Daniel Egan, MD April 13, PDF Free Download

Daniel Egan, MD April 13, 2012

Aug 2006 (at age 15): Acute unprovoked DVT in left common femoral vein Factor V Leiden heterozygous Positive lupus inhibitor Lovenox BID 2 weeks later: increased clot burden, so transitioned to UFH warfarin Difficult to maintain therapeutic INR Reportedly taking warfarin 20mg per day May 2007: anticoagulation discontinued Dec 2009: Intermittent left leg swelling. Angiogram revealed a long segment of stenotic left iliac vein, suggestive of May-Thurner syndrome. s/p balloon angioplasty, endovascular stent x 2 Plavix

Sep 2010: Established care at UMWC Had been started on fondaparinux 7.5mg daily for symptoms of venous claudication June 2011: Continued symptoms of venous claudication Femoral vein-to-ivc bypass PFTE graft Maintained on fondaparinux and clopidogrel Multiply recurrent graft thromboses Aug 2011: subtherapeutic on 7.5mg fondaparinux Increased fondaparinux to 10mg daily + clopidogrel July 2011: Seizure-type activity, EEG negative Recurrent thromboses in Nov 2011, Jan 2012 while on fondaparinux + clopidogrel s/p catheter-directed thrombolysis & thrombectomy Feb 2012: Admitted for GI bleed secondary to duodenal ulcers Resolved. Anticoagulation quickly resumed. Fondaparinux peak & trough therapeutic on 10mg; also on clopidogrel Prolonged hospitalization for pain, nausea, infection

March 2012: New pulmonary embolism Fondaparinux peak & trough sub-therapeutic despite same dose of 10mg Testing: Anti-cardiolipin & anti-b2 glycoprotein negative Repeat lupus inhibitor positive

2006 International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). Miyakis S et al. J Thromb Haemost 2006; 4:295. DVT 55% Pulmonary embolism 25% MI 3-16% Stroke / TIA 30% Pregnancy Loss?%

Livedo Reticularis Thrombocytopenia 11-22% 20-40% Epilepsy Migraine Hemolytic Anemia 11-22% 20% 10% Vianna JL, Khamashta; Am J Med 1994;96:3-9 Mchrani T, Petri M; Amsterdam: Elsevier; 2009. p.13-34 Cervera R; Autoimmun Rev 2008; 7:174-8

2006 International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). Miyakis S et al. J Thromb Haemost 2006; 4:295.

B2GPI Cardiolipin Prothrombin, Protein C, Protein S, HMW kininogen, annexin, factors Giannakopoulis, Blood 2009; 113: 985. Passam; Pathology 2004; 36:129 Antibodies recognize B2GPI, cardiolipin, or both.

drvvt aptt Kaolin clotting time Silica clotting time Taipan venom time Prothrombin time Hanly, CMAJ 2003; 113: 985

60 50 40 30 20 10 In prospective In a retrospective analysis 360 Italian analysis 30-40% of patients Infection with and either patients with apl and LA inflammation or acl followed may SLE or collagen over be associated 4 years, there with vascular disease had was transient a 2.5%/year apl thrombosis incidence Love Ann Intern of Med. 1990 May thrombotic 1;112(9):682-98 event. Finazzi G; Curr Rheumatol Rep 2001;3:271-6 15-34% 12-44% 10-19 % 52.9 % 0 1-5% 1-5% General Population SLE In an ICU ANY LAC acl ab2gpi Mchrani T, Petri M. Epidemiology of the antiphospholipid syndrome. In: Asherson RA, editor, Handbook of systemic autoimmune diseases, vol 10. Amsterdam: Elsevier 2009. Wenzel. Crit Care Med 2002, 30: 763.

Among 7 studies (a mix of case-control and prospective): acl is associated with increased risk for thrombosis The higher the titer, the stronger the association Galli et al, Blood 2003; 101:1827

Among 4 studies (a mix of case-control and prospective): LA is consistently associated with increased risk for thrombosis In a retrospective cohort study of 198 patients with apl, while LA was associated with thrombosis, combined presence of B2-GPI and LA carried a stronger risk. Galli et al, Blood 2003; 101:1827 de Laat HB, Blood 2004;104:3598-3602

Proposed mechanisms include: Activation of platelets Activation of endothelium and monocytes Increased expression of Tissue Factor and cytokines Increased expression of adhesion molecules Activation of the complement pathway Binding to and inhibition of ATIII, Protein C, Protein S, Annexin V Inhibition of B2GPI itself (assuming it has an anticoagulant function)

