acquired hemophilia a
DESCRIPTION
Acquired Hemophilia ATRANSCRIPT
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.