Antiphospholipid Antibody Syndrome: Management Issues for the Hematologist Wisconsin Institute of Discovery Karen Rossi/Bristol-Myers Squibb Morey A. Blinder, MD Washington University, St. Louis, MO March 9, 2018
Disclosure: Morey A. Blinder, M.D. Dr. Blinder has received honoraria for speaking from Janssen.
Antiphospholipid Antibodies (APA) Functional test ACA IgM, IgG Criteria LA β 2 GPI IgM, IgG Non-criteria ACA-IgA Anti-prothrombin ab Other APA (e.g. phosphotidyl serime) Level of APA Antibody tests (ELISA)
Case 1 A 42 year old man in good health presented with LE petechiae 1 year ago, was found to have a platelet count of 9,000/µl and was diagnosed with ITP. He was treated with dexamethasone and IVIG. One month later his platelet count was 157,000/µl. After a 6 hour car ride he developed a (R)LE DVT. Platelet count was 29,000/µl. Lupus anticoagulant was positive and anti-cardiolipin and b 2 GPI antibodies were present.
Case 1 - Questions How common are APA in ITP? What is the risk of thrombosis in APAassociated ITP? Should the patient with APA-associated ITP be treated differently than patients with primary ITP?
Stasi R et al. Blood 1994; 84:4203-4206 Diz-Kucukkaya et al. Blood 2001; 98:1760-1764 Prevalence of APA-associated ITP At diagnosis Stasi R et al. Blood 1994 Platelet count <50,000 Diz-Kucukkaya et al. Blood 2001 Platelet count <100,000 No. pts. 71 82 ACA 9 11 Lupus anticoagulant 17 8 LA + ACA 13 12 Overall prevalence 39/78 (50%) 31/82 (38%) No difference in: Gender Age Initial platelet count Severity of hemorrhage
Response to initial therapy of ITP Response to steroids and IVIG are similar Presence of APA does not predict treatment outcome Treatment with prednisone ± IVIG APL-positive (N=20) APL-negative (n=50) p value Transient response (<3 mo) Sustained response ( 3 mo) Time to respond 9/17 (53%) 26/47 (55%) 8/17 (47%) 21/47 (45%) 0.41 Pred +IVIG 2.3 (1-12) 2.9 (1-15) 0.72 Pred 7.3 (2-26) 5.9 (1-34) 0.50 Yang Y. et al. Kor J Intern Med 2011; 26:449-454
Is ITP a thrombophilic disorder? Reference n Follow up (mo) Sapatwari et al. (2000) Enge et al. (2000) Severinsen et al. (2010) Incidence x 100 person-years Patients Controls RR P 1070 46.7 0.66 0.42 1.58 (1.01-2.48) 3131 15 0.41 0.09 2.89 (1.33-6.29) 391 0.53 0.20 2.65 (1.27-5.50) <0.05 <0.05 <0.05 Noorgard et al. (2015) 1821 0.67 0.28 2.39 <0.05 Rodeghiero F. Am J. Hematol 2016; 91:39-45
Risk of Thrombosis in Patients with APA-associated ITP 10 studies have assessed risk of thrombosis in patients with ITP and APA (LA, ACA or anti-b 2 GPI) Including arterial and venous events LA positive LA negative OR (95% CI) Total 38/242 41/1303 6.11 (3.40-10.99) ACA-positive ACA-negative OR (95% CI) Total 23/156 27/505 2.14 (1.11-4.12) Moulis G et al. Autoimmunity Rev 2016 15:203-209
Presence of lupus anticoagulant is strongly associated with thrombotic events in ITP Lupus anticoagulant Cumulative thrombosis-free survival Cumulative thrombosis-free survival Time (months) Time (months) Diz-Kucukkaya R et al. Blood 2001; 98:1760-1764
Thrombotic risk of TPO-RA in ITP Number of patients with TEEs Romiplostim Eltrombopag APA-ITP ITP controls 39/653 (5.9%) 19/302 (6.3%) Arterial 26 12 Venous 40 14 TEE per 100 pt.-yrs. 7.5 2.53 Arterial 2.8 ~1.0 ~0.9 Venous 4.3 0.4-0.67 0.09-0.42 Rodeghiero F. Am J. Hematol 2016; 91:39-45
Treatment of APA-ITP with Thrombopoietin receptor agonists ITP with triple-positive APA (LA, ACA, b 2 GPI) 2 patients with romiplostim: Patient 1 - Digital thrombosis, stroke and transaminitis Patient 2 - Digital ischemia in feet, thrombosis of thoracic aorta Thrombosis occurred at 4 and 11 weeks of therapy Platelet counts at time of thrombosis were 156,000/µl and 111,000/µl LaMoreaux B. et al. Sem Arth Rheum 2016; 45:10-12
Case 2 A 41 year old woman was diagnosed with an (L)LE DVT about 4 months ago after presenting with swelling. Work up demonstrated a lupus anticoagulant and an ACL. She is treated with warfarin. She has had no further thrombotic events but her INR fluctuates so that frequent testing is done and the TTR is ~40%. She is consulting regarding recommendations for further approaches to therapy.
