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.

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.

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.

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 anticoagulant B.Malignancy related inhibitor C.Acqd VWD D.Mild hemophilia

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)

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.

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

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 Jun 30;45(3):

 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 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 years of age Acquired Hemophilia Characteristics

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

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

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 disorders  May be seen with lymphoproliferative disorders  Occur any age but increase incidence of spontaneous inhibitors in the elderly

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.

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

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

Incidence of Clotting Factor Inhibitors Special associations – more  Cancers are associated with acquired inhibitors  FV with Waldenstroms macroglobulinemia  FXI with Bladder/prostate cancers  Lymphoproliferative disorders / MGUS with VWF/VIII particularly but also with other factors  Other autoimmune disorders are associated with clotting factor inhibitors-SLE, RA, etc

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 Correction No correction RESULT ARESULT B 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

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

Treatment of Clotting Factor Inhibitors FACTOR 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

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 AVAILABLE  Bypassing agents  Recombinant FVIIa (90  g/kg q 2-6 hrs) (94% effective) (common doses  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

Treatment of Clotting Factor Inhibitors ERADICATION OF THE INHIBITOR  Prednisone is mainstay of treatment with variable results  IVIg may work with any inhibitors - particularly with VWF inhibitors  Rituximab has been increasingly tried - limited data  Immunosuppressive drugs are often used - cyclophosphamide and azothiaprine most commonly  No treatment is an option if no clinical bleeding  Spontaneous remission or remission with treatment of underlying disorder occurs ~ 30-80%  Induction of immune tolerance does not work

Efficacy Results at End of Treatment With rFVIIa 92% good/partial response rate with salvage therapy 100% excellent/good response rate with first-line therapy Compassionate Use: Acquired Inhibitors Hay CRM, et al. Thromb Haemost. 1997;79: Good Partial Poor Bleeding episodes (%) 1st Line Salvage % 75% 17% 8%

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:

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)