Factor VIII inhibitors

Inhibitors to factor VIII (FVIII) typically present later in life.

Acquired hemophilia A (AHA) is a rare disorder caused by autoantibodies against factor VIII.

Acquired factor VIII deficiency, also known as AHA, may be caused by autoimmune disease, malignancy or medications, but it is usually idiopathic.

Inhibitors are neutralizing antibodies that develop in approximately 30% of patients with hemophilia A and up to 10% of those with hemophilia B who are treated with exagenous factor VIII or factor IX, respectively.

These antibody inhibitors, prevents exogenous clotting factor concentrates from achieving hemostasis, which leads to increased morbidity and mortality.

Its estimated incidence is about 1 person per million per year.

Following exposure to factor VIII, alloantibodies that neutralize factor VIII clotting function develop in approximately 30% of patients with severe hemophilia A.

Recombination and plasma derived factor VIII products confer similar risks of development of factor VIII inhibitors (Gouw SC et al).

Patients who develop such acquired factor VIII inhibitors may present with catastrophic bleeding episodes.

It usually presents as unexplained bruising or bleeding and is only rarely diagnosed by an incidentally noted prolonged aPTT. 

The severity of bleeding is variable and can include subcutaneous, soft-tissue, retroperitoneal, gastrointestinal, and intracranial hemorrhage.

AHA is considered idiopathic in more than half of cases. 

For patients with an identified cause, the most common causes are malignancy and autoimmune disease.

In about 30% of children inhibitory antibodies to factor VIII develop and make usual treatment with factor VIII and prophylaxis impossible.

Patients with congenital hemophilia A treated with factor VIII preparations have about a 15% chance of developing factor VIII inhibitors.

In this setting, inhibitors develop in response to recombinant factor VIII exposure.

Acquired factor VIII deficiency is rare and is due to the development of auto antibodies against factor VIII, and manifests  over weeks-months.
The incidence increases with age with the median age of the diagnosis of 78 years.
Bleeding can be severe and intramuscular bleeding can occur.

Acquired factor VIII deficiency symptoms are associated with cancer and autoimmune diseases, but more than 50% of cases have an unknown cause.

Drugs have rarely been associated with factor VIII inhibitors; interferon, blood thinners, antibiotics, and psychiatric medications,

Recombinant and plasma derived factor VIII confer similar risks of inhibitor development (Gouw SC et al).

With the development of high titers of factor VIII inhibitors, greater than five Bethesda units, bleeding no longer responds to standard factor VIII replacement

The disorder is rare, but can cause significant morbidity and mortality.

Most acquired FVIII inhibitors bind to the A2, A3 or C2 domains.

Anti-C2 antibodies disrupt the binding of FVIII to phospholipid and vWF, while antibodies to A2 and A3 interfere with FVIII binding to factor X and factor IXa.

In congenital hemophilia A patients treated with factor VIII, alloantibodies to FVIII develop in 20–40% of patients.

Acquired inhibitors/autoantibodies against FVIII in nonhemophiliacs occur in only about one case per million per year.

Acquired factor VIII inhibitor diagnosis is considered in patients with acute bleeding and unexplained prolonged  PTT;patient with unexplained PTT should be evaluated prior to surgery even if asymptomatic.

In acquired hemophilia, autoantibodies are characteristically non-complement fixing, non-precipitating immunoglobulins from the IgG family that bind FVIII in a time, temperature related way..

Acquired hemophilia has no known genetic inheritance pattern and is seen in males and females equally.

Most acquired hemophilia occurs in adults, rather than in children.

The median age at presentation of acquired Factor VIII inhibitor disease is between 60 and 67 years.

Factor VIII inhibitor diagnosis can be tested by measuring factor VIII activity and inhibitor concentrations using the Bethesda essay for an anti-factor VIII enzyme linkED immunoabsorbent assay.

Hemarthroses are the hallmark of congenital hemophilia, but they seldom occur in acquired hemophilia, as patients usually present with purpura or soft tissue bleeding.

Patients with acquired hemophilia may present with severe muscle bleeding, hematuria, epistaxis, gastrointestinal bleeding and even intracerebral bleeds.

Inhibitor development in congenital hemophilia not presently associated with increased mortality, while it is still the case in acquired hemophilia.