Case 2 - Questions What is the risk of a thrombotic event in patients with APA and should patients receive any thromboprophylaxis? What is the risk of a second thromboembolic event? How long should a patient with APA-associated thrombosis be treated? What is the role for DOACs?
Risk of thrombosis with APAS: Related to APA profile 1 positive APA test ACA or β 2 GPI alone no increase in thrombotic risk LA Possible increase in thrombotic risk 2 positive APA tests LA + β 2 GPI increased thrombosis risk [OR ~4x] LA + ACA + β 2 GPI - strongly associated with thrombosis [OR 5-33x] Additional risk factors inherited thrombophilia, pregnancy, immobilization, surgery SLE often associated with APA; increased risk Lim W. ASH Education Book 2013
Primary Thromboprophylaxis: Aspirin therapy APLASA Trial Multicenter, randomized, double-blind, placebo controlled trial with asymptomatic, persistently positive APA individuals Median follow up 28 mo. 98 patients enrolled, randomized to receive ASA 81 mg (n=48) or placebo (n=50) Study terminated early due to unexpectedly low rate of thrombosis (3/98, all in ASA group) Erkan D et al. Arthritis and Rheumatism 2007; 56:2382-91
APS: Hydroxychloroquine q Hydroxychloroquine qin patients with SLE, reduced risk of initial arterial and venous thrombotic events ( APA) Study Study design Thrombosis studies But no current data to support use in patients without autoimmune disease Outcomes Wallace et al (1987) Retrospective (n-92) Arterial/venous P<0.05 Petri et al. (1994) Prospective (n=393) Arterial OR 0.36 Ruiz-Irastorza et al. (2008) Prospective cohort (n=232) Arterial/venous HR 0.26 Tekionidou et al. (2009) Jung et al. (2010) Curr Rheumatol Rep 2011; 13:77-80 Case-control (cases 144; controls 144) Case-control Cases 54; controls 108) Arterial/venous HR 0.99 Arterial/venous OR 0.32 q Role in APA patients without SLE is not defined
APS: Statins q Statins: possible role as anti-inflammatory, immunomodulatory agent q Retrospective study of 152 newly diagnosed SLE patients q80 patients had APA/LA qstatin use was up to clinician q1/15 (6.7%) pts. with thrombosis was on statin q22/65 (33.8%) of pts. without thrombosis were on statin qmedian follow up 69 months q Role in APA patients without SLE is not defined Watanabe T. et al. Lupus 2018; 27:225-234
The How I Treat Approach 1. Establish the diagnosis 1. Patient has positive APA without prior thrombosis or pregnancy morbidity 2. Confirm that patient has persistent APA 2. Factors to consider 1. Consider primary prophylaxis only if patient has other risk factors (e.g. cardiovascular risk) 2. Consider hydroxychloroquine statin if patient has SLE 3. Consider short-term anticoagulation during high risk situations (e.g. post-operative) 4. Limit other reversible risk factors (e.g. estrogens, smoking) Chaturvedi S and McCrae KR. ASH Education Program. Hematology 2015
Treatment of Initial Venous Thromboembolism (VTE) Legacy therapy: Anticoagulation with UFH or LMWH with transition to VKA is standard treatment for first VTE Effect on laboratory testing: LA may elevate baseline PTT (Anti-Xa Activity) LA may interfere with INR (Vitamin K dependent factors 15-25% is therapeutic
