26
Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Embed Size (px)

Citation preview

Page 1: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Acquired Hemophilia

Sandeep Kumar Rajan, MDUNMC, Omaha Nebraska

Page 2: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Hemophilia detected later in life

• Mild congenital hemophilia in patients with minimal hemostatic stressors.

• Mild congenital hemophilia with balancing thrombophilia.

• Mild congenital hemophilia with pronounced bleeding due to development of other coagulopathies.

• Development of acquired inhibitors of clotting factors.

Page 3: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Case 1

• A 22y male, sports store manager has had no bleeding history. He was raised by adoptive parents. He slips and falls on ice and hurts his shoulder. X-ray reveals humeral neck fracture. Severe pain and starts developing paresthesia and tingling in forearm. ER physician thinks neural damage by fracture fragments. Obtains MRI, large hematoma. PTT is 60s. CBC, PT are normal. PTT corrects on mixing, normal fibrinogen. FVIII is 8%. No inhibitor.

Page 4: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

• Mild hemophilia diagnosed. • Inadequate response to DDAVP• Factor VIII supplementation began. Surgery performed

and continuous infusion FVIII recombinant concentrate given. Levels for 2 weeks maintained 60-80%.

• 4 weeks later c/o worsening shoulder pain at site of injury. MRI shows no hardware abnormalities but recurrent hematoma. No recalled trauma. FVIII is <1%.

• Inhibitor screen is positive. 8 BU.• FEIBA used emergently.• Immune tolerance induction began with 200U/kg.• By d-14, inhibitor 1.4BU, day 26, no detectable inhibitor.• ITI continued.

Page 5: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Case 2• A 63 patient male had no h/o hemarthrosis or childhood bleeds. • At 21y, bled after dental extraction. Dentist put stich and gave Vitamin K. • Went on to adult age when at age 62 he was noted with neck lump. Biopsy

showed lymphoma. No bleeding from surgical site. Had bone marrow biopsy had platelets reduced at 30K and bled for 3 days and was given platelet transfusion, bleeding stops. He had normal PT.

• He starts chemotherapy for his lymphoma, develops superficial phlebitis at IV site. No previous DVT. No anticoagulation.

• After one cycle of chemotherapy for Stage IV intermediate grade lymphoma, he has regressed lymphnodes and normalized platelet count. Hb always normal. He notes headache, an MRI scan notes meningeal enhancement. Lumbar puncture is planned, PTT gets done and is prolonged at 72s (upto 38s is normal).

What is the diagnosis:A. Lupus anticoagulantB. Malignancy related inhibitorC. Acqd VWDD. Mild hemophilia

Page 6: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

• Patient has normalization of PTT on 50:50 mixing study

• Lupus anticoagulant is negative• FVIII is 6%. VWF activity and antigen are normal.• Normal platelet aggregation• No FVIII inhibitor.• Homozygous Factor V Leiden• Close introspection of family in Germany reveal

3 maternal cousins with mild hemophilia A and a maternal aunt with 5 miscarriages and paternal grandmother died at childbirth suddenly (? heart attack/Pulmonary embolism)

Page 7: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Case 3• 57 y female, was diagnosed 25y ago with type I VWD when had

massive bleeding perioperatively while undergoing hysterectomy for menorrhagia.

• Cryoprecipitate and blood transfusions given.• Post hysterectomy noted to have VWFag 21%, VW RcA 18%. With

DDAVP reached 62 and 75%.• Was started on HRT, no clinical bleeding. • 15 y back diagnosed with HCV. No bleeding hence defaulted f/u HTC. • Saw outside hepatologist and 8 and 6 y ago treated for HCV with poor

tolerance.• Now develops worsening chronic liver disease. Had normal PT and

PTT, had paracentesis, but serosanguinous oozing from needle track site.

• VWF ag 67%, VWF Rcac 62%. DDAVP given. No response.• W/u at HTC revealed low fibrinogen. DWBCLT prolonged. Accelerated

fibrinolysis confirmed. Treated with amicar, prompt response.

Page 8: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Case 4

• 75y male with h/o rheumatoid arthritis. Did hernia surgery, carpal tunnel surgery and dental extraction without problems.

