ACQUIRED HEMOPHILIA AACQUIRED HEMOPHILIA ACase descriptions 

and a current approach to management

Martin H Ellis MD

Hematology Institute and Blood BankMeir Medical Center

IsSTH November 2012

Patient #1Patient #1

• 78 year old man• Prostate cancerProstate cancer• Admitted with extensive subcutaneous b i i d ibruising and anemia

• PT normal, PTT >150 sec,• Mixing study – no correction of PTT• F VIII activity=5%• BU= 16BU  16

»Dg: Acquired hemophilia A

Patient #1Patient #1

• Rapid clinical deterioration• GI bleedingGI bleeding• Treated with methylprednisolone and red cell 

f itransfusions• Supportive measures institutedpp• Died within 1 week

Patient #2

• 64 year‐old woman64 year old woman• Macroscopic hematuria• Leg and arm bruising• No previous Hx of bleeding• No previous Hx of bleeding• PT normal, PTT > 100 sec• Clinical suspicion of acquired deficiency• Mixing study failed to correct• Mixing study failed to correct• F VIII=15% and BU=4

»Dg: Acquired hemophilia A

Patient #2Patient #2

• No hemostatic agents given• Prednisone and Cyclophosphamide startedPrednisone and Cyclophosphamide started• Resolution of bleeding• Increase in F VIII – normal within 3 weeks• Drugs tapered over 6 week periodDrugs tapered over 6 week period• Stable ( 9 months after diagnosis)

Patient #3Patient #3

• 78 year‐old woman• History of MDS (? CMML) – mild, untreatedHistory of MDS (? CMML)  mild, untreated• (Mild) dementia• CHF, obesity, hypertension• Fell at home ‐minor traumaFell at home  minor trauma

Patient #3Patient #3

• Platelets = 110K –stable• Ortho called heme consult• PT normal PTT=90 secPT normal, PTT=90 sec• Mixing study failed to correct• F VIII activity= 6%• BU= 8• BU= 8

»Dg: Acquired hemophilia A»Dg: Acquired hemophilia A

Patient #3Patient #3

• Treatment: prednisone & cyclophosphamide• Red cell transfusionsRed cell transfusions• Extensive bruising after BP measurements, blood ddraws

• Poor venous access• Pulmonary congestion• Single dose of F VIII• rFVIIa 90 µg/kg periprocedure (PICC line)rFVIIa 90 µg/kg periprocedure (PICC line)

August 2012August 2012

Patient #3Patient #3

• Gradual stabilizationPTT d d ti li d• PTT decreased over time normalized

• Prednisone and Cyclophosphamide tapered y p p pover 6 weeks

• Skin defect on dorsum of hand conservatively• Skin defect on dorsum of hand‐conservatively managed

November 2012November 2012

November 2012November 2012

Background•Bleeding disorder caused by an auto‐antibody to factor VIII•Severe bleedingSevere bleeding Soft tissue and mucosal bleedingFVIII level poor guide to bleeding riskFVIII level poor guide to bleeding riskHigh morbidity and mortality

•Patient group•Patient groupElderlyCo morbiditiesCo‐morbidities

•Presentation to non‐specialistsDi i d d lDiagnostic and treatment delayDifficulties transferring patients to specialist centers

Acquired haemophilia literature• Randomized controlled trial Single published study                  Green T&H 70:753‐757,1995g p y• Insufficient patients to draw conclusions

• Cohort study• UKHCDO consecutive cohort        Blood 109:1870‐77,2007

• Meta‐analysis• Meta analysis Delgardo et al B J H 121 21 35 2003• Meta‐analysis Delgardo et al         Br J  Haem 121:21‐35,2003(Publication bias of more severe patients and good outcomes)

• Registry– European Acquired Haemophilia (EACH2) Registry 

Blood 120:39‐46,2012Blood 120:47‐55,2012

Associated Conditions in AHAHemotological; Chronic lymphocytic leukemia, multiple myeloma, Waldenstrom Macroglobulinemia, non-Hodgkin lymphoma, myelodyplasia myelofibrosis

Malignancies

myelodyplasia, myelofibrosisSolid tumors:Prostate,pancreas,colon,lung,stomach,melanoma,breast,kidney,cervix,head, and neck

Systemic lupus erythematosis, rheumatoid arthritis, temporal arteritis, ulcerative colitis, Sjogren syndrome, Goodpasture syndrome, multiple sclerosis, myasthenia gravis, graft-versus-host disease autoimmune thyroid disorders and

Autoimmune disorders

versus host disease,autoimmune thyroid disorders, and autoimmune hemolytic anemia

Rarely during pregnancy, usually 1 to 4mo postpartumPregnancy-related

Beta-lactam antibiotics,chloramphenicol,sulfa drugs, phenytoin, methyldopa,interferon-a, depot thioxanthene,NSAIDs,fludarabine,clopidogrel, and BCG

Drug-induced

Psoriasis and pemphigusDermatological diseases

Acute hepatitis B and C chronic obsructive pulmonaryOth di Acute hepatitis B and C, chronic obsructive pulmonary disease, asthma, MGUS, and polymyalgia rheumatica

Other diseases

Sem Thromb hemostasis 2012

IncidenceIncidence• Estimated incidence in defined populations

Wales1 :1 34/million/year– Wales1 :1.34/million/year– UK2 1:48/million/year

• Assuming similar incidence throughout Europe– EACH2 recruited 15% of European patients over 6 years3EACH2 recruited 15% of European patients over 6 years

