Antiphospholipid-associated thrombocytopenia or autoimmune hemolytic anemia in patients with or without definite primary antiphospholipid syndrome according to the Sapporo revised classification criteria : a 6-year follow-up study Lucía Comellas-Kirkerup, Gabriela Herna´ndez-Molina, and Antonio R. Cabral BLOOD, OCT VOL. 116, NUMBER 16 R2. 홍 성 훈 / Prof. 이 재 진

Introduction

Manifestations of the primary APSManifestations of the primary APS - Thrombocytopenia : 30%~46% - AIHA & Evans syndrome : 4% & 10% Deleze´ etcDeleze´ etc - patients with thrombocytopenia had greater levels and positivity of IgG aCL. - patients with thrombocytopenia had greater levels and positivity of IgG aCL. - patients with AIHA were more frequently positive and had greater levels of the IgM isotype - patients with AIHA were more frequently positive and had greater levels of the IgM isotype Alarco´n-Segovia and collaborators.Alarco´n-Segovia and collaborators. - AIHA and thrombocytopenia could be considered part of a set of - AIHA and thrombocytopenia could be considered part of a set of preliminary classification criteria of APS in patients with SLE. preliminary classification criteria of APS in patients with SLE. The recent reveised Sapporo APS criteriaThe recent reveised Sapporo APS criteria - include thrombosis or pregnancy morbidity as clinical criteria for the classification of APS - include thrombosis or pregnancy morbidity as clinical criteria for the classification of APS - Thus, a patient with aPL antibodies and a hemocytopenia without a history of thrombosis or pregnancy morbidity is not classified as having APS. - Thus, a patient with aPL antibodies and a hemocytopenia without a history of thrombosis or pregnancy morbidity is not classified as having APS.

As is known, these hematologic manifestations may antedate thrombosis or pregnancy morbidity.As is known, these hematologic manifestations may antedate thrombosis or pregnancy morbidity. Even more, some authors have proposed that this subgroup of patients might indeed represent a prethrombotic state preceding the onset of APS.Even more, some authors have proposed that this subgroup of patients might indeed represent a prethrombotic state preceding the onset of APS. We studied patients with thrombocytopenia, autoimmune hemolytic anemia, or both with positive aPL according to the updated laboratory criteria for APS.We studied patients with thrombocytopenia, autoimmune hemolytic anemia, or both with positive aPL according to the updated laboratory criteria for APS. And compared them (hemocytopenic patients vs defiinite APS)And compared them (hemocytopenic patients vs defiinite APS)

Methods Retrospectively reviewed the medical records of 187 consecutive,Retrospectively reviewed the medical records of 187 consecutive, unselected patients with primary APS (1986~2008) unselected patients with primary APS (1986~2008) This registry includes patients who fulfilled the revised classification criteria for APS as well as patients with positive aPL and noncriteria clinical manifestations of APS.This registry includes patients who fulfilled the revised classification criteria for APS as well as patients with positive aPL and noncriteria clinical manifestations of APS. - Platelet < 100,000 - Platelet < 100,000 - AIHA : low Hb, direct positive Coombs test, corrected reti. Count(>2%) - AIHA : low Hb, direct positive Coombs test, corrected reti. Count(>2%) elevated indirect bilirrubin, elevated LD, and low haptoglobin levels. elevated indirect bilirrubin, elevated LD, and low haptoglobin levels. - Pt. with 2 or more positive determinations 12 weeks apart of - Pt. with 2 or more positive determinations 12 weeks apart of 1) IgG or IgM to aCL, 1) IgG or IgM to aCL, 2) IgG or IgM to anti–β2GP-I 2) IgG or IgM to anti–β2GP-I 3) lupus anticoagulant test (LAC). 3) lupus anticoagulant test (LAC). ExclusionExclusion - (+) anti-dsDNA - (+) anti-dsDNA - (+) ANA - (+) ANA - 4 or more criteria for SLE (ACR) - 4 or more criteria for SLE (ACR)

