Hemophilia is caused by mutations in genes encoding for factor VIII or factor IX on the X chromosome. A woman can act as a carrier by having an abnormal gene in one of her X chromosomes. She will not suffer from hemophilia herself because she carries a pair of X chromosomes. She can pass the abnormal gene to her children, which means that there is a 50% chance that any sons will inherit the abnormal gene and suffer from hemophilia. Daughters will have a 50% chance of being a carrier for an abnormal gene causing hemophilia. It is rare for a daughter to be born with hemophilia unless her father suffers from hemophilia and her mother carries the abnormal gene for hemophilia, leading to abnormal genes in both X chromosomes. Spontaneous gene mutations are related to 20% of all hemophilia cases. In such cases, the patient does not have any family history of abnormal bleeding.¹

Factor VIII Inhibitors

Researchers are still investigating the etiology of inhibitor development in hemophilia. Patients with severe hemophilia A tend to develop antibodies, which are also known as inhibitors. It is estimated that this occurs in 10% to 20% of patients. After patients are treated with exogenous factor VIII (FVIII), they tend to develop antibodies against FVIII. Patients with heavy chains, light chains, or both tend to develop epitope mapping. Inhibitor development is associated with FVIII mutations. The partial conversion and frequency of inhibitors in patients have not been extensively studied, as the duration of the presence of antibodies and the inhibitor titer are not reported. A previous study showed that patients with FVIII gene inversion developed inhibitors; it was reported in 7 of 12 patients with severe hemophilia. More research is required to understand inhibitor development and its association with FVIII inversion. One of the reported cases of hemophilia A with inhibitors had nonsense mutations or deletions in their FVIII gene.²

Inhibitors in Mild and Moderate Hemophilia A

Patients with severe hemophilia A tend to develop more inhibitors than patients with mild or moderate hemophilia. The cumulative incidence of inhibitor development is estimated to be between 3% and 13%. The circulating FVIII leads to partial immune tolerance towards infused FVIII. The baseline FVIII activity level drops to less than 0.01 IU/mL due to cross-reactivity between the inhibitor and endogenous FVIII. Limited data exist on the etiology of inhibitor development, and more studies need to be conducted on this. Various risk factors are associated with inhibitor development, and research shows that it plays a role in mild and moderate hemophilia. A positive family history of inhibitors shows that it is present in patients with mild or moderate hemophilia and a familial predisposition.³

Life-Threatening Bleeding in Acquired Hemophilia A

Spontaneous and recurrent hemorrhages can occur in patients with acquired hemophilia A (AHA). AHA is a rare and life-threatening disorder that occurs due to antibodies against FVIII. It is categorized as an autoimmune disease. The clinical manifestation of AHA involves bleeding within the skin and soft tissue compartment; it does not affect the internal viscera. A case study showed that patients with AHA can suffer from persistent postoperative hemorrhage. It can cause clinically significant and life-threatening bleeding. The incidence of AHA is rare, with 1 case per 1,000,000 individuals per year. It predominantly affects the elderly population, with the median age of patients being 77 years. AHA is associated with collagen vascular disorder, malignancies, infections, respiratory disorders, infections, and drugs. AHA is considered idiopathic. If a patient presents with persistent hemorrhage and spontaneous bleeding after undergoing a surgical procedure, AHA should be considered. Laboratory studies of affected patients show prolonged aPTT while the rest of the values are normal. Diagnosis is confirmed based on reduced FVIII levels and increased FVIII inhibitors.⁴

Severe Hemophilia and Hemorrhage

Intra-abdominal hemorrhage can lead to spontaneous arterial bleeding from vessels feeding the arteries for unknown reasons. It can also lead to ileus by hematoma or intestinal ischemia. Researchers are still determining whether hemophilia is a risk associated with spontaneous intra-abdominal hemorrhage. Spontaneous intra-abdominal hemorrhage occurs in the greater omentum, retroperitoneal structures, and mesenterium. It can be treated with recombinant coagulation factor VII. It can occur in healthy individuals.⁵

Spontaneous intra-abdominal hemorrhages are related to surgical procedures wherein 8.6% of patients die annually from arterial bleeding. The mortality rate is more than 50% for these cases. Patients with severe hemophilia have a high mortality rate following invasive procedures. Patients with severe hemophilia can suffer from spontaneous intra-abdominal hemorrhage, as well as hemorrhagic stroke. The elevation of abdominal pressure is considered a critical factor. Certain cases of hemophilia can be controlled by conservative medical management with recombinant coagulation factor replacements. Patients with severe hemophilia are disadvantaged in emergency surgical and non-surgical procedures due to anticipated spontaneous intra-abdominal hemorrhage.⁵

Prompt diagnosis and appropriate treatment are critical for patients with AHA. AHA is considered a severe autoimmune disorder. The etiology of the disorder is unclear, as half of patients with AHA have additional underlying conditions. It is categorized as a rare disease that requires effective control due to the presence of autoantibodies against clotting factors. The therapy for AHA is aimed towards terminating acute bleeding episodes and eliminating or reducing the inhibitors.⁶

References

  1. Hemophilia. Cleveland Clinic. Accessed August 2, 2021.
  2. Antonarakis SE, Kazazian HH, Tuddenham EG. Molecular etiology of factor VIII deficiency in hemophilia A. Hum Mutat. 1995;5(1):1-22. doi:10.1002/humu.1380050102
  3. Gouw SC, van den Berg HM. The multifactorial etiology of inhibitor development in hemophilia: genetics and environment. Sem Thromb Hemost. 2009;35(8):723-734. doi:10.1055/s-0029-1245105
  4. Hollmig ST, Perry AG, Cook J. Acquired hemophilia: a potentially life-threatening etiology of persistent bleeding after Mohs micrographic surgery. Dermatol Surg. 2014;40(9):1056-1058. doi:10.1097/01.DSS.0000452640.53468.ce
  5. Morichika K, Tomoyose T, Nishi Y, Nakachi S, Fukushima T, Masuzaki H. The intractable intra-abdominal hemorrhage with unknown etiology in a patient with severe hemophilia A. Am J Emerg Med. 2015;33(1):129.e1-3. doi:10.1016/j.ajem.2014.06.038
  6. Franchini M. Acquired hemophilia A. Hematology. 2006;11(2):119-125. doi:10.1080/10245330600574185

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

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