Acquired factor VIII antibodies in non-hemophiliacs is rare with this incidence of 1.3-1.5 per million per year.

The incidence of acquired hemophilia increases with age.

Acquired hemophilia has a biphasic age distribution with a small peak between 20-40 years of age, and a larger peak in patients H. 68-80 years.

In the earlier peak there are more women do to higher rates found in the postpartum period, and in the latter peak the incidence is similar between men and women.

Most patients with acquired hemophilia present with uncontrolled bleeding.

Acquired hemophilia associated with other illnesses for up to 50% of cases.

Death is more frequent within the first few weeks after finding of symptomatic manifestation of acquired hemophilia, making rapid diagnosis and treatment essential.

Acquired hemophilia treatment is focused on stabilization of initial bleeding and long-term eradication of the acquired inhibitor.

Patients with a confirmed diagnosis of factor VIII inhibitor, acquired, and clinically relevant bleeding should be treated with a hemostatic agent, such as recombinant factor VIIa, activated prothrombin complex concentrate or recombinant factor VIII.

The most common associated illnesses are autoimmune in 17-18% of cases, with the most common systemic lupus erythematosus, rheumatoid arthritis or Sjögren’s syndrome.

Other frequently reported associated processes include solid tumors and lymphoproliferative malignancies.

May be associated with skin disorders such as pemphigus and epidermolysis bullosa, drug reactions, infections, chronic graft-versus-host disease, and in the postpartum state.

The development of autoantibodies has the potential for significant morbidity and mortality.

All patients should be started on immunosuppressive therapy: prednisone/rituximab/cyclophosphamide.

Initial treatment of AHA often focuses on stopping an acute hemorrhage by either raising circulating levels of factor VIII or bypassing it in the coagulation cascade.

Death is more frequent within the first few weeks after the symptomatic manifestation of the process, and early treatment is vital.

Clinical manifestation acquired hemophilia with autoantibodies ranges from minimal or no bleeding,to spontaneous life-threatening hemorrhage.

In acquired hemophilia early hemorrhagic death is associated with severe pulmonary or gastrointestinal hemorrhage, while late deaths are more often associated with CNS or retroperitoneal bleeds.

The typical bleeding episodes in congenital hemophilia muscle bleeds and hemarthroses, or rare in acquired hemophilia.

80% of bleeds or soft tissue bleeds, but mucocutaneous, gastrointestinal, and urogenital bleeds also occur.

Bleeding episodes correspond to iatrogenic interventions failing to respond to treatment.

6% of patients with acquired hemophilia present with no clinically significant bleeding (Collins PW).

Acquired hemophilia associated with severe bleeding in up to 90% of patients, with a mortality rate ranging from 3-33%.

In approximately 50% of case, especially in the elderly the process is idiopathic.

Pregnancy and acquired hemophilia accounts for 10% of all cases.

Factor VIII autoantibodies develop associated with pregnancy is 80% associated with first pregnancy, and reemergence of such antibodies in subsequent pregnancies is rare.

The prognosis is good in postpartum acquired hemophilia.

Factor VIII autoantibodies manifests commonly 1-4 months after delivery, but may be up to 1 year after delivery.

Most cases of pregnancy associated acquired hemophilia mild, with low potency inhibitor, with spontaneous disappearance of the inhibitor in a mean period of 30 months, and a low mortality rate of 0-6%.

In patients with high titer inhibitors persistence indicates evaluation for the presence of auoimmune or malignant disease.

Inhibitors of Factor VIII are IgG in nature and increase the risk of fetal hemorrhage from transplacental transfer of the inhibitor.

Autoimmune disease associated Factor VIII autoantibody levels are high and less likely to resolve than lower levels associated with pregnancy.

Associated with 17% of autoimmune diseases.

Malignancy, solid organ or hematologic, accounts for 10% of cases of acquired hemophilia.

The most common screening laboratory abnormality seen is an isolated prolonged aPTT, with a normal PT, thrombin time and platelet count.

Mixture studies with normal control plasma will correct the test value to the normal range in the presence of a factor deficiency but not in the presence of an acquired inhibitor.

