Hemophilia is the most common and severe form of hereditary hemorrhagic disorder. Hemophilia types A and B occur due to factor VIII and factor IX protein dysfunction or deficiency, respectively. Prolonged and excessive bleeding after minor trauma, or spontaneous bleeding in some cases, are the main characteristics of the disorder. A third type, hemophilia C, is very rare and occurs due to a deficiency in clotting factor XI.1 

History

Hemophilia is also labelled “the royal disease.” The Queen of England from 1837 to 1901, Victoria, was a carrier of hemophilia B. Hence, many royal family members in Europe were affected by this disease. Her eighth child, Leopold, suffered from hemophilia B, and he died at the age of 31 due to brain hemorrhage. Two daughters of Queen Victoria, Alice and Beatrice, were hemophilia B carriers, and the disease was transferred to the German, Spanish, and Russian royal families.2

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Hemophilia shows an equal distribution among all ethnic groups globally. The estimated frequency of the disease is approximately 1 in 10,000 live births, and the number of individuals worldwide with this disease is around 400,000.1

Hemophilia A

Hemophilia A is an X-linked recessive disease occuring due to a deficiency in functional plasma clotting factor VIII (FVIII) that is either inherited or due to spontaneous mutations.3

Hemophilia A is the most common type, constituting approximately 80% of the total hemophilia population. It is observed in 1 in 5000 live male births. Because the disease shows an X-linked inheritance pattern, geographical areas containing a higher incidence of consanguineous marriages, such as Egypt, show a greater disease prevalence.4

The symptoms correlate with the level of FVIII activity. Hemophilia patients can present with easy bruising, insufficient clotting due to trauma or mild injury, and spontaneous hemorrhage in severe cases.3 The concentration of FVIII is expressed in international units (IU) per 1 mL of pooled plasma or in the associated percentages, with normal levels ranging from 50% to 150%. Severe cases of hemophilia A have either no measurable FVIII or less than 0.01 IU/mL (1%), and thus show spontaneous bleeding. Moderate or mild hemophilia cases have FVIII levels of 0.02 to 0.05 IU/mL (2% to 5%) or 0.06 to 0.40 IU/mL (6% to 40%), respectively. These cases exhibit excessive bleeds after relatively insignificant trauma.4 Severe hemophilia is usually noticed in the first few months of life, while mild or moderate cases can present later in childhood or adolescence incidentally or after trauma.4

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Factors VIII and IX circulate in inactive forms. Upon activation, these 2 factors cleave and activate factor X, which is the main enzyme that regulates the conversion of fibrinogen to fibrin. Hence, a deficiency in FVIII activity significantly affects clot formation and results in uncontrolled bleeding.3

A known family history, excessive bleeding following traumatic injury, or raised activated partial thromboplastin time (aPTT) are important for the diagnostic evaluation of hemophilia. Cases having a normal hemogram and prothrombin time with elevated aPTT points towards the hemophilia, and levels of factors VIII and IX should be measured.4 

In severe and life-threatening hemorrhage, recombinant FVIII is administered to achieve a 100% desired FVIII level. In cases of mild to moderate hemorrhage, the administration of FVIII is done to achieve a 30% to 50% desired FVIII level.4

Hemophilia B

Hemophilia B occurs due to a deficiency in factor IX clotting activity, resulting in prolonged oozing after tooth extractions, injuries, or surgery, as well as episodes of recurrent or delayed bleeding prior to complete wound healing. The level of factor IX clotting activity shows a correlation with the age at diagnosis and frequency of bleeding episodes.5

The prevalence of hemophilia B is 1 in 40,000 live males, which comprises about 15% of total hemophilia cases. It has an equal distribution among all ethnic groups. Specific communities, such as Egyptians and Ashkenazi Jews, show higher rates of the disease due to a higher incidence of consanguineous marriages.6 Bleeding episodes are more commonly seen in childhood and adolescence than in adulthood.5

Synthesis of factor IX takes place in the hepatocytes, and it forms the main part of the intrinsic pathway. Its deficiency results in defects in the coagulation cascade and inadequate fibrin mesh formation.6

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The characteristic clinical feature of hemophilia B is joint involvement or hemarthrosis, which is seen in severe cases. The joints are inflamed, painful, warm, and swollen with reduced movement. Recurrent episodes of hemarthrosis ultimately lead to joint cartilage erosion and Charcot arthropathy. The most commonly affected joints are the knees, elbows, ankles, shoulders, wrists, and hips.6

The diagnosis of hemophilia B is based on reduced factor IX clotting activity.5 A prolongation of aPTT is noted, indicating disruptions in the intrinsic pathway of coagulation; however, a normal aPTT cannot rule out hemophilia. Replacement of factor IX forms the basis of hemophilia B treatment.6

Hemophilia C

​​Factor XI deficiency is also referred to as hemophilia C or Rosenthal syndrome. It was identified for the first time in 1953 in individuals who had severe bleeding after dental extractions. The disorder is rare, with an estimated prevalence of 1 in 1,000,000. Higher prevalence has been found in the populations where consanguinity is common (8% of Ashkenazi Jews in Israel).7

The disease occurs due to mutations in the factor XI gene (f11) on chromosome 4, consisting of 15 exons spanning a genomic region of 23 kb. Around 253 mutations have been described in previous studies.8

The bleeding episodes are commonly noticed in areas with high fibrinolytic activity, such as the oral cavity, pharynx, and genitourinary tract, usually in concurrence with surgical procedures. This disorder is usually not associated with spontaneous bleeding like hemarthrosis, however, it can be seen with repeated trauma such as in athletes.7

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A factor XI assay aids in confirmation of the diagnosis.7 Factor XI deficiency can cause prolonged aPTT, but a normal aPTT cannot rule out mild deficiency and can cause false negative results.9

Hemophilia C cases require careful preprocedural planning. In cases undergoing major procedures with severe factor XI deficiency or a previous history of major bleeding, it is recommended to monitor factor XI activity during the perioperative period and replenish with factor XI concentrates or fresh frozen plasma.7

References

  1. Mehta P, Reddivari AKR. Hemophilia. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2021.
  2. Franchini M, Mannucci PM. Past, present and future of hemophilia: a narrative review. Orphanet J Rare Dis. 2012;7:24. doi:10.1186/1750-1172-7-24
  3. Drelich DA. Hemophilia A. Medscape. Updated June 5, 2020. Accessed July 23, 2021.
  4. Salen P, Babiker HM. Hemophilia A. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2021.
  5. Konkle BA, Huston H, Nakaya Fletcher S. Hemophilia B. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle, WA: University of Washington, Seattle; 2000.
  6. Alshaikhli A, Rokkam VR. Hemophilia B. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2021.
  7. Jayakrishnan T, Shah D, Mewawalla P. Hemophilia C: a case report with updates on diagnosis and management of a rare bleeding disorder. J Hematol. 2019;8(3):144-147. doi:10.14740/jh522
  8. Rimoldi V, Paraboschi EM, Menegatti M, et al. Molecular investigation of 41 patients affected by coagulation factor XI deficiency. Haemophilia. 2018;24(2):e50-e55. doi:10.1111/hae.13378
  9. Salloum-Asfar S, de la Morena-Barrio ME, Esteban J, et al. Assessment of two contact activation reagents for the diagnosis of congenital factor XI deficiency. Thromb Res. 2018;163:64-70. doi:10.1016/j.thromres.2017.12.023

Reviewed by Debjyoti Talukdar, MD, on 8/10/2021.