Hemophilia is a rare, inherited hemorrhagic disorder that results from the deficiency or dysfunction of coagulation protein factors.1,2 Factor VIII (FVIII) and factor IX (FIX) deficiencies and dysfunctions are the pathological basis of hemophilia A and hemophilia B, respectively.2 These diseases lead to spontaneous and recurrent bleeding in the joints and soft tissues, progressively causing further damage to the skeletal muscles.2 This damage can culminate in hemophilic arthropathy, compromising joint mobility and function. Trauma or surgical procedures can induce severe blood loss in patients with hemophilia.1 

Genetics and Coagulation Factors VIII and IX in Hemophilia 

Both hemophilia A and B are X-linked Mendelian disorders with missing functional copies of the genes encoding for FVIII and FIX, respectively, as a result of mutation, deletion, or gene inversion.1 The genes encoding for FVIII and FIX are located on the long arm of the X chromosome, and mutations lead to a decrease in protein expression, activity, or both. About 5% to 10% of hemophilia A cases result from dysfunctional protein. In these cases, the protein is produced, however, activity is compromised. The percentages of dysfunctional protein are higher in patients with hemophilia B at nearly 40% to 50%.3 About 1 in 5000 and 1 in 25,000 male births are affected by hemophilia A and B, respectively.1 Females inheriting 1 affected X chromosome are asymptomatic or exhibit mild disease.2

FVIII is a plasma glycoprotein comprising 2351 amino acids. The synthesis of this protein occurs mainly in the liver; however, reduced quantities of this protein are synthesized by the kidneys and lymphatic and endothelial tissues. FVIII circulates in the plasma, forming a complex with von Willebrand factor (VWF). This factor is important for preventing the degradation of FVIII while also ensuring that FVIII is present in appropriate amounts when vascular injury occurs.4

FIX is a serine protease with 415 amino acids, also synthesized in the liver. FIX is the largest protein that is vitamin K-dependent. Vitamin K has an essential role in aiding the carboxylation of FIX, which is essential for normal protein functioning and activity.4

Hemophilia and the Roles of Factors VIII and IX in the Coagulation Cascade

The primary goal of coagulation in the human body is to maintain the integrity of the blood vessels and endothelium.3 In a basal state, the coagulation system is nonthrombogenic, as the coagulation factors exist in an inactivated form and the endothelium is nonthrombogenic. When trauma occurs and the endothelium is disrupted, the subendothelium is exposed, and as this tissue is thrombophilic, the hemostatic mechanism takes place.3 The formation of a stable fibrin clot involves the clotting cascade, with the intervention of several different proteins.1

Coagulation starts after tissue factor (TF) in the subendothelium is exposed. TF binds circulating activated (a) FVII, and the resulting TF-FVIIa complex activates zymogen FX to FXa and FIX to FIXa. Prothrombin (FII) is then converted to thrombin (FIIa) by FXa. FIIa formation allows for the subsequent release of FVIII from VWF and further activation of FVIII to FVIIIa. FIIa also activates platelets and induces a prothrombotic activated platelet surface, which leads to the binding of coagulation proteins, including FIXa.1,3 

The proteins that are deficient in patients with hemophilia, FVIII and FIX, form what is called the Tenase complex.1,3 This complex also includes calcium and phospholipids, and it recruits and activates FX to FXa. The combination of FXa, calcium, and phospholipids is called the prothrombinase complex, and this complex is responsible for transforming prothrombin into thrombin, which in turn cleaves fibrinogen into fibrin.1 FXIII, also activated by thrombin, stabilizes the fibrin monomers and consequently the clot.3

The normal hemostatic process therefore relies on the association of FVIIIa and FIXa on the surface of activated platelets and on the formation of the Tenase complex, culminating in the formation of the fibrin clot. When the levels or activities of FVIII or FIX are compromised, dysfunctional clotting occurs.3 In hemophilia, primary hemostasis occurs with the formation of a platelet plug, however, secondary hemostasis is deficient as thrombin is not generated in sufficient amounts and the fibrin clot stabilization is weakened.4

The severity of hemophilia can be classified according to the factor activity levels, which in turn correlate with the detected genetic defect. Hemophilia can be considered severe when less than 1% of the normal factor activity levels are detected, moderate when factor activity levels are between 1% and 5%, and mild when factor activity levels are detected to be 5% to 50%.1

Treatment of hemophilia occurs either at the time of bleeding or prophylactically and is based on replacement therapy with clotting factors.2 In the last decade, other therapeutic approaches have been explored, including engineered clotting factors and gene therapy.1

References

1. Peters R, Harris T. Advances and innovations in haemophilia treatment. Nat Rev Drug Discov. 2018;17(7):493-508. doi:10.1038/nrd.2018.70

2. Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet. 2016;388(10040):187-197. doi:10.1016/S0140-6736(15)01123-X

3. Zimmerman B, Valentino LA. Hemophilia: in review. Pediatr Rev. 2013;34(7):289-294; quiz 295. doi:10.1542/pir.34-7-289

4. Bolton-Maggs PHB, Pasi KJ. Haemophilias A and B. Lancet. 2003;361(9371):1801-1809. doi:10.1016/S0140-6736(03)13405-8

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