• Starts bruising easily, platelets are normal. Also anemic, Hb 9.5. normochromic normocytic.

• Has a colonoscopy, 2 polyps are resected. He develops hematochezia. 2 years back PT, PTT were normal now PTT is 78s.

• Mixing study does not correct. Lupus anticoagulant negative. FVIII <1%. Inhibitor: 240BU

Page 9: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Prevalence of Acquired FVIII i• 1.3 to 1.5 per 1000,000. Majority were over 50 years of age• Equal male : female distribution• Etiological factors:

– Rheumatoid arthritis was present in 8% of the cases, – 7% occurred during pregnancy or the post-partum period,– Association with allergy to penicillin, asthma, "auto-immune" diseases, or malignancy. – In 46% of cases, no underlying disorders were identified.

• Clinical presentation: – Major bleeding was observed in 87% of patients– In 22%, death was attributed either directly or indirectly to the presence of the inhibitor.

• Clinical course and response:– 11 of 31 (35%) inhibitor disappeared in median of 14m with no therapy other than supportive care (blood

products/ concentrates). – Corticosteroids responded in 22 of 45 patients (49%).– 28 patients received azathioprine as well as corticosteroids; two third responded with decline in titer.– 80 patients were treated with cyclophosphamide; in 37 (46%) there was a favorable outcome. – Inhibitors in children and post-partum patients had higher spontaneous response or with steroid therapy.– Those with rheumatoid arthritis or other "autoimmune" disorders required alkylating agents.

Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to Factor VIII. Thromb Haemost. 1981 Jun 30;45(3):200-3.

Page 10: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Most individuals are previously healthy-idiopathic

Some have defined or evolving associations: Autoimmune (SLE, RA) Lymphoproliferative disease Multiple Sclerosis Graft-vs.-Host after allogeneic

BM transplant Asthma, Inflammatory Bowel

Disease, Pempigus Severe allergic reactions to:

antibiotics, interferon-,

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 Characteristics

Page 11: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

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

Page 12: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Definition of a Coagulation Inhibitor

AN ANTIBODY THAT NEUTRALIZES THE FUNCTION OR REMOVES A CLOTTING

FACTOR FROM CIRCULATION

Usually presents as spontaneous or excessive bleeding

May present as laboratory abnormality; ie, prolonged PTT/PT

Page 13: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Types of Inhibitors

Alloantibodies – occur in patients with a congenital clotting factor deficiency

Autoantibodies – arise de novo in people without a history of a clotting factor deficiency

May occur with other autoimmune disordersMay be seen with lymphoproliferative disordersOccur any age but increase incidence of

spontaneous inhibitors in the elderly

Page 14: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Kinetics of type 1 and type 2 FVIII inhibitors

• Type 1 inhibitors develop in patients with congenital hemophilia A and are generally alloantibodies that show complete neutralization of FVIII activity.

• Acquired inhibitors to FVIII show type 2 kinetics, with a rapid neutralization phase, followed by an equilibrium in which residual FVIII activity can be detected in vitro.

Page 15: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Incidence of Clotting Factor Inhibitors

ALL AUTOANTIBODIES ARE UNCOMMON

Most frequent – Factor VIII, VWF, Factor II (APS?)

Less common – Factor V, IX, XI, XIII Rare but reported – Fibrinogen, VII, X

Page 16: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Clotting Factor Acquired Inhibitors

Special associations FV with topical thrombin products – cross reaction to

Bovine FV in some preps FV with aminoglycosides or cephlosporins FII or thrombin with topical thrombin preps FII or thrombin with Antiphospholipid antibodies FVIII with penicillin derivatives FXIII with Isoniazid FX with amyloidosis FXI with genital urinary defects/cancers FVIII, FIX, fibrinogen with pregnancy

Page 17: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Incidence of Clotting Factor Inhibitors

Special associations – more

Cancers are associated with acquired inhibitors FV with Waldenstroms macroglobulinemiaFXI with Bladder/prostate cancersLymphoproliferative disorders / MGUS with

