See hemophilia A and factor IX (hemophilia B)
Hemophilia A and B are caused by the failure to produce blood clotting factors that are required to prevent bleeding.
These clotting factors are part of a cascade that results in the formation of thrombin, an enzyme that cleaves fibrinogen to form fibrin, which then forms a blood clot to stop their bleeding.
FVIII in the case of hemophilia A and FIX in the case of hemophilia B.
Mutations in F8/F9 genes lead to either deficiency of factors or impaired factors functions, that result in either hemophilia A or B, respectively.
Hemophilia A and B are clinically similar, given that the main target site for bleeding occurs in the joints.
Hemophilia is classified into three main forms: severe come moderate, and mild, depending on the residual coagulant activity in the blood.
Patient with a coagulation factor level of less than one are you per deciliter are classified as severe and constitute about half of diagnosed cases.
Severe hemophilia as defined as less than 1% of endogenous Factor VIII activity can result in excessive bleeding after injury, and without prophylactic replacement may have more than 30 bleeding episodes per year.
Moderate hemophilia is defined as a factor level of one to less than five IU per deciliter, and mild disease as 5 to less than 40 international units per deciliter.
The goal of prophylaxis for severe hemophilia a has been maintenance of trough activity of plasma Factor VIII of more than 1%, that is >1IU per deciliter.
Presently treatment goals are expanded to include long-term outcomes associated with higher systemic Factor VIII levels.
Gene mutation identification is important to help understand the prognosis, the risk of inhibitor formation, and can identify female carriers.
Patients with large deletions and nonsense mutations carry the highest risk for inhibitor formation, whereas missense and slicing mutations carry the lowest risk.
Most inhibitors are either transient or resolve with immune tolerance therapy,
15% of patients with hemophilia Avand 3% with hemophila B have persistent inhibitors.
Immune tolerance therapy is successful in 70% of patients and requires frequently administerd,large doses of factor VIII for many months or even years.
Patients with high tighter inhibitor’s frequently develop serious bleeding that does not respond to standard factor VIII replacement therapy, and must be treated with bypassing agents recombinant factor VIIa and activated prothrombin complex concentrates.
Some studies suggest patients with hemophilia B have a lower bleeding frequency than those with hemophilia A.
Spontaneous bleeding occurs in the joints and 70 to 80% of hemorrhagic episodes.
The most frequent side of spontaneous intra-articular bleeding in children and adults is the ankle, followed by the elbow and the knee.
Approximately 50% of children with severe hemophilia have a muscle bleed or hematoma by 6-8 months of age.
With severe hemophilia spontaneous hemorrhage may occur in the muscles of the lower legs, buttocks, iliopsoas muscle, and forearms.
Recurrent joint hemorrhage induces inflammatory and degenerative changes that injure the synovium, cartilage and bone.
Hemophilic arthropathy leads to pain, loss of range of motion, and muscle atrophy with decreases in the quality of life.
Prophylaxis is the standard of care, and is generally effective in preventing hemophilic arthropathy.
Prophylaxis with Factor VIII products that have an extended half-life as advanced the treatment of severe hemophilia by improving the control of bleeding, joint health, quality-of-life, and by reducing treatment burden.
The incidence of intracranial hemorrhage is approximately 1.9%, a frequency of 390 advance per 100, 000 patient-years with an intracranial hemorrhage mortality of 19.6%.
Prophylactic replacement of factors VIII/IX is the optimal treatment regimen and is likely to be effective in preventing intracranial hemorrhage.
Prophylaxis refers to treatment with Factor concentrate to prevent bleeding and joint distraction, and has the aim of maintaining normal musculoskeletal function.
Primary prophylaxis refers to the initiation of prophylaxis prior to or shortly after the first joint bleed and requires 2-3 infusions to week depending on the factor concentrate.
Secondary prophylaxis begins after the onset of joint disease.
In mild forms of hemophilia A the synthetic vasopressin analogue desmopressin can be used to increase plasma concentrations of Factor eight and Von Willebrand’s factor by intravenous, intranasal, or subcutaneous administration..
Blood in the joint space releases iron into the synovial fluid which is pro-inflammatory and pro angiogenic.
New blood vessels, which are friable are formed and increase the joint to bleeding risk.
The combination of bleeding, iron accumulation, synovium hypertrophy, and recurrent bleeding lead to permanent joint damage.
Now it is more typical for patients with severe hemophilia to be treated prophylactically with FVIII or FIX infusions at least once weekly and often several times a week.
The major limitations a factor concentrates is the need to infuse them intravenously and relative frequently due to short half lives of 8-12 hours for factor VIII and 18-24 hours for factor IX.
Bioengineering has extended half-life recombinant clotting factors with PEGylation or the fusing of factors to another proteins with a much longer half-life such as fragmented FC region of immunoglobulin G or human albumin, both which delay lysosomal degradation of the factor and recycle the,back into circulation: Increasing the half-life by 3-6 times for recombinant factor IX and roughly 1.5-1.6 times for recombinant factor VIII.
When the diagnosis is suspected, the measurement of factor VIII or IX clotting activity will reveal the diagnosis.
All of vitamin K dependent factors, including factor IX or reduced at birth, whereas factor VIII levels are normal or even elevated at birth.
Hemophilia A can be diagnosed immediately after birth, whereas mild hemophilia B may be difficult to diagnose at birth, and testing should be repeated at six months for a diagnostic confirmation.
New options are given subcutaneously and less frequently than standard recombinant FVIII or FIX.
Newer therapies range from extended half-life recombinant factor products, antibodies that mimic the function of FVIII, agents that target the anticoagulant protein tissue factor pathway inhibitor (TFPI), and RNA interference (RNAi) therapies that target antithrombin.
Treatment and management includes mimicking or replacing missing or inhibited factors, or inhibiting clotting proteins for patients have developed inhibitor antibodies against clotting factors.
Patients with inhibitors are refractory to standard FVIII or FIX, and have poorly responsive bleeds, which are associated with high morbidity and high cost.
The development of neutralizing alloantibodies of factor VIII/ IX coagulant activity represents the main complication of factor treatment of hemophilia, occurring approximately 1/3 of patients previously untreated with hemophilia A and approximately 1% in 5% with those of hemophilia B.
Alloantibody development is associated with increased mortality and decrease quality-of-life in patients with hemophilia.
Novel treatment approaches include: bispecific antibodies that mimic the coagulation function of factor VIII, inhibition of anticoagulation proteins such as anti-thrombin with an RNA interference molecule, and tissue factor pathway inhibitor with monoclonal antibodies.
((Emicizumab-kxwh)) is a bispecific antibody that mimics the function of factor VIII by bringing factor IX and factor X together to produce the tenase complex.
The tenase complex is essential to the generation of factor Xa, which is intern is crucial for thrombin generation and hemostasis.
Emicizumab-kxwh Is it ministered subcutaneously in varying weekly, every other week, and every four week regimens.
It restores the endogenous function of factor VIII.
Emicizumab can increase thrombosis when added to activated, prothrombin complex concentrates.
Emicizumab interferes with many coagulation tests and requires factor VIII level monitoring.
Gene therapy involves the one time transfer of a functional copy of the defective gene in an adeno associated viral vector resulting in endogenous Factor VIII, or IX production.
Gene therapy responses have been durable. Add an estimated 4 to 8 years.
Gene agents available are Etranocogene and Valoctocogene.
