Anticoagulation in Antiphospholipid Antibody Syndrome Mark Kochenderfer Resident Grand Rounds March 5, 2002 Case • Patient is a 28 year old female with SLE diagnosed six years ago. Patient presented to general medicine last year with a thrombus in her subclavian vein. She had a history of a prior DVT and four miscarriages. Further testing revealed anticardiolipin antibodies. Introduction • Antiphospholipid Antibodies recognize phospholipids and/or proteins associated with them. • First recognition came in 1906 in conjunction with syphilis research • First description of syndrome with thrombosis, recurrent miscarriage and thrombocytopenia by Hughes in 1983 • Advances in our understanding of the immune system has led to the discovery of antibodies that are associated with this syndrome. • Rapid advances in technology and basic science knowledge have outdistanced clinical studies causing some studies to be essentially worthless at completion because the knowledge behind them changed during Purpose of Presentation • Review basic current understanding of pathogenesis and clinical features of APS • Look at current issues in anticoagulation in APS • Review data on anticoagulation in APS Outline “Where we are at and where we are going” • I. Introduction • II. Pathogenesis • A.theories on f(x) • B.types of ab • C.prevalance Pathogenesis • Antibodies are directed against phospholipids, plasma proteins bound to phospholipids, or unique antigens revealed during the interaction of the two. • Mechanism of pathology poorly understood • Some claim antibodies extraneous to APS • Most plausible theory is antibodies interact with plasma proteins that bind to phospholipids. Many of these proteins are also anticoagulants in the clotting cascade like beta 2 glycoprotein 1 and prothrombin. Neutralization of these proteins disrupts physiologic anticoagulation. The Antibodies • Lupus Anticoagulant (LA) • Anticardiolipin Antibodies (aCL) • anti Beta 2 glycoprotein antibodies Lupus Anticoagulant • Now thought to react against prothrombin • May result in elevated PTT • Higher thrombotic potential than aCL when each are present alone Anticardiolipin Antibodies • Used to be thought to react against cardiolipin but it is now thought to interact with B2GP1 • 85% of APS pts have both LA and aCL Anti Beta 2 GP1 • Discovered after LA and aCL • Found without other two in 11% of APS pts and commonly with others. • Binds to B2GP1 disrupting f(x) • B2GP1 has anticoagulant activity through the inhibition of the conversion of prothrombin-thrombin, regulation of protein S, and/or activation of platelets. Prevalence of Antibodies • AB present in many conditions • transient elevations common • elevations common in autoimmune disease and infections ex. HIV, Hep C, syphilis • 7% of 1014 admits to Gen Med at University Hospital had APA. Only 2% had APS Prevalence in Elderly • 89 healthy females age 75-102 • 64% were aCL + • 32% were anti B2GP1 + • differences in isotypes present or possibly reactivity towards B2GP1 may explain this phenomena Isotypes • IgG in mid to high titer most often associated with APS • IgM not uncommon in APS • IgA uncommon in APS except in African- Americans Clinical Features • APS causes problems in multiple organ systems. • Basic pathologic change is thrombotic microangiopathy without perivascular inflammation • APS is subdivided into primary and secondary APS Primary and Secondary APS • Primary APS -APS in the absence of lupus • Secondary APS-APS in pt with lupus • Study compared pts with each and found only differences to be secondary had higher rate of hemolytic anemia, neutropenia, and low c4 levels Preliminary Criteria for Classification of definite APS • Designed by International Symposium on Antiphospholipid Antibodies as to aid in research • Include clinical and laboratory crteria. Must have one of each for APS to be present. Clinical Criteria • 1. Vascular Thrombosis: One or more clinical episodes of arterial, venous or small vessel thrombosis in any tissue or organ. Thrombosis must be confirmed by imaging or Doppler studies. • 2. Pregnancy Morbidity • a. one or more unexplained deaths of a morphologically normal fetus at or beyond 10th week of gestation, with normal fetal morphology documented by ultrasound or direct exam of fetus OR • b. one or more premature births of a morphologically normal fetus at or before the 34th week of gestation because of • (continued) severe placental insuffiencey. OR • c. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded. Laboratory Criteria • 1. Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer, on two or more occasions, at least 6 wks apart, measured by ELISA for B2GP1 dependent anticardiolipin antibodies. • 2. Lupus anticoagulant present in plasma, on 2 or more occasions at least 6 wks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostatis in the following steps: • a. Prolonged phospholipid-dependent coagulation demonstrated on a screening test eg aPTT,kaolin clotting time, dRvvt. • B. Failure to correct the prolonged coagulation time on the screening test by mixing with normal platelet poor plasma. • C. Shortening or correction of the prolonged coagulation time on the screening test by addition of excess phospholipid. • D Exclusion of other coagulopathies eg. Factor VIII inhibitor Features Associated with APS • CLINICAL • LABORATORY • Livedo reticularis • low titer aCL • Cardiac valvulopathy • IgA aCL • MS like syndrome • Seizures • antiB2GP1 ab • Thrombocytopenia • ab to prothrombin or • Hemolytic anemia annexin • TIAs • False + test for syphilis APS in Different Systems Thrombosis • Both arterial and venous • Two prospective studies found LA present in 8.5% and 14% of pts with first dvt • another study pts with dvt and aCL were twice as likely to have subsequent dvts than those with dvt that are aCL negative CNS • Ischemic attacks most common, APA are present in 46% of pts with CVA under the age of 50. • Increased seizure activity • MS-like syndrome Skin • Livedo reticularis classic finding. Has mottled purple reticular fishnet pattern. • Skin ulcerations also common Cardiovascular • 35-75% of pts with APS have valvular disorders • strong correlation between valvular disorders and CVAs • role of APA in in CAD controversial Renal • Hypertension • Thrombi in glomerulus • Renal involvement more common than once believed Pregnancy • 7-25% of women with recurrent miscarriages have APS as primary cause, in these women rate of untreated miscarriage 90% • Loss can occur throughout pregnancy, but what role APA have prior to 10 weeks controversial Pregnancy • Severe eclampsia and preeclampsia are also common • Even in treated populations preterm delivery rate 25% • APA present in 5% of all pregnancies Testing for APA in Pregnancy • 1. Severe preeclampsia before 34 wks • 2. Unexplained stillbirth or fetal death after 10 wks gestation • 3. Severe intrauterine growth restriction prior to term • 4. Abortions prior to 10 wks controversial. Most advocate screening after two 1st trimester losses with no other cause Thrombocytopenia • Present in 25% of patients • Responds to steroids and other immunomodulating drugs • Direct antibody interaction and platelet activation both play a role Hemolytic Anemia • Rare complication • antibody mediated Catastrophic APS • Small % of APS pts develop failure of multiple organs in rapid succession • mortality within 5 years 50% Monitoring Warfarin Therapy in APS Basic Hematology Review • Coumadin inhibits gamma carboxylation of coag factors II,VII,IX,X making inactive these vit K dependent factors and interrupting normal coagulation cascade. • Coumadin also inhibits vit K dep Proteins C and S which are natural inhibitors of coagulation. Basic Hematology Review • Different commercial thromboplastins used in calculating PT and these vary in sensitivity to factors II, VII, X (thromboplastin is insensitive to to IX) • To account for this INR created • Calculated using international sensitivity index (ISI) for thromboplastin used Heme con’t • ISI a correction factor for a particular thromboplastin used • Of note, ISI and INR correct only for differences in sensitivities to vit K dependent coagulation factors • INR invalid when coagulation problems occur in other proteins, eg liver disese • Many reactions in cascade phospholipid dep Do APA interfere with INR? • Ptt and dilute Russel viper venom time have been shown to have small elevations in APS • Few studies mid 1990s implied Lupus Anticoagulant interference with PT resulted in high INR • Tests were small and suffered form ISI calibration errors so a large multicenter study was undertaken to answer question Laboratory control of oral anticoagulant treatment by the INR system in patients with the antiphospholipid antibody syndrome and lupus anticoagulant. A. Tripodi, V. Chantarangkul et al. British Journal of Hematology 12/2001 Methods • 58 cases of APS on Coumadin and 57 antibody negative patients on Coumadin included • Target INRs similar • Samples collected frozen and shipped to coordinating center • INRs calculated using nine most widely used thromboplastins which were calibrated at center and ISIs assigned Results • 8/9 thromboplastins showed no statistical significance. • Thromborel R showed significant difference in INR between cases and controls as defined by percentage of patients with INR that was 20% greater than mean