VWF/VIII particularly but also with other factors Other autoimmune disorders are associated

with clotting factor inhibitors-SLE, RA, etc

Page 18: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

MIXING STUDY

NORMAL BLOOD:FACTOR LEVEL 100%

aPTT 28 sec

PATIENT BLOOD:FACTOR LEVEL 0%

aPTT 80 sec

NOTE: ONLY 30-40% FACTOR REQUIRED FOR NORMAL aPTT

50% PATIENT : 50% NORMAL

FACTOR LEVEL 50%

aPTT 30 sec

FACTOR LEVEL 20%

aPTT 50 sec

INHIBITOR FACTOR DEFICIENCY

CorrectionNo correction

RESULT A RESULT B

Diagnosis of Clotting Factor Inhibitors

Page 19: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Diagnosis of Clotting Factor Inhibitors

The PT and PTT are the screening studies

Prolonged PT +/- PTT that CORRECTS PLUS low factor level = “clearing” antibody that does not interfere with protein function

Prolonged PT +/- PTT that FAILS to correct = “neutralizing” antibody that prevents protein function and may or may not accelerate clearance

Page 20: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Diagnosis of FV, FVIII & FXIII inhibitors

The PT and PTT are the screening studies:

PT + PTT that initially corrects on mix but then prolongs with 1-2 hour incubation = FV inhibitor

PTT that initially corrects on mix but then prolongs = FVIII inhibitor

Normal PT + PTT with new hematomas/bleeding = FXIII inhibitor

Page 21: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Treatment of Clotting Factor InhibitorsFACTOR REPLACEMENT

Platelet transfusion may help with FV, fibrinogen, VWF, or FXIII replacement - factor “hidden” from antibody

FFP, cryoprecipitate, or clotting factor concentrate, depending on factor involved have limited success

rVIIa reported to be used with FII, FV, FVIII, FIX, VWF, FXIII and FXI antibodies ( approved for FVIII and FIX)

Plasmapheresis/exchange tried with limited success to decrease antibody titer to allow replacement to work

May NOT need replacement if no active bleeding particularly with FV or FII antibodies

Page 22: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Acute management of Bleeding in Factor VIII Autoantibodies

Human Factor VIII Concentrates (if < 5 BU)Porcine Factor VIII (90 U/kg q 12 hrs) (80%

effective) NOT CURRENTLY AVAILABLEBypassing agents

Recombinant FVIIa (90 g/kg q 2-6 hrs) (94% effective) (common doses 90-200 g/kg q 2-6 hrs-not studied)FEIBA (70 U/kg q 8-12 hrs) (81% effective)Autoplex (>50 U/kg) (75-80% effective) NOT AVAILABLE

Page 23: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Treatment of Clotting Factor Inhibitors

ERADICATION OF THE INHIBITORPrednisone is mainstay of treatment with variable results IVIg may work with any inhibitors - particularly with VWF

inhibitorsRituximab has been increasingly tried - limited data Immunosuppressive drugs are often used -

cyclophosphamide and azothiaprine most commonly No treatment is an option if no clinical bleedingSpontaneous remission or remission with treatment of

underlying disorder occurs ~ 30-80% Induction of immune tolerance does not work

Page 24: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Efficacy Results at End of Treatment With rFVIIa

92% good/partial response rate with salvage therapy100% excellent/good response rate with first-line therapy

Compassionate Use: Acquired Inhibitors

Hay CRM, et al. Thromb Haemost. 1997;79:1463-1467.

GoodPartialPoorBleeding

episodes (%)

1st LineSalvage0

102030405060708090

100 100%

75%

17%8%

Page 25: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Arterial and Fatal Thromboembolic SAEsData from ICH Study

Arterial and Fatal Thromboembolic SAEsData 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.

Page 26: Acquired Hemophilia Sandeep Kumar Rajan, MD UNMC, Omaha Nebraska

Rituximab for acquired antibodies to factor VIII

Dose - 375mg/m2 weekly X 4 most common (same as lymphoma) CR-78%, Median time to CR-8.3wks, 66% in CR at 2y.

haematologica2007; 92(01)