acquired hemophilia a
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DESCRIPTIONAcquired Hemophilia A
ACQUIRED HEMOPHILIA A
ACQUIRED HEMOPHILIA A CHARACTERISTICSIncidence 0.2-1.0 case per million per year is incidence increasing???80-90% present with major hemorrhages10-22% mortality attributed to inhibitorBiphasic age distributionSmall peak in young postpartum womenMajor peak in 60-80 years of age
ACQUIRED HEMOPHILIA A CHARACTERISTICSMost individuals are previously healthy-idiopathic.Some have defined or evolving associations.
CLINICAL MANIFESTATIONS OF ACQUIRED HEMOPHILIAOvert bleeding -most frequently bruising, muscle hematomas, GI bleeding, hematuriaIatrogenic - IV lines, bladder catheterization or post surgical bleedingAcute complications - compartment syndromes, airway compression 2nd to subglottic bleedingValues 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 FVIIIBoggio, LN, Green D. Rev Clin Exp Hematol. 2001;5:389-404Autoantibody Inactivation Kinetics
Display type II kinetics Clearance is not linear Difficult to overwhelm with clotting factor replacement
LABORATORY EVALUATION IN A BLEEDING PATIENTPLATELET COUNTBLEEDING TIME (BT)PROTHROMBIN TIME (PT)PARTIAL THROMBOPLASTIN TIME (PTT)THROMBIN TIME (TT)
CLINICAL FEATURES OF BLEEDING DISORDERS
Platelet Factor DisordersCoagulation disordersSite of bleedingSkin, Mucous membranes (epistaxis, gum, vaginal, GI tract)Deep in soft tissues (joints, muscles)PetechiaeYesNoEcchymoses (bruises)Small, superficialLarge, deepHemarthrosis / muscle bleedingExtremely rareCommonBleeding after cuts & scratchesYesNo
Bleeding after surgery or traumaImmediateDelayed (1-2 days)
THE CLOTTING MECHANISMPROTHROMBIN THROMBINFIBRINOGENFIBRIN(II)(III)(I)VXTissue ThromboplastinCollagenVIIXIIXIIXVIIIaPTTPT
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 METHODThe 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 METHODSome 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 37C 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 Differentiation of Factor Deficiency and Inhibitors By Mixing StudiesTable adapted from McKenzie, S.,, Clinical l Laboratory Hematology, 2004, p. 790.
1:1 Mixing Study ResultsNot incubatedIncubatedFactor deficiencyCorrectionCorrectionImmediate acting inhibitorNo correctionNo correctionTime/temperature dependent inhibitorCorrection (Falsely)No correction
THE BETHESDA UNITKasper, 1975One Bethesda Unit:The amount of antibody thatinhibits half of the factor VIIIactivity in a 1 to 1 mixture ofpatient plasma and normalplasma incubated at 37C for 2 hours
Treatment of Bleeding in Factor VIII Autoantibodies-Control Bleeding and Eliminate InhibitorsFor 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 InhibitorsMost bleeding associated with low titer inhibitors (ie,
Treatment of Bleeding in Factor VIII Autoantibodies-Control Bleeding and Eliminate InhibitorsFor 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 only1Haemostasis and NovoSeven mode of action; Feb 2006rFVIIa works locally at the site of vascular injury, where tissue factor (TF) is exposed and activated platelets are found1Binding 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 burst3,4 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 AutoantibodiesRecombinant FVIIa - Thrombosis (< 2%) FEIBA and AutoplexThrombosisAllergic 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 groupMayer SA et al. N Engl J Med. 2005;352:777-785.
Management of Autoantibody to Factor VIIIImmunosuppressive MedicationsImmediate 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 diseaseOthersCombined Rx - prednisone plus cyclophosphamide Cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, interferon .Rituximab has been used in refractory cases in a dose of 375 mg/m2 every week for 4 weeks.
Management of Autoantibody to Factor VIIIThe 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.
TREATMENTThere 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 VIIIPhysical 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 MALM PROTOCOL (MBMP)Large-volume immunoadsorption (IA) (2.5-3x total plasma volume on days 1-5)I.v. IgG substitution (0.3 g/kg body weight (BW)/d, on days 5-7)Immunosuppression with cyclophosphamide (1-2 mg/kg BW/d) and prednisolone (1 mg/kg BW/d) from day 1 until remission (dose reduction),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 TREATMENTPrimary 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 patients aPTT or inhibitor titer more often than every two to four weeks once immunosuppressive therapy has been started.
SUMMARYWhen 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.Immunoadso