the number or function of platelets.
Chronic hepatitis, progressive cirrhosis, liver failure, and hepatocellular carcinoma are more common in older individuals with hemophilia B who received the less pure earlier products. Before the introduction of hepatitis B vaccine, as many as 90% of persons with hemophilia had antibodies to hepatitis B surface antigen, and as many as 15% became long-term carriers. Hepatitis C virus (HCV) seropositivity is common in patients who started treatment before 1985.
The principal sites of bleeding in patients with hemophilia are as follows. Bleeds affect weight-bearing joints and other joints. The muscles most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is dangerous because of the large volumes of blood loss and because of compression of the femoral nerve.
In the genitourinary tract, gross hematuria may occur in as many as 90% of patients. In the GI tract, bleeding may complicate common GI disorders. Bleeding in the CNS is the leading cause of hemorrhagic death among patients with hemophilia.
Physical Examination
Systemic signs of hemorrhage include the following:
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Tachycardia
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Tachypnea
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Hypotension
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Orthostasis
Organ system–specific signs of hemorrhage include the following:
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Musculoskeletal (joints) - Tenderness, pain with movement, decreased range of motion, swelling, effusion, and warmth
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Central nervous system - Abnormal neurologic exam findings, altered mental status, and meningismus
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Gastrointestinal - Can be painless; hepatic/splenic tenderness and peritoneal signs
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Genitourinary - Bladder spasm/distension/pain, costovertebral angle pain
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Other - Hematoma leading to location-specific signs (eg, airway obstruction, compartment syndrome)
Direct the examination to identify signs related to bleeding in the joints, muscles, and other soft tissues that has occurred spontaneously or after minimal challenge. Observe the patient's stature. Examine the weight-bearing joints, especially the knees and ankles, and, in general, the large joints for deformities or ankylosis.
Especially in older patients, look for manifestations of chronic infectious disease, such as the following: include the following:
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Fatigue, poor appetite, and loss of energy with progression of chronic viral illnesses, including HIV and hepatitis C virus infection
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Jaundice, spider angiomas, hepatomegaly, abdominal tenderness, splenomegaly, and other signs related to chronic hepatitis/cirrhosis
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Weight loss, adenopathy, and opportunistic infections, particularly as a manifestation of AIDS
Clinical Classification
Hemophilia is classified according to the clinical severity as mild, moderate, or severe (see Table 1, below). Patients with severe disease usually have less than 1% factor activity. It is characterized by spontaneous hemarthrosis and soft tissue bleeding in the absence of precipitating trauma. Patients with moderate disease have 1-5% factor activity and bleed with minimal trauma. Patients with mild hemophilia have more than 5% factor VIII (FVIII) activity and bleed only after significant trauma or surgery.
Table 1. Severity, Factor Activity, and Hemorrhage Type (Open Table in a new window)
Classification |
Factor Activity, % |
Cause of Hemorrhage |
Mild |
>5-40 |
Major trauma or surgery |
Moderate |
1-5 |
Minor trauma or surgery; occasional spontaneous hemarthrosis |
Severe |
< 1 |
Lifelong spontaneous hemorrhages and hemarthroses starting in infancy |
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Coagulation Cascade
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Obituary in the Salem Gazette (Massachusetts) of a 19-year-old man, March 22, 1796.
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The hemostatic pathway: role of factor IX.
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Activation of factor IX and function of the intrinsic tenase complex. Activation of factor IX is followed by formation of the intrinsic tenase complex, which activates factor X to activated factor X, leading to a second and larger burst of thrombin production during activation of hemostasis.
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Vitamin K–dependent carboxylation of precursor factor IX to procoagulant factor IX. Carboxylation of glutamate (Glu) to gamma-carboxyglutamate (Gla) residues in the precursor protein of the vitamin K–dependent factors occurs in the endoplasmic reticulum of the hepatocyte. Reduced vitamin K is oxidized in this process. Warfarin prevents the reduction and recycling of oxidized vitamin K.
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Cell surfaced-directed hemostasis. Initially, a small amount of thrombin is generated on the surface of the tissue factor (TF)–bearing cell. Following amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot) formation. (Adapted from Hoffman and Monroe, Thromb Haemost 2001, 85(6): 958-65.)
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Knee radiographs in a patient with advanced hemophilic arthropathy demonstrate chronic severe arthritis, fusion, and loss of cartilage and joint space.
Tables
Classification |
Factor Activity, % |
Cause of Hemorrhage |
Mild |
>5-40 |
Major trauma or surgery |
Moderate |
1-5 |
Minor trauma or surgery; occasional spontaneous hemarthrosis |
Severe |
< 1 |
Lifelong spontaneous hemorrhages and hemarthroses starting in infancy |
Indication or Site of Bleeding |
Factor level Desired, % |
FIX Dose, IU/kg* |
Comment |
Severe epistaxis; mouth, lip, tongue, or dental work |
20-50 |
20-50 |
Consider aminocaproic acid (Amicar), 1-2 d |
Joint (hip or groin) |
40 |
40 |
Repeat transfusion in 24-48 h |
Soft tissue or muscle |
20-40 |
40 |
No therapy if site small and not enlarging (transfuse if enlarging) |
Muscle (calf and forearm) |
30-40 |
40 |
None |
Muscle deep (thigh, hip, iliopsoas) |
40-60 |
40-60 |
Transfuse, repeat at 24 h, then as needed |
Neck or throat |
50-80 |
50-80 |
None |
Hematuria |
40 |
40 |
Transfuse to 40% then rest and hydration |
Laceration |
40 |
40 |
Transfuse until wound healed |
GI or retroperitoneal bleeding |
60-80 |
60-80 |
None |
Head trauma (no evidence of CNS bleeding) |
50 |
50 |
None |
Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) |
100 |
100 |
Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented† |
Trauma with bleeding, surgery |
80-100 |
100 |
10-14 d |
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