History
For patients in whom hemophilia is suspected, inquire about the following:
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History of hemorrhage disproportionate to trauma
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History of spontaneous hemorrhage
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Bleeding disorders in the family
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Concomitant illness (especially those associated with acquired hemophilia, such as chronic inflammatory disorders, autoimmune diseases, hematologic malignancies, and allergic drug reactions)
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Recent pregnancy
For individuals with documented hemophilia, ascertain the type of deficiency (eg, factor VIII [FVIII], FIX, von Willebrand), degree of factor deficiency, known presence of inhibitors, and HIV/hepatitis status. For patients with mild-to-moderate disease, determine responsiveness to desmopressin acetate (DDAVP). [7]
Signs and symptoms of hemorrhage include the following:
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General - Weakness and orthostasis (related to anemia/hypovolemia secondary to bleeding)
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Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, refusal to use the joint (young children)
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Central nervous system (CNS) - Headache, stiff neck, vomiting, lethargy, irritability, spinal cord syndromes
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Gastrointestinal (GI) - Hematemesis, melena, frank red blood per rectum, abdominal pain
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Genitourinary - Hematuria, renal colic, post-circumcision bleeding
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Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, contusions, excessive bleeding with routine dental or other procedures
Evidence of infectious disease includes the following:
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HIV/AIDS-related symptoms
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Hepatitis-related symptoms
Newborn boys with severe hemophilia may present with prolonged bleeding at circumcision. Easy bruising may occur at the start of ambulation or primary dentition. Older patients may have a history of hemarthroses and prolonged bleeding with surgical procedures, trauma, and dental extraction, and may have spontaneous bleeding in soft tissues.
A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is diagnosed. Factors that elevate FVIII levels (eg, age, ABO blood type, stress, exercise) may mask mild hemophilia.
Weight-bearing joints and other joints are principal sites of bleeding in patients with hemophilia. 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 volume of blood loss and because compression of the femoral nerve may occur.
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 in patients with hemophilia.
Acquired hemophilia
Acquired hemophilia due to an autoantibody in previously hemostatically normal individuals tends to affect elderly persons who have comorbid conditions, but may also develop post partum. Persons with acquired hemophilia may experience extensive, often life threatening, bleeding before the condition is recognized.
In contrast to persons with severe inherited hemophilia A, in whom joint bleeding is common, patients with acquired hemophilia present with large intramuscular, retroperitoneal, limb, subcutaneous, genitourinary, GI, or excessive postoperative or postpartum bleeding. Bleeding into an extremity can result in findings that are easily confused with deep vein thrombosis. Massive upper extremity bleeding can be precipitated by a simple venipuncture. Bleeding can develop at any site.
Postpartum acquired hemophilia usually comes to attention 2 to 5 months after delivery, when bleeding symptoms supervene. Rarely, the inhibitor may develop during pregnancy.
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 and symptoms of hemorrhage include the following:
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Musculoskeletal (joints) - Tenderness, pain with movement, decreased range of motion, effusion, and warmth
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Central nervous system (CNS) - Abnormal neurologic exam findings, altered mental status, and meningismus
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Gastrointestinal (GI) - Can be painless; hepatic/splenic tenderness, and peritoneal signs
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Genitourinary - Bladder spasm/distension/pain and costovertebral angle pain
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Other - Hematoma leading to location-specific signs (eg, airway obstruction, compartment syndrome)
Signs of infectious disease include the following:
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HIV/AIDS-related signs
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Hepatitis-related signs
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.
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 children grow and become more physically active, hemarthroses 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.
Petechiae usually do not occur in patients with hemophilia. The reason is that petechiae are manifestations of capillary blood leakage, which is typically the result of vasculitis or abnormalities in the number or function of platelets.
Hemophilia is classified according to clinical severity as mild, moderate, or severe (see Table 1, below). Patients with severe disease usually have less than 1% factor VIII (FVIII) activity and experience spontaneous hemarthrosis and soft-tissue bleeding in the absence of apparent precipitating trauma. Patients with moderate disease have 1-5% FVIII activity and bleed with minimal trauma. Patients with mild hemophilia have more than 5% factor activity and bleed only after significant trauma or surgery.
Table 1. Hemophilia 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 |
Mild-to-moderate trauma |
Severe |
< 1 |
Spontaneous |
Direct the examination to identify signs related to spontaneous bleeding, or bleeding with minimal challenge, in the joints, muscles, and other soft tissues. Observe the patient's posture. Examine the weight-bearing joints, especially the knees and ankles, and, in general, the large joints for deformities or ankylosis. Look for jaundice and other signs of liver failure (eg, cirrhosis), and for signs of opportunistic infections in patients who are HIV positive.
