Hemophilia is an inherited disorder in which patients can receive factor replacement therapies that are safe and efficacious. Hemophilia A, B, and C are associated with factor VIII, IX, and XI deficiencies, respectively. The prevalence of hemophilia A and B is 1 in 5000 males. Women who inherit the affected X chromosome can demonstrate bleeding symptoms.¹ The severity of hemophilia can be classified based on plasma procoagulant levels or clinical bleeding symptoms. Based on the plasma procoagulant levels, if a patient is suffering from a factor deficiency of less than 1%, it is termed as severe; 1% to 5% is moderately severe, and greater than 5% is considered mild. The classification based on clinical symptoms states that if the deficient factor (factor VIII or factor IX) is less than 1% with little to no spontaneous bleeding, it is termed clinically moderate or mild. Patients with procoagulant activities of 1% to 5% with frequent spontaneous bleeds are termed severe. The dual classification system has led to some source of confusion, where patients with 2% to 4% factor levels have been enrolled in studies and termed as severe hemophiliacs.²

Clinical Presentation of Hemophilia

The clinical presentations of hemophilia A and hemophilia B are quite similar, as they both involve bleeding in the joints. The hallmark of hemophilia is spontaneous bleeding. Between 70% and 80% of spontaneous bleeding episodes occur in the joints. One of the most frequent sites of nontraumatic (spontaneous) intra-articular bleeding is the ankle; it is prevalent in both adults and children. Other intra-articular bleeding sites are the knee and elbow. Half of children with hemophilia are aged 6 to 8 years old. They can suffer from hematomas or muscle bleeds. In severe cases, they can suffer from spontaneous hemorrhage in the buttocks, iliopsoas muscle, forearms, and lower legs. Patients can also suffer from degenerative and inflammatory processes that injure cartilage, bone, and synovium. Affected joints are referred to as target joints if they suffer 3 or more spontaneous bleeds within a consecutive period of 6 months, as defined by the International Society on Thrombosis and Haemostasis. Cartilage has degenerative changes, and blood in the joint spaces causes inflammatory changes of the synovium; both changes occur simultaneously. Iron acts as a key stimulant in these changes, as it has pro-angiogenic and pro-inflammatory features and is released from synovial fluid.¹

Signs and Symptoms Associated With Hemophilia

Bleeding is the hallmark of hemophilia. Hemophilia A and B are related to each other in terms of identical signs and symptoms along with the propensity to bleed. Types of bleed are related to the severity of the factor deficiency and the age of the patient. Neonates with a severe form of hemophilia are at increased risk of intracranial hemorrhage (ICH) during birth. Affected neonates born by vaginal delivery are at risk of ICH due to the use of forceps-assisted delivery or vacuum extraction. The incidence rate of ICH (3% to 4%) in affected neonates is 40-80 times higher than that of the general population. Immediate infusion of factor concentration is required for neonates if they have known hemophilia and show signs of ICH.³

Older children and adults with severe forms of hemophilia usually suffer an increased incidence of musculoskeletal bleeds such as hematomas and bleeding in the muscles, joints, or soft tissues. There is usually an absence of bleeding after the neonatal period until they are 6 to 12 months old. Long-term complications of hemophilia are related to musculoskeletal bleeds. Bleeding from the gastrointestinal tract, ICH, hematuria, and oral cavity bleeds are considered less common types of bleeding. Children with severe forms of hemophilia tend to bleed more frequently if they are not put on prophylaxis. The number of such bleeds can vary from 20 to 30 each year for older children and adults. Bleeding correlates with a patient’s baseline factor levels, as patients with mild or moderate forms of hemophilia suffer from fewer bleeds.³

Diagnosing Acquired Hemophilia A

It is recommended that invasive diagnostic or therapeutic procedures are avoided unless they are essential and cannot be delayed. Venipuncture should be kept to a minimum because it can lead to severe bleeding. Lumbar puncture without hemostatic cover and intramuscular injections are contraindicated. Patients with acquired hemophilia A (AHA) often exhibit other underlying conditions such as systemic lupus erythematosus, malignancies, dermatological conditions like pemphigoid, and pregnancy-associated and polymyalgia rheumatica. Patients with AHA can present with a bleeding pattern that is distinct from congenital hemophilia. The deficiency of factor VIII can predict the severity of congenital hemophilia, and patients predominantly experience soft tissue bleeds, hemarthrosis, and trauma-induced muscle bleeds. Patients with AHA typically have subcutaneous bleeds. The involvement of soft tissues and mucosal bleeding into the urogenital tract (postpartum), muscle hematomas, and other mucosal sites have also been noted.⁴

Screening Tests for Hemophilia

Screening tests involve complete blood count (CBC), which measures the amount of hemoglobin, number of platelets, size and number of red blood cells, and amounts of different types of white blood cells. CBC tests for patients with hemophilia are usually normal. However, prolonged or unusual bleeding can cause a reduction in red blood cells and hemoglobin. Hemoglobin is critical for the body because it transports oxygen. It is situated inside the red blood cells. The activated partial thromboplastin time (APTT) test measures the clotting ability of factors VIII, IX, XI, and XII. Patients deficient in any of these factors will take longer to clot, thus the clotting time will be longer for patients with hemophilia A or B. Prothrombin time (PT) measures the clotting ability of factors I, II, V, VII, and X. It will take longer for the patient to clot if they are lacking any of these factors, but the result of this test will be normal for patients with hemophilia A and B because they lack factors VIII and IX, respectively. A fibrinogen test is ordered if the patient has an abnormal PT or APTT test. Clotting factor tests help physicians to diagnose patients based on specific factor deficiencies and assess their severity to prepare their treatment based on factor levels.⁵

References

  1. Kizilocak H, Young G. Diagnosis and treatment of hemophilia. Clin Adv Hematol Oncol. 2019;17(6):344-351.
  2. White GC II, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J; Factor VIII and Factor IX Subcommittee. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 2001;85(3):560. doi:10.1055/s-0037-1615621
  3. Carcao MD. The diagnosis and management of congenital hemophilia. Semin Thromb Hemost. 2012;38(7):727-734. doi:10.1055/s-0032-1326786
  4. Collins P, Baudo F, Huth-Kühne A, et al. Consensus recommendations for the diagnosis and treatment of acquired hemophilia A. BMC Res Notes. 2010;3:161. doi:10.1186/1756-0500-3-161
  5. Diagnosis of hemophilia. Centers for Disease Control and Prevention. Assessed August 2, 2021.

Reviewed by Harshi Dhingra, MD, on 8/10/2021.

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