Crowther M. NEJM 2003, Finazzi J Thromb Haemost 2005 Treatment of Initial VTE: Warfarin Intensity Two RCT evaluated standard intensity (INR 2-3) versus high intensity (INR 3-4) anticoagulation with warfarin in patients with APS No difference in rates of recurrent thrombosis or major bleeding
Risk of Recurrent VTE with APA Meta-analysis relative risk for recurrent VTE after stopping anticoagulant Quality of evidence pertaining to the risk of recurrent thrombosis among patients with APA is low Garcia D, et al. Blood 2013;122:817-824
Direct Oral Anticoagulants (DOACs) in APS: Venous thromboembolism u RAPS trial v Rivaroxaban vs. warfarin for APS (RAPS) trial v With or without SLE u Methods: v Patients received standard warfarin therapy for 3 months v Randomized, controlled open-label phase 2/3 non-inferiority trial v Laboratory endpoints over 6 wks. v No thrombotic events over 6 months Cohen H. et al. Lancet 2016;122:817-824
RAPS Study Results Endogenous thrombin potential Baseline Day 42 ETP for rivaroxaban was higher than warfarin and did not meet the non-inferiority threshold (set at <20% difference from warfarin) Peak thrombin generation But the peak thrombin generation is not different between rivaroxaban and warfarin Cohen H. et al. Lancet 2016;122:817-824
Direct Oral Anticoagulants (DOACs) in APS: Venous thromboembolism u TRAPS (Rivaroxaban for Thrombotic Antiphospholipid syndrome) v Rivaroxaban vs. warfarin for APS (RAPS) trial v Triple positive APA u ASTRO-APS (Apixiban for the secondary prevention of Thromboembolism Among Patients with APS) u Apixiban vs. warfarin u Clinical APS Raschi E. et al. Pharmacol Rev 2017;120:206-218
Treatment of Arterial Thrombosis in APS WARRS trial compared ASA 325 mg to warfarin for ischemic stroke No difference in recurrent ischemic stroke or death Subgroup analysis of patients with APA N Engl J Med 2001 JAMA 2004
Recurrent Thrombosis while on Anticoagulation Approach to patients with recurrent thrombosis is not defined If you are on warfarin Can increase INR range to higher intensity Addition of antiplatelet therapy Change anticoagulation from warfarin to heparin/lmwh If you are on DOAC Change anticoagulation from DOAC to warfarin or LMWH
Case 3 A 31 year old woman with a history of SLE presents with painful fingertips Several days later, she develops focal neurologic findings and is found to have a stroke and her creatinine increased A skin biopsy shows microvascular thrombosis
Case 3 What are the treatment recommendations?
Catastrophic Antiphospholipid Antibody Syndrome (CAPS) Defined as thrombosis affecting 3 or more organs within a period of 1 week with histologic confirmation of small vessel thrombosis Occurs in <1% of patients with APL Mortality rate of 33 50%, most commonly due to cerebral and cardiac thrombosis or renal failure
Treatment for CAPS Treatment not standardized Combination of anticoagulation, corticosteroids, plasma exchange considered frontline Retrospective analysis of 250 patients from CAPS registry found highest rate of recovery (78%) achieved with this combination Rituximab for refractory/relapsed cases (or if anticoagulation contraindicated) Additional therapies may include IVIG, cyclophosphamide, eculizumab Cervera R. et al. Autoimmun Rev 2014;13:699-707