Pseudotumors are produced by a slow expansion of repeated hemorrhages in bone or soft tissues. They can be restricted by the fascial planes of a muscle, cause resorption of neighboring bone by pressure-induced ischemia, or develop under the periosteum, leading to erosion of the bony cortex. They develop slowly over months to years and often are asymptomatic, unless pressure on the nerves or vascular compromise occurs.
Pseudotumors contain a brownish material and can become infected. The buttock, pelvis, and thighs are common locations for a pseudotumor (see the images below).
Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional limb). This photo shows black-brown old blood, residual muscle, and bone.
Photograph of a patient who presented with a slowly expanding abdominal and flank mass, as well as increasing pain, inability to eat, weight loss, and weakness of his lower extremity.
Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.
Photograph depicting extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
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Coagulation pathway.
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The hemostatic pathway. APC = activated protein C (APC); AT-III = antithrombin III; FDP = fibrin degradation products; HC-II = heparin cofactor II; HMWK = high-molecular-weight kininogen; PAI = plasminogen activator inhibitor; sc-uPA = single-chain urokinase plasminogen activator; tc-uPA = two-chain urokinase plasminogen activator; TFPI = tissue factor pathway inhibitor; tPA = tissue plasminogen activator
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Structural domains of human factor VIII. Adapted from: Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional structure of membrane-bound coagulation factor VIII: modeling of the factor VIII heterodimer within a 3-dimensional density map derived by electron crystallography. Blood. Feb 15 2002;99(4):1215-23; Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. NY: McGraw-Hill; 2001:1639-57; and Roberts HR. Thoughts on the mechanism of action of FVIIa. Presented at: Second Symposium on New Aspects of Haemophilia Treatment; 1991; Copenhagen, Denmark.
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Possible genetic outcomes in individuals carrying the hemophilic gene.
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Photograph of a teenage boy with bleeding into his right thigh as well as both knees and ankles.
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Photograph of the right knee in an older man with a chronically fused, extended knee following open drainage of knee bleeding that occurred many years previously.
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Photograph depicting severe bilateral hemophilic arthropathy and muscle wasting. The 3 punctures made into the left knee joint were performed in an attempt to aspirate recent aggravated bleeding.
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Radiograph depicting advanced hemophilic arthropathy of the knee joint. These images show chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.
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Radiograph depicting advanced hemophilic arthropathy of the elbow. This image shows chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.
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Photograph of a hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required.
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Large amount of vascular synovium removed at surgery.
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Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, diffuse deposits would be demonstrated; iron-laden macrophages are present.
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Large pseudocyst involving the left proximal femur.
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Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional limb). This photo shows black-brown old blood, residual muscle, and bone.
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Dissection of a pseudocyst.
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Transected pseudocyst with chocolate brown-black old blood.
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Photograph of a patient who presented with a slowly expanding abdominal and flank mass, as well as increasing pain, inability to eat, weight loss, and weakness of his lower extremity.
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Plain radiograph of the pelvis showing a large lytic area.
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Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.
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Photograph depicting extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
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Magnetic resonance image of an extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
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Coagulation Cascade
Tables
Classification |
Factor Activity, % |
Cause of Hemorrhage |
Mild |
>5-40 |
Major trauma or surgery |
Moderate |
1-5 |
Mild-to-moderate trauma |
Severe |
< 1 |
Spontaneous |
Indication or Site of Bleeding |
Factor level Desired, % |
FVIII Dose, IU/kg |
Comment |
Severe epistaxis; mouth, lip, tongue, or dental work |
20-50 |
10-25 |
Consider aminocaproic acid (Amicar), 1-2 d |
Joint (hip or groin) |
40 |
20 |
Repeat transfusion in 24-48 h |
Soft tissue or muscle |
20-40 |
10-20 |
No therapy if site small and not enlarging (transfuse if enlarging) |
Muscle (calf and forearm) |
30-40 |
15-20 |
None |
Muscle deep (thigh, hip, iliopsoas) |
40-60 |
20-30 |
Transfuse, repeat at 24 h, then as needed |
Neck or throat |
50-80 |
25-40 |
None |
Hematuria |
40 |
20 |
Transfuse to 40% then rest and hydration |
Laceration |
40 |
20 |
Transfuse until wound healed |
GI or retroperitoneal bleeding |
60-80 |
30-40 |
None |
Head trauma (no evidence of CNS bleeding) |
50 |
25 |
None |
Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) |
100 |
50 |
Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented† |
Trauma with bleeding, surgery |
80-100 |
50 |
10-14 d |
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