Since an acquired inhibitor is time and temperature dependent the mixing studies should be incubated 1-2 hours at 37°C.

Once an inhibitor is suspected as the cause of a prolonged aPTT, further testing should be done to eliminate the two most common causes: heparin contamination and the lupus anticoagulant.

After a mixing study confirms the presence of an inhibitor and other nonspecific inhibitors have been ruled out, the FVIII activity should be measured.

If the FVIII activity is low, the titer of the FVIII antibody should be ascertained.

The strength of an inhibitor can quantified by using the Bethesda assay.

The Bethesda assay measures residual FVIII activity after incubation of normal plasma with serial dilutions of patient plasma for 2 hours at 37°C.

The inhibitor titer in Bethesda units represents the reciprocal of the dilution of the patient’s plasma that leads to 50% inhibition in the assay.

Treatment of the underlying disorder or removal of an offending drug can aid in removal of the inhibitor.

Treatment requires initial treatment of bleeding and its complications and removal and/or eradication of the inhibitor

Initial treatment of bleeding utilizes agents that increase FVIII levels with DDAVP or FVIII infusions to raise the plasma FVIII levels to 30–50% in a patient with acquired hemophilia.

With inhibitors patients generally require immune tolerance reduction with daily infusions of high-dose factor VIII:this approach is effective in 70 to 80% of patients and standard bleeding prophylaxis with factor VIII can resume.

In the remaining 20 to 30% of patients factor VIIa based bypassing agents are required to treat bleeds: either recombinant factor VIIa or factor VIII inhibitor bypassing activity, a plasma, derived product.

DDAVP can provide a transient rise in factor VIII levels, enough for therapeutic purposes in patients with type 1 von Willebrand’s disease and most patients with mild hemophilia A and in patients with acquired hemophilia A who have very low titer inhibitors (< 3 BU).

Infusions of human factor VIII in patients with low-titer inhibitors (<5BU) may provide hemostasis.

Factor VIII concentrate (human or recombinant porcine factor VIII) may be effective in patients with low inhibitor titers (< 5 BU).

Higher doses are often required than those used in congenital hemophilia A. Factor VIII concentrate is usually combined with immunosuppressive treatment to lower the factor VIII inhibitor level 

FVIII treatment may be more effective if combined with plasmapheresis and immunomodulatory medications.

With severe bleeding and an inhibitor titer greater than 5 BU, therapy with an agent that bypasses FVIII, either an activated prothrombin complex concentrate (aPCC) or recombinant factor VIIa (rVIIa) is utilized.

The bypassing agents anti-inhibitor coagulant complex and recombinant activated factor VII control approximately 80% of bleeding episodes in patients with hemophilia and inhibitors.

No single agent is considered to be the standard of care for providing hemostasis in acquired hemophilia.

Immunosuppressive agents are the mainstay of AHA treatment to lower the inhibitor level.

AHA is associated with significant risk of morbidity and death related to bleeding, complications of treatment and underlying disease.

The only aPCC available is FEIBA, a plasma-derived concentrate containing activated clotting factors that has undergone a single-viral inactivation with dry heat vapor treatment.

Overall complete response rate of 86% with a dosing regimen of FEIBA at 75 units/kg every 8–12 hours with a median number of 10 doses to control a severe bleed.

A maximum dose of 200 units/kg within a 24-hour period should not be exceeded, due to a risk of thromboembolism.

Prophylaxis with anti-inhibitor coagulant complex, FEIBA, decreases the frequency of joint and other bleeding events in patients with severe hemophilia A and factor VIII inhibitors (Leissinger C et al).

rFVIIa binds to the surface of activated platelets, where it supports thrombin generation, thus bypassing the need for FVIII and does not have the potential to transmit human pathogens.

Early studies using rFVIIa as a second-line agent for the treatment of acquired hemophilia showed a complete response rate in 75% of bleeding episodes and a partial response in an additional 17%.

Dosing for rFVIIa is 90–120 µg/kg every 3 hours until bleeding is stopped.

It is possible to use extracorporeal means to remove the autoantibodies to FVIII with either plasmapheresis or immunoadsorption with staphylococcal protein A.

Prednisolone at 1 mg/kg/day results in inhibitor resolution in approximately 30% of patients.

