ACQUIRED HEMOPHILIA A

ACQUIRED HEMOPHILIA A CHARACTERISTICS

Incidence 0.2-1.0 case per million per year – is incidence increasing???

80-90% present with major hemorrhages 10-22% mortality attributed to inhibitor Biphasic age distribution

Small peak in young postpartum women Major peak in 60-80 years of age

ACQUIRED HEMOPHILIA A CHARACTERISTICS

Most individuals are previously healthy-idiopathic.

Some have defined or evolving associations.

CLINICAL MANIFESTATIONS OF ACQUIRED HEMOPHILIA

Overt bleeding -most frequently bruising, muscle hematomas, GI bleeding, hematuria

Iatrogenic - IV lines, bladder catheterization or post surgical bleeding

Acute complications - compartment syndromes, airway compression 2nd to subglottic bleeding

Values of more than 5 BU/ml are defined as high titer inhibitors and are generally associated with more aggressive bleeding and delayed responses to treatment .

FVIII INHIBITORS INACTIVATE FVIII

Boggio, LN, Green D. Rev Clin Exp Hematol. 2001;5:389-404

Autoantibody Inactivation Autoantibody Inactivation KineticsKinetics

• Display type II kineticsDisplay type II kinetics• Clearance is not linearClearance is not linear• Difficult to “overwhelm” Difficult to “overwhelm”

with clotting factor with clotting factor replacementreplacement

LABORATORY EVALUATION IN A BLEEDING PATIENT

PLATELET COUNT BLEEDING TIME (BT) PROTHROMBIN TIME (PT) PARTIAL THROMBOPLASTIN TIME

(PTT) THROMBIN TIME (TT)

CLINICAL FEATURES OF BLEEDING DISORDERS

Platelet Factor Disorders

Coagulation disorders

Site of bleeding Skin, Mucous membranes (epistaxis, gum, vaginal, GI tract)

Deep in soft tissues (joints, muscles)

Petechiae Yes No

Ecchymoses (“bruises”) Small, superficial Large, deep

Hemarthrosis / muscle bleeding

Extremely rare Common

Bleeding after cuts & scratches

Yes No

Bleeding after surgery or trauma

Immediate Delayed (1-2 days)

Platelet Coagulation

Purpura

Ecchymoses

Petechiae

THE CLOTTING MECHANISM

PROTHROMBIN THROMBIN

FIBRINOGEN

FIBRIN(II) (III)

(I)V

X

Tissue ThromboplastinCollagen

VII

XII

XI

IXVIII

aPTT PT

Look at Thrombin Time!!!

When you see isolated PROLONGED aPTT, the next test to order is……

aPTT MIXING STUDY!!!!

PTT MIXING STUDIES:

Mixing studies are tests performed on blood plasma used to distinguish factor deficiencies from factor inhibitors, such as lupus anticoagulant (LA), or specific factor inhibitors, such as antibodies directed against factor VIII.

PTT MIXING STUDIES:

Mixing studies take advantage of the fact that factor levels that are 50 percent of normal should give a normal Prothrombin time (PT) or Partial Thromboplastin time.

PTT MIXING STUDIES:

Mixing studies can help determine the appropriate next steps to take to diagnose the cause of an abnormal APTT or PT.

TEST METHOD

The patient plasma is mixed 1:1 with Normal pooled plasma that contains 100% of the normal factor level results in a level ≥ 50% in the mixture (say the patient has an activity of 0%; the average of 100% + 0% = 50%).

Therefore, correction with mixing indicates factor deficiency; failure to correct indicates an inhibitor.

TEST METHOD Some inhibitors are time dependent. The clotting test

performed immediately after the specimens are mixed may show correction because the antibody has not had time to inactivate the added factor (false positive). A test performed after the mixture is incubated for 2 hours at 37°C will show prolongation. Nonspecific inhibitors like the lupus anticoagulant

usually are not time dependent; the immediate mixture will show prolongation.

Many specific factor inhibitors are time dependent, and the inhibitor will not be detected unless the test is repeated after incubation (factor VIII inhibitors are notorious for this).

INTERPRETATION

1:1 Mixing Study Results

Not incubated Incubated

Factor deficiency Correction Correction

Immediate acting inhibitor No correction No correction

Time/temperature dependent inhibitor

Correction (Falsely)

No correction

Differentiation of Factor Deficiency and Inhibitors By Mixing Studies

Table adapted from McKenzie, S.,, Clinical l Laboratory Hematology, 2004, p. 790.

VALUES EXPECTED

THE BETHESDA UNIT

Kasper, 1975

One Bethesda Unit:The amount of antibody thatinhibits half of the factor VIIIactivity in a 1 to 1 mixture ofpatient plasma and normalplasma incubated at 37°C for 2 hours

Treatment of Bleeding in Factor VIII Autoantibodies-Control Bleeding and Eliminate Inhibitors

For patients with non life-threatening bleeding and low inhibitor titers, DDAVP at a dose of 0.3 mcg/kg SQ per day given for three to five days may be sufficient for control of bleeding or for hemostatic coverage of invasive procedures .

Treatment of Bleeding in Factor VIII Autoantibodies-Control Bleeding and Eliminate Inhibitors

Most bleeding associated with low titer inhibitors (ie, <5 Bethesda units) may be treated with human factor VIII concentrates at high doses (eg, 20 IU/kg for each Bethesda unit of the inhibitor plus an additional 40 IU/kg, with monitoring of factor VIII activity 10 minutes following bolus injection, and repeat IV bolus dosing if the incremental recovery is not adequate).