The group of patients was further subdivided into 2 subgroups.The group of patients was further subdivided into 2 subgroups. 1) Clinical APS : both the serologic and clinical APS criteria. 1) Clinical APS : both the serologic and clinical APS criteria. 2) the serologic criteria but without any obstetric or 2) Nonclinical APS : the serologic criteria but without any obstetric or thrombotic event during follow-up. thrombotic event during follow-up. Response to treatment - ≥100,000 ← ≥50000 greater than a platelet count increased of at least from baseline to a final value greater than AIHA : reached 10 g/dL in the absence of hemolysis (normal corrected - AIHA : reached 10 g/dL in the absence of hemolysis (normal corrected reticulocyte count, normal LD, and haptoglobin levels) reticulocyte count, normal LD, and haptoglobin levels) aPL assaysaPL assays - according to published methods. - according to published methods. Statistical analysis - Categorical variables - Categorical variables : the χ2 or Fisher exact test Continuous variables : the Student t test or Mann-Whitney U test - Continuous variables : the Student t test or Mann-Whitney U test

Results

Discussion It is still controversial whether these hematologic manifestations are partIt is still controversial whether these hematologic manifestations are part of the APS. of the APS. Our group has considered thrombocytopenia and/or AIHA as APS clinical manifestations since 1992.Our group has considered thrombocytopenia and/or AIHA as APS clinical manifestations since We hypothesized that there could be a group of patients who would continue having thrombocytopenia and/or AIHA as their main and only clinical manifestation. (despite fulfilling the revised Sydney laboratoryWe hypothesized that there could be a group of patients who would continue having thrombocytopenia and/or AIHA as their main and only clinical manifestation. (despite fulfilling the revised Sydney laboratory criteria for APS) Patients with definite APS were more frequently positive for LAC than those without it, regardless of their hematologic manifestation. Hemocytopenic patients with or without clinical APS had the same global response to treatment, number of relapses, prednisone, aspirin or use immunosupressive use, and frequency of splenectomy.Hemocytopenic patients with or without clinical APS had the same global response to treatment, number of relapses, prednisone, aspirin or use immunosupressive use, and frequency of splenectomy. Thrombosis-free state occurred in patients with IgG anti–β2GP-I antibodies, which not only confer high risk for thrombosis3 but also are frequently responsible for the in vitro lupus anticoagulant activityThrombosis-free state occurred in patients with IgG anti–β2GP-I antibodies, which not only confer high risk for thrombosis3 but also are frequently responsible for the in vitro lupus anticoagulant activity

In the current work, approximately 1/2 of our aPL-positive(+) pt. with thrombocytopenia developed APS.In the current work, approximately 1/2 of our aPL-positive(+) pt. with thrombocytopenia developed APS. Whereas 1/2 of them remained free of thrombosis and/or pregnancy morbidity.Whereas 1/2 of them remained free of thrombosis and/or pregnancy morbidity. It appears then that depending upon their aPL profile,It appears then that depending upon their aPL profile, patients with hematologic manifestations belong to a subset of patients with APS, some develop thrombosis during follow-up patients with hematologic manifestations belong to a subset of patients with APS, some develop thrombosis during follow-up whereas some continue having thrombocytopenia or hemolytic anemia as isolated clinical manifestations whereas some continue having thrombocytopenia or hemolytic anemia as isolated clinical manifestations

Results Patients with definite APS were more frequently positive for the lupus anticoagulant (63%) than lupus anticoagulant positive patients without APS (30%) (odds ratio, 3.5; 95% confidence interval, ; P <.02). Anticardiolipin or anti–β2-glycoprotein-I antibodies were highlyAnticardiolipin or anti–β2-glycoprotein-I antibodies were highly prevalent among the study groups. prevalent among the study groups. Our study suggests that, depending upon their antiphospho- lipid profile, patients with hemocytopenias appear to comprise a peculiar subset of patients with APS ; some develop thrombotic and/or obstetric APS whereas others continue with hematologic APS.