The addition of cyclophosphamide at 50 to 100 mg/day to corticosteroids can increase the response rate to 60–70%.

Other agents that have been used are azathioprine, vincristine, , Cyclosporine A, mycophenolate mofetil, 2-chlorodeoxyadenosine, and Rituximab.

Immunosuppressive agents show response in 3 to 6 weeks, but some may have a prolonged response time, and recur when the agents are discontinued.

Infusion of intravenous immunoglobulin (IVIG) has also been used with a response rate of 30%.

Pathologic circulating antibodies that result from immune response to factor VIII recognized associated a foreign antigen and which may develop after one or more infusions of plasma derived or recombinant clotting factor treatment.

May decrease or entirely eliminate hemostatic activity of the factor VIII molecule.

Development in any one patient is unpredictable.

Patients who undergo treatment at a young age are at increased risk of inhibitor development.

Spontaneous remission may occur in one third of patients.

Patients with family history of hemophilia with inhibitors run a higher risk of developing inhibitors.

F8 gene mutation may be responsive for familial predisposition of acquiring inhibitors.

Ethnic factors have a strong effect with a much higher risk among nonwhite individuals.

A weak correlation exists for MHC class I/II genotypes.

Associated with interleukin 10 gene and inhibitor development.

Rituximab may be effective therapy.

Individuals with severe hemophilia a may develop alloantibody inhibitors that neutralize Factor VIII.

Develops more frequently in severe disease and more prevalent than in hemophilia B, with an overall incidence of 20-30%.

Patients often develop recurrent and poorly controlled joint bleeds leading to arthropathy and permanent impairment

Detected in up to 50% of patients with severe hemophilia A.

Highest incidence in severe hemophilia A in children under the age of 5 years.

Risk of development of an inhibitor is greatest at the onset of replacement therapy in previously untreated patients with severe hemophilia compared to patients exposed to coagulation concentrates.

Bethesda assay quantifies Factor VIII neutralization by alloantibody inhibitor.

One Bethesda unit is defined associated the reciprocal or inhibitor dilution required to sustain a 50% residual factor VIII activity in a mixture of patient plasma and pooled normal plasma.

Majority of Factor VIII inhibitors are low-titer inhibitors with less than 5 Bethesda units, may be short lived and spontaneously disappear.

With low-titer inhibitors Factor VIII replacement therapy may provide a subclinical response while patients with high-titer (greater than 10 Bethesda units), will not respond.

High-titer patients display an anamnestic rise on re-exposure to any source of factor VIII.

Present with normal prothrombin time but a prolonged partial thromboplastin time which may show immediate correction after mixing studies with normal plasma, but with incubation at 37’C for 1-2 hours the correction fails as factor VIII neutralization by the alloantibody are relatively slow.

Risk for severe bleeding higher in patients with inhibitors than patients without such inhibitors.

Treatment requires bypass reagents such a protein complex concentrates and activated factor VII.

Bleeding in patients with low titer inhibitors, <5 Bethesda units, increased doses of Factor VIII or Factor IX concentrates can be used to overcome the inhibitor, particularly in patients with low responding inhibitors that do not increase anamnestically after exposure to the deficient clotting factor.

In patients with bleeding and high responding or high inhibitors bypassing agents able to circumvent the inhibitors effect of hemostasis and include: activated prothrombin complex concentrates (FEIBA) and activated recombinant factor VII (NovoSeven).

Treatment with inhibitor eradication with immune tolerance induction is the most effective treatment for patients with history responding inhibitors.

Emicizumab  a factor VIII mimetic is a bispecific anybody that links factors IXa & X, limiting factor VIII cofactor function: it has been approved for prevention of episodes of bleeding in adults and children with hemophilia A, and can be effective in patients with factor VIII inhibitors.

Emicizumab Prophylaxis reduce reduces the annualized rate of treated bleeding events by 88% with inhibitors.

Concizumab is an anti-tissue factor pathway, inhibitor, monoclonal antibody, designed to achieve hemostasis in all hemophilia types, with subcutaneous administration.

Among patients with hemophilia, A or B  with inhibitors, the annualized bleeding rate is lower withConcizumab prophylaxis, than with no prophylaxis.

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