126 Antibody-Mediated Coagulation Factor Deficiencies

Question 1

The most commonly targeted coagulation factor by an autoantibody is

Answer 1

Factor VIII (acquired hemophilia A)

The incidence of autoantibodies to factor VIII is 0.2 to 1 per 1 million persons per year.

Question 2

Factor VIII inhibitors in congenital and acquired hemophilia nearly always consist of a polyclonal Ig____ population

Answer 2

IgG

Inhibitory antibodies are primarily directed to the A2, C1, and C2 domains in factor VIII

More frequenty IgG4

Question 3

Causes of acquired hemophilia A

Answer 3

• Idiopathic
• Associated with:
• Autoimmune disorders
• Malignancy
• Postpartum period
• Use of drugs (eg, penicillin and sulfonamides)

Idiopathic cases most commonly occur in elderly patients of either sex with the median age at diagnosis of 70 years

Question 4

TRUE OR FALSE

Acquired hemophilia A is more likely to have a less severe bleeding diathesis than patients with hemophilia A and an inhibitor.

Answer 4

FALSE

Acquired hemophilia A is more likely to have a more severe bleeding diathesis than patients with hemophilia A and an inhibitor.

Acquired hemophilia A patients usually present with spontaneous bleeding, which often is severe and life or limb-threatening.

Question 5

Common bleeding sites are

Answer 5

Soft tissues, skin, and mucous membranes

In contrast to patients with congenital hemophilia A, hemarthroses and intramuscular and central nervous system bleeding are rare.

Question 6

Lab findings:

Answer 6

• Prolonged activated partial thromboplastin time (aPTT) and a normal prothrombin time (PT).
• The presence of a prolonged aPTT in a 1:1 mixture between patient and normal plasma establishes the diagnosis of a circulating antibody.

Specific assays for factor VIII activity and/or antigen will confirm the diagnosis

Question 7

Once the identity of an inhibitor has been established, its titer is determined using the

Answer 7

Bethesda assay

Inhibitors are classified as low titer or high titer when the titers are less than 5 BU/mL or greater than 5 BU/mL, respectively.

Question 8

Patients with a factor VIII inhibitor titer of less than 5 or with titers between 5 and 10 BU/mL also may respond to ________________

Answer 8

Recombinant or plasma-derived factor VIII concentrates

Whereas those with titers greater than 10 BU/mL generally do not respond.

Dose of factor VIII 70 IU/kg every 8 h, targeting trough levels of factor VIII of 50% of normal

Question 9

The mainstays of management of patients with a high titer of an inhibitor.

Answer 9

Factor VIII bypassing agents

Two agents, recombinant activated factor VII (rFVIIa) and plasma-derived factor VIII inhibitor bypassing agent (FEIBA; also called activated prothrombin complex concentrate), are approved by the US Food and Drug Administration for treatment of acquired hemophilia A.

A major concern with the use of rFVIIa and activated coagulation factor concentrates is that there is no laboratory method available for predicting response to therapy or monitoring patients on therapy.

Question 10

The recommended dose range of rFVIIa for the treatment of patients with hemorrhage due to acquired hemophilia

Answer 10

70 to 90 μg/kg repeated every 2 to 3 hours until hemostasis is achieved

The minimum effective dose in acquired hemophilia has not been determined.

Question 11

Recommended doses of FEIBA depend on the type of bleeding:

Answer 11

• Joint hemorrhage: 50 U/kg is recommended at 12-hour intervals, which may be increased to doses of 100 U/kg
• Mucous membrane bleeding: 50 U/kg is recommended at 6-hour intervals
  If hemorrhage does not stop, the dose may be increased to 100 U/kg at 6-hour intervals.
• Severe soft-tissue bleeding, such as retroperitoneal bleeding: 100 U/kg at 12-hour intervals
• Central nervous system bleeding: 100 U/kg at 6- to 12-hour intervals.

One should not exceed a daily dose of FEIBA of 200 U/kg.

Question 12

The major serious adverse event associated with bypassing agents is

Answer 12

Thrombosis

The incidence appears higher in patients with acquired hemophilia A compared to congenital hemophilia

Escalating doses of either bypassing agent or combination of the two agents should be done with caution, especially in older patients

Question 13

TRUE OR FALSE

Initiation of immunosuppressive therapy at the time of diagnosis to eradicate the inhibitor is recommended because of the serious course of this condition.

Answer 13

TRUE

Initiation of immunosuppressive therapy at the time of diagnosis to eradicate the inhibitor is recommended because of the serious course of this condition.

Question 14

Immunosuppressive agents that have been used in acquired Hemophilia A:

Answer 14

• Cyclophosphamide
• Azathioprine
• Cyclosporine A
• Intravenous immunoglobulin
• Rituximab

Plasmapheresis and immunoadsorption of the inhibitory antibody have been used.

Finally, immune tolerance induction using human factor VIII has been used successfully.

First-line immunosuppressive regimens at many centers consist of glucocorticoids alone or glucocorticoids combined with cyclophosphamide

Question 15

Has been used successfully in patients in whom factor VIII bypassing agents failed, and as first-line therapy

Answer 15

Recombinant porcine factor VIII (Obizur)

Question 16

Antibodies inhibiting thrombin and________________ frequently coexist in immune responses to commercial products that contain thrombin (eg, adhesive tissue glue, gels for interventional endoscopic procedures).

Thrombin products have been used widely in surgical and less invasive procedures.

Answer 16

Factor V

Usually, these antibodies cause no clinical problems.

However, mild to life-threatening hemorrhage can occur, especially if the titer of antihuman factor V antibodies is high.

Question 17

The risk of bleeding is higher in patients who receive __________________ because of the development of a secondary immune response.

Answer 17

Bovine thrombin products more than once

Question 18

Lab features of patients with inhibitory antibodies to factor V

Answer 18

• Prolonged PT and aPTT
• Low factor V levels
• Normal thrombin time
• The diagnosis of a factor V inhibitor is based on the specific loss of factor V coagulant activity when patient and normal plasma are mixed in a coagulation assay

Question 19

Treatment for inhibitory antibodies to factor V

Answer 19

• (high-dose) fresh frozen plasma or
• Bypassing agent, such as rFVIIa

Question 20

Antiprothrombin antibodies are most commonly associated with

Answer 20

Antiphospholipid syndrome

The antiphospholipid syndrome is caused by lupus anticoagulants, which are defined as antibodies that produce phospholipid-dependent prolongation of in vitro coagulation assays.

However, most patients with lupus anticoagulants have demonstrable antiprothrombin antibodies or a hypoprothrombinemia but no bleeding diathesis.

Question 21

TRUE OR FALSE

There is a relatively high prevalence of pathogenic anti–protein C antibodies.

Answer 21

FALSE

There is a relatively high prevalence of pathogenic anti–protein S antibodies.

An acquired inhibitor to protein C associated with a fatal thrombotic disorder has been reported but is evidently rare.

Anti–protein S antibodies appear to be a risk factor for venous thrombosis and can be manifested in vitro as activated protein C resistance.