INR p<0.001 • Factor X amidolytic activity and INR similar in cases and controls Prophylaxis of patients with Antiphospholipid Antibodies • High incidence of thromboembolic events has led some to consider primary prophylaxis with aspirin or coumadin • Difficult to study because of holes in our knowledge of APA • To attempt to address question a decision analysis model was used Prophylactic Antithrombotic Therapy for Patients with Systemic Lupus Erythematosus with or Without Antiphospholipid Antibodies D. Wahl, H. Bounameaux et al. Archives of Internal Medicine Methods • The following assumptions were made in the model • 1. Daily ASA dose 100-325mg QD • 2. INR targeted to 2-3 • 3. Only major hemorrhagic events considered • 4. pts that suffered thrombotic event were still subject to future events. Methods • Options in Analysis were: • 1. observation • 2. prophylactic aspirin • 3. prophylactic warfarin • Outcomes were measured by tracking # thromboembolic events prevented and # bleeding events induced Results • Aspirin group performed best in model. In this group 8 thrombotic events were prevented and only 1 hemorrhagic event induced per 100 patients over 5 year period. • In Coumadin group it was estimated that 10.2 thrombotic events were prevented and 10.4 hemorrhagic events induced. Results • Computer also calculated months of quality adjusted survival gain as part of Markov subtree model • For the aspirin group survival gains varied between 14.7 months for a 20yo and 4.9 monts for a 60 yo Comment • Study has obvious limitations of being computer simulation • Risk of bleed with ASA was intentionally overestimated • Not something to base practice decisions on but may lend some support to a practice many doctors elect to do anyway. Anticoagulation in APS • Use of oral Coumadin mainstay of therapy • Until 1992 management outside of pregnancy unexplored • We will look at the four major studies on this subject Antiphospholipid Thrombosis: Clinical Course after the First Thrombotic Event in 70 Patients M. Rosove and M. Petronella Annals of Internal Medicine 1992 Methods • Retrospective study • 80% pts had primary APS 20% secondary • average age 45.3 SD 17.3 • 72% + aCL • 64% + Lupus Anticoagulant • 26% + false positive test result syphilis Methods • Outcomes were measured by observing site of initial and recurrent thrombotic events (venous or arterial) , kind of anticoagulation, and intensity of anticoagulation. Results • 1. Thrombotic events: 37pts (53%) had a total of 54 thrombotic events. In 23 patients with 1st event in venous circulation had 26 of 31 recurrent events in the venous circulation. 14 pts with initial event in arterial circulation all 23 subsequent events were in the arterial system. 91% of recurrences were ipsilateral. Anticoagulation and Thrombotic Events • 1. No treatment group had 0.19 events peryear of followup • 2. Aspirin alone group had .32 events per year which did not differ from no tx group • 3. Warfarin group with INR<1.9 conferred no protection from thrombotic activity • 4. Warfarin with target INR 2.0-2.9 had an event rate of 0.07 but did not reach significance (p=0.12) Results • 5. INR > 3.0 group had no events (p<0.001) • 6. Adding aspirin to Coumadin made no difference in outcomes. The Management of Thrombosis in the Antiphospholipid Antibody Syndrome M. Khamashta, M. Cuadrado et al. NEJM 1995 Methods • 147 pts with APS and h/o thrombosis were reviewed retrospectively. • 62 primary APS, 66 secondary APS, 19 APS with lupus like illness • Median age 32 • 84% female Results • 1. Ipsilateral vascular tree recurrence was again seen with 93% of patients with initial event in arterial circulation having subsequent events on arterial side and 76% of pts with initial event on venous side having subsequent events there. Results • 1. No treatment group had .29 events per follow-up year • 2. ASA was significantly different from no treatment group in initial analysis (p=0.013), however the no treatment group included a number of pregnant women so an analysis was done taking into account hypercoagulable states the difference disappeared. Results • 3. Patients on warfarin with a target INR of 2.0-3.0 had .23 events per year of follow-up and did not differ significantly from the no treatment group in events. P=.27 Results • 4. Pts in warfarin group with target INR > 3.0 had significantly fewer events. Rate was 0.015 events/ yr f-u (p<0.001) • 5. Adding aspirin to warfarin made no difference from warfarin without asa targeted to same INR • 6. It was noted in the data that there was a significant increase in the rate of thrombosis in the 6 months after warfarin cessation. Results • 6. (cont) There were 21 events in 39 pts during this period. When compared with baseline rates of thrombosis difference is significant (p<0.001) This was also noted by Derksen in a smaller study. A Retrospective Review of 61 Patients With Antiphospholipid Syndrome S.Krnic-Barrie, C. O’Connor et al. Archives of Internal Medicine 1997 Methods • 1. Retrospective Study • 2. 