Lim, JAMA 2006; 295: 1050 Treatments In APS patients treated initially for VTE, there was a 52-69% recurrence rate at 5-6 years of follow-up APASS: Nested in two prospective retrospective cohort studies. study within Rosove, Warfarin Ann Intern Aspirin Med Recurrent 1992; 117:303. Stroke Study Khamashta, NEJM (JAMA 1995; 2004; 332:993. 291:576) In another No difference prospective in thrombosis study, the or Hazard bleeding Ratio for between recurrence warfarin at 3 months at INR was 1.4-2.8 4.0 for & aspirin patients with +apl 325mg Kearon, NEJM 1999; 340:901.

Two RCTs have shown high-intensity warfarin (INR 3.0-4.0) is not better than moderate-intensity (INR 2.0-3.0) in preventing recurrence. Crowther, NEJM 2003; 349:1133. Finazzi, J Thromb Haemost 2005; 3:848. The role of low-molecular weight heparin in patients with refractory APS is limited to case series and case reports Vargas-Hitos et al retrospectively evaluated 23 patients (half with primary APS) for an average of 36 months after switching from warfarin to LMWH and none had any recurrent thrombosis Vargas-Hitos, Ann Rheum Dis 2011; 70:1652 There are no studies evaluating fondaparinux for APS There are no studies evaluating dabigatran or rivaroxiban for APS Catastrophic APS: Observational data of plasma exchange, steroids and anticoagulation

The role of antibodies in the pathogenesis of APS is established. Possible strategies: Decrease antibody production Interfering with actions of antibody B cell Targeted therapy: Antibody production Act as antigen presenting cells Other immune functions B effector regulatory cells Cytokine production Hydroxychloroquine: Hematologic effects Cardiovascular benefits Immunomodulation?

NZW BXSB F1 mouse model of APS & SLE nephritis: Male offspring produce anti-nuclear antibodies (ANA), including antideoxyribonucleic acid (DNA) autoantibodies and high levels of anti-cardiolipin (acl) antibodies by 12 weeks of age The mice develop clinical manifestations of APS & SLE, such as myocardial infarction, thrombocytopenia, and glomerulonephritis. acl in NZW x BXSB F1 mice require a plasma cofactor such as β2-glycoprotein I (β2gpi) to bind to cardiolipin (CL) and thus possess binding properties similar to the acl in the serum of patients with SLE Gharavi AE, Am J Reprod Immunol 1998, 39:310. Previous studies in NZW BXSB F1 mice demonstrated that T cellinhibitory CTLA4-Ig blocked class switching and prevented the emergence of auto-antibodies, and mice did not develop coronary arterial thromboses or nephropathy Akkerman A, Autoimmunity 2004;37:445 51. BAFF: a TNF-like cytokine which supports the survival and differentiation of B cells Acts on the B cell receptors BAFF-R and TACI

B cell therapy: animal APS model NZW BXSB F1 mice injected at either 8 or 12 weeks with an adenovirus expressing BAFF-R-Ig: inhibits action of BAFF (decreases B cell activity) BAFF-R-IG resulted in: 1. Less acl in splenic tissue (not shown) 2. No statistically significant difference in serum acl (not shown) 3. Decreased cardiac damage 4. Improved survival Myocardial damage score: 1 - a single area of necrosis, 2 - several areas of necrosis and fibrosis, 3 - extensive focal areas of necrosis and fibrosis, and 4 - full- thickness myocardial infarct Kahn P, Arthritis Rheum 2008; 58:2824

Ioannou et al: Within a cohort of 32 patients with refractory SLE treated with rituximab, a retrospective study of 7 patients with > 2 previous positive assays for acl was performed. Rituximab administered as 1g IV x 2 doses two weeks apart Also received chlorpheniramine 4mg PO and methylprednisone 250mg IV A reduction in acl noted in all 7 patients

Female 14 15 18 Male 7 Kumar et al reviewed all studies of ritixumab in APS published as of August 2009. 18 articles documenting 21 patients. No RCTs. Age: 5-69 Median age: 39 16 Manifestations 8 11 4 Others: Seizures, livedo reticularis, papilledema, nephropathy, chorea, fluctuating INR 5 2 5 LA acl ab2gpi