Treatment of Bleeding in Factor VIII Autoantibodies-Control Bleeding and Eliminate Inhibitors

For patients with higher titer factor VIII inhibitors (>5 BU) or severe bleeding, treatment with activated prothrombin complex (eg, factor VIII inhibitor bypassing activity [FEIBA]) or human recombinant human factor VIIIa (rfVIIa) can be employed.

Bypassing agents achieve an 86% control in all bleeding types and a 76% control in severe bleedings.

Recommended doses are similar to those employed in hemophilia patients with inhibitors (eg, typical FEIBA dose 75 units/kg; rfVIIa median starting dose 90.4 mcg/kg, range 45 to 181 mcg/kg).

NovoSeven® (rFVIIa) controls bleeding at the site of vascular injury only1

Haemostasis and NovoSeven® – mode of action; Feb 2006

rFVIIa works locally at the site of vascular injury, where tissue factor (TF) is exposed and activated platelets are found1

Binding of factor VIIa or rFVIIa to TF initiates the coagulation generating small amounts of thrombin2

At pharmacological doses rFVIIa directly activates factor X on the surface of activated platelets resulting in a “thrombin burst”3,4

The thrombin burst leads to the formation of a stable haemostatic plug which controls the bleeding3

Adapted from Hoffman M et al., 2001.1

Side Effects of Treatment of Bleeding in Autoantibodies

Recombinant FVIIa - Thrombosis (< 2%) FEIBA and Autoplex

ThrombosisAllergic ReactionsLow risk for transmission of infectious agents

Arterial and Fatal Thromboembolic SAEs DATA from ICH Study

Arterial thromboembolic SAEs occurred significantly (P = 0.01) more frequently with rFVIIa treatment (5%) than with placebo (0%) These events manifested in the form of myocardial ischemic

events (7) and cerebral infarction (9) Thromboembolic SAEs that were fatal or disabling

occurred in 2% of rFVIIa-treated patients compared with 2% in the placebo group

Mayer SA et al. N Engl J Med. 2005;352:777-785.

Management of Autoantibody to Factor VIII

Immunosuppressive Medications Immediate initiation of immunosuppressive therapy after

confirmation of AHA diagnosis is recommended.Prednisone 60 mg/day x 3-6 wksWork better in low titer, new inhibitors with no

associated disease Others

Combined Rx - prednisone plus cyclophosphamide Cyclosporine, tacrolimus, azathioprine, mycophenolate

mofetil, interferon α. Rituximab has been used in refractory cases in a dose

of 375 mg/m2 every week for 4 weeks.

Management of Autoantibody to Factor VIII

The above therapies have been shown to achieve a complete remission (CR) rate of inhibitor eradication between 52- 82%.

Complete remission is defined as normal Factor VIII activity (70%-140%) without factor substitution and undetectable inhibitor titer levels.

Partial remission can be defined as attaining a minimum of FVIII recoveries of 30% and/or a reduction of the inhibitor titer to less than 5 BU without further bleeding events.

TREATMENT

There is no evidence that one immunosuppressive therapy is clinically superior to all others in treating AHA or that a certain therapy should be chosen depending on inhibitor titer or the hemorrhagic status.

Therefore, first-line treatment is determined by evaluation of disease condition and consideration of possible adverse effects.

MANAGEMENT OF AUTOANTIBODY TO FACTOR VIII

Physical removal of inhibitors by plasma exchange therapy or protein A adsorption column is effective for transient removal of inhibitors in patients with acute, severe bleeding.

MODIFIED BONN MALMÖ PROTOCOL (MBMP)

1. Large-volume immunoadsorption (IA) (2.5-3x total plasma volume on days 1-5)

2. I.v. IgG substitution (0.3 g/kg body weight (BW)/d, on days 5-7)

3. Immunosuppression with cyclophosphamide (1-2 mg/kg BW/d) and prednisolone (1 mg/kg BW/d) from day 1 until remission (dose reduction),

4. Administration of FVIII, typically 100 IU/kg BW every 6 hours.

Zeitler H et al. Atheroscler Suppl. 2009 Dec 29;10(5):122-5.

MONITORING RESPONSE TO TREATMENT

Primary goal of treatment is cessation of bleeding, followed ultimately by a decrease in the titer of the inhibitor.

The former is monitored via the usual clinical and laboratory observations (eg, observable blood loss, blood in urine or stool, repeated blood counts).

Since inhibitor titers drop very slowly following successful treatment, it is neither necessary nor advisable to check the patient’s aPTT or inhibitor titer more often than every two to four weeks once immunosuppressive therapy has been started.

SUMMARY

When encountered with a bleeding elderly patient with isolated prolonged PTT-think coagulation factor inhibitors vs acquired VWD vs Lupus Anticoagulant (associated more with thrombosis).

If thrombin time is normal, heparin as the etiology for prolonged PTT less likely.

Call the lab and expedite PTT Mixing study.

Make sure the lab does the delayed phase of the PTT Mixing Study.

Treat bleeding aggressively with bypass agents and immunosuppressives simultaneously.

Immunoadsorption is a safe and highly effective alternative with a high potential to cure severe AH.