61 patients were identified. • 3. Outcomes measured were site of event, frequency of occurrence, and whether there was an elevation in events in the 6 months after cessation of warfarin. • 4. Warfarin was not stratified by target INR Results • 1. There was no difference between the aspirin and no treatment groups. • 2. Only 51% of recurrences were ipsilateral • 3. Warfarin group had significantly lower rate of thrombus over the no treatment group. (p=0.008) • 4. There was no elevation in rate of events in six months after warfarin cessation. Anticardiolipin Antibodies Predict Early Recurrence of TE and Death among Pts with Venous TE following Anticoagulant Therapy S. Schulman, E. Svenungsson et al. American J Med 1998 Methods • Purpose of study to explore length of anticoagulation in APS • prospective study. Pts with first event randomized to warfarin for 6 weeks or 6 months while those with a second event randomized to 6 months of warfarin or indefinite therapy. Pts then tested for aCL. • Target INR 2.0-2.85 Methods • 412 in first event group and 211 in second event group • study lasted four years • only venous events were in study Results • 1. 6 week group was not analyzed secondary to study dfficulties • 2. Overall risk of death in aCL + pts was 7% vs. 2.2% in non aCL group. (p=0.002) • 3. Indefinite anticoagulation group there was one DVT in 19 pts over length of study.This person quit taking anticoagulation 2-8 months prior to event. Results • In the group with their first recurrence anticoagulated for six months there was a significant difference between the aCL + and aCL negative groups in number of TE events over course of study (p=0.0013) • Sharp rise in rate of TE was noted in the six months after cessationof warfarin Comments • 1 difficult to analyze • 2 Raises question of lifetime anticoagulation Hemorrhagic Complications • Rosove: 0.031 major events per year • Khamashta: 0.017 major bleeding events per year • These rates are similar to those for non APS patients anticoagulated to similar INRs APS refractory to warfarin • No studies • Possibilities include increasing target INR to 4.0, adding aspirin, or adding LMWH Anticoagulation in Pregnancy with APS Randomised controlled trial of aspirin plus heparin in pregnant women with APS R. Rai, H. Cohen et al. BMJ 1997 Methods • 90 women with APS were randomized into two groups with one receiving 75mg of ASA and the other ASA and 5000u SQ heparin q12h • outcomes measured were number of live births and number of miscarriages Results • In the ASA group there were 19 live births and 26 miscarriages • In the ASA+heparin group there were 32 live births and 13 miscarriages • Improvement in outcomes with heparin significant (p=0.01) General guidelines for anticoagulation of APS in pregnancy • SQ heparin 10,000u q12 or lovenox 1mg/kg sq qd • Aspirin • If miscarriage occurs with heparin and aspirin group and patient becomes pregnant again IVIG can be tried although RCT failed to show benefit • Prednisone Future Possibilities • PAPRE warfarin intensity • PRECLUDE primary prevention • LMWH, IVIG Conclusions • 1. Although little data supporting use of aspirin for primary prevention I would still strongly consider it. • 2. Pts with APS need anticoagulated to a target INR of 3.0 • 3. Measurement of INR is generally unaffected by APA although specific thromboplastins have been shown to be effective. • 4. In pregnancy use of ASA and heparin sq has been shown to reduce miscarriages. • 5. Duration of anticoagulation therapy needed in APS patients not well characterized. A sharp increase with cessation of therapy has been noted for the first six months off Coumadin. Rate then seems to be linear. Long term anticoagulation should be strongly • 6. It is difficult to practice EBM without evidence • 7. My typing skills have eroded since college. • 8. It is difficult to work on grand rounds in the MIRC when Mohanty is on call. Back to the case... • Pt has cont to have multisystem involvement causing frequent hospitalizations. She developed renal failure last summer and is now on dialysis. Pt is not compliant with anticoagulation while out of the hospital and pain medicationsgiven to treat pain from lupus have caused dependence problems. Pt also beginning to have problems from long term • Use of steroids to control her lupus. She turns 29 next month.