Details are somewhat limited All 21 received anticoagulation All received rituximab Most: 375 mg/m 2 weekly x4 2 pts: R + CHOP 2 pts: R + Cytoxan All received either PO or IV steroids Some received other immunomodulatory drugs (CsA, hydroxychloroquine, azathioprine) All 5 with CAPS received IVIG or plasmapheresis Reported Improvements 9 9 3 1 1 1

Phase II, single-center, open-label trial Not yet published Inclusion Criteria: Age 18 or older + Standard laboratory criteria Any of 6 non-aps criteria manifestations Thrombocytopenia, AIHA, valvular disease, chronic skin ulcers, nephropathy, cognitive dysfunction Intervention: 1g Rituximab x 2 doses + solumedrol Primary outcome: Death, adverse events Secondary outcomes: Clinical improvement for each manifestation Laboratory measures NOT RECURRENT THROMBOTIC EVENTS

In vitro and animal studies Rituximab decreased apl levels in patients with SLE Case reports and small case series Some improvements in frequency of thromboses or CAPS reported Many other successes reported are based on other clinical manifestations or lab values An phase II clinical trial of rituximab in primary APS is ongoing but designed to examine safety and improvement in noncriteria manifestations, not thrombotic events

Rationale for Hydroxychloroquine (HCQ) in SLE & APS HCQ historically used as DVT prophylaxis in the 1970s and 1980s Multiple studies showed HCQ improved lipid profiles in patients with autoimmune disease In vivo: Inhibits platelet aggregation in vivo Jancinova, Thromb Res 1994; 74: 495 504 HCQ prevents increased expression of GPIIb/IIIa in platelets exposed to apl Espinola Thromb Haemost 2002; 87: 518 522 Interferes with antigen processing Lombard-Platlet, Immunology 1993; 80: 566 573 Decreases binding of apl to phospholipid bilayer Rand, Blood 2008; 112: 1687 Decreases inflammatory cytokines Lombard-Platlet, Immunology 1993; 80: 566 573

Dose not established in APS In lupus: a dose of 400mg daily or 400mg BID is given for a few weeks until disease response then continued at 200-400mg daily for maintenance Side effects: Myopathy Visual changes Use with caution in G6PD-deficiency

Ruiz-Irastorza, Lupus 2006, 15: 577. Prospective cohort study of 232 patients with SLE Not selected for apl status Followed for 15 years Primary endpoint: thrombosis 150 patients (64%) received anti-malarials for a median of 52 months 62: Hydroxychloroquine 46: Chloroquine 42: Both In Cox proportional hazards model: Anti-malarials were protective (HR 0.28)

Tektonidou, Arthritis Rheum 2009, 61: 29. 144 patients with SLE & apl+ vs 144 apl- age/sex-matched controls Prospectively followed for approximately 9 years Doses of HCQ not reported. There was no significant overall difference in whether HCQ was ever used among +apl patients with or without thrombosis, but a trend towards increased duration of use in those without thrombosis.

In multivariate analysis by Cox proportional hazards model: apl+ patients receiving hydroxychloroquine had a 1% lower risk of developing thrombosis per 1 month of treatment (HR per 1 month 0.99) Tektonidou, Arthritis Rheum 2009, 61: 29.

A single-center, cross-sectional study compared: 77 apl+ pts with APS (non-pregnant) 56 asymptomatic apl+pts (identified from a SLE registry, or lab database) Examined the last 6 months preceding a thrombotic event versus 6 months prior to last hospital visit for the control group + Thrombus No thrombus ASA 1/77 18/56 p < 0.001 HCQ 4/77 21/56 p < 0.001 Steroids 14/77 25/56 p = 0.002 IS 9/77 8/56 No dose information provided. Use of HCQ was significantly more frequent in the asymptomatic group. In logistic regression analysis, the probability of an event was reduced by HCQ. Erkan, Rheumatology 2002: 41: 924.

In vitro studies Retrospective and prospective studies show a survival benefit and antithrombotic benefit in patients with SLE In patients specifically with apl+: There is a suggestion of benefit in a prospective study In patients with APS: Case reports A cross-sectional study shows a reduced risk for thrombosis with HCQ 13 th International Congess Guidelines on Antiphospholipid Antibodies (Lupus 2011, 20:206): Consider HCQ for recurrent thrombosis (a non-graded recommendation)

Transitioned from bivalirudin to dabigatran 150mg BID Hydroxychloroquine 400mg po daily Rituximab 375 mg/m2 IV (2 of 4 doses)