1. Br J Haem 124:86‐90,20042. Blood 109:1870‐77,2007,3. JTH10:622‐31,2012

Fatal bleeds

1981 Green 22%

2007 UKHCDO 8%

2012 EACH2 3%

Fatal bleeding in acquired hemophilia: UKHCDO study

INHIBITOR TITER AT F VIII AT PRESENTATIONSITE OF FATAL BLEEDTIME OF DEATH AFTER PRESENTATIONPRESENTATION

NOT STATED<1GI0

24GI2

54LUNG4

154INTRACRANIAL14

89POSTOP17

182RETROPERITONEAL19

1.49INTRACRANIAL24

2195GI66

64GI106109<1INTRACRANIAL136142RETROPERITONEAL148412MULTIPLENOT STATED

• Patients at risk of fatal bleeding until inhibitor eradicated• Patients at risk of fatal bleeding until inhibitor eradicated• FVIII level and lack of bleeding at presentation does not protect against fatal bleeding

Diagnostic pitfallsDiagnostic pitfalls

FVIII i hibi i d d• FVIII inhibitors are time dependent– Incubation of 50/50 mix for 2 hours

• All intrinsic factors may appear low– Inhibition of FVIII by the inhibitor in intrinsic factor assays

– Dilution restores factor levels due to non‐specific inhibition

• Lupus anticoagulant may interfere with factor assays

• Refer sample to a reference laboratory

Diagnostic delay:Diagnostic delay:

• Patients are often put at unnecessary risk of severe bleedingg

B d i d• Better education and awareness

• Role of laboratory to further investigate l d i t t ltsamples and interpret results

Management principlesManagement principles

• Early and rapid diagnosis• Avoid iatrogenically induced bleedsAvoid iatrogenically induced bleeds

– Limit venepuncture and BP monitoringN i i d l i l– No invasive procedures unless essential

• Control bleedingg– Bypassing agents

• Eradicate the inhibitor• Eradicate the inhibitor– Immunosupperssion 

Treatment of bleeding: principles• Some bleeds do not need treatment 

20 30%– 20‐30%– Subcutaneous bruising rarely needs treatment

• Majority of bleeds need early treatment– NB thrombotic risk of agentsg

• OptionsBypassing agents– Bypassing agents

rFVIIa or FEIBA

– Raising factor VIIIFactor VIII/DDAVP/F VIII and immunoadsorption

Thrombotic adverse eventsVTEMICVATotal N(%)

1269 (6 5)S 139 1269 (6.5)Sumner n=139Only rFVIIa

56112(3 9)EACH2 n=307 56112(3.9)EACH2 n=307rFVIIa,FEIBA,FVIII and DDAVP

EACH2 data

rFVIIa 5/174 (2.9%) Caution with dosingFEIBA 3/63 (4.8%) Avoid rFVIIa 270 mcg/kgFEIBA 3/63 (4.8%) Avoid rFVIIa 270 mcg/kgFVIII/DDAVP 0/70 (0%)No data 4

Inhibitor eradication in AHAInhibitor eradication in AHA

Th i l i i i i AHA i• The optimal immunosuppressive regimen in AHA is unknown

M i– Most common regimens are• Steroids alone• Steroids and cyclophosphamide• Rituximab based regimens

– Outcome is a balance between• Inhibitor eradication • Adverse effects, including death• Risk of relapseRisk of relapse

Analysis of Immunosuppressive regimens EACH2

l l d• First line regimens analysed– Steroids alone– Steroids and cyclophosphamideSteroids and cyclophosphamide– Rituximab based regimens

• Definitions– Complete remission (CR)

Inhibitor negative, FVIII>70 IU/dL and immunosuppression stoppedstopped 

– RelapseRecurrence of inhibitor after CR

– Stable remissionCR with no relapse after immunosuppression stopped 

Blood epub 18 th April 2012 

Hemostatic

RecommendedFVIII bypassing agents- rFVIIa (90-120µg./kg every 2-3 hrs)

PCC (50 100 i /k 8 12 h )Treatment - aPCC (50-100 iu/kg every 8-12 hrs)

Alternative: (if bypassing agents unavailable)-human FVIII concentrate

Bleeding-Desmopressin

Salvage treatmentImmunoadsorption/plasmapheresis

InhibitorEradication

Recommended

Prednisone (1 mg/kg/d 4-6 wks) alone or Eradication(IST)Diagnosis

Of AHA

( g g )in combination with cyclophosphanide (1.5-2 mg/kg/d maximum 5 wks)

line treatment-Second

N bl di

-Rituximab (375 mg/m2 weekly for 4 weeks) usually in association with steroids.Alternative second-line treatmentCyclosporine, azathioprine,

h l i i iNo bleeding mycophenolate, vincristine

Not recommendedHigh- dose immunoglobulins

Haematologica 2009

Identification and treatment of underlying conditions

ConclusionsConclusions

• Early diagnosis– Education– Laboratory

• Early treatment of bleeds with bypassing agent• Early treatment of bleeds with bypassing agent– Not all bleeds need treatment– Thrombotic events are seen

• Immunosuppression as soon as diagnosis made– Optimal regimen debated– Cyclophosphamide prednisone seems preferableCyclophosphamide, prednisone seems preferable