Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies

TY - JOUR

T1 - Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies

AU - Fuchs, Tobias A

AU - Kremer Hovinga, Johanna A

AU - Schatzberg, Daphne

AU - Wagner, Denisa D

AU - Lämmle, Bernhard

PY - 2012/8/9

Y1 - 2012/8/9

N2 - Thrombotic microangiopathies (TMAs) are a group of life-threatening disorders characterized by thrombocytopenia, fragmentation of erythrocytes, and ischemic organ damage. Genetic disorders, autoimmune disease, and cancer are risk factors for TMAs, but an additional, unknown trigger is needed to bring about acute disease. Recent studies suggest that DNA and histones are released during inflammation or infection and stimulate coagulation, thrombosis, thrombocytopenia, and organ damage in mice. We show that extracellular DNA and histones as well as markers of neutrophils are present in acute TMAs. Analysis of plasma from TMA patients of different clinical categories revealed elevated levels of DNA-histone complexes and myeloperoxidase (MPO) from neutrophil granules as well as S100A8/A9, a heterocomplex abundant in neutrophil cytosol. During therapy of thrombotic thrombocytopenic purpura, a subtype of TMAs often associated with severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) deficiency, plasma DNA and MPO were inversely correlated with platelet counts, and their levels indicated amelioration or exacerbation of the disease. ADAMTS13 deficiency together with increased levels of plasma DNA and MPO were characteristic for acute thrombotic thrombocytopenic purpura. A minor infection often precedes acute TMA and extracellular DNA and histones released during the inflammatory response could provide the second hit, which precipitates acute TMA in patients with pre-existing risk factors.

AB - Thrombotic microangiopathies (TMAs) are a group of life-threatening disorders characterized by thrombocytopenia, fragmentation of erythrocytes, and ischemic organ damage. Genetic disorders, autoimmune disease, and cancer are risk factors for TMAs, but an additional, unknown trigger is needed to bring about acute disease. Recent studies suggest that DNA and histones are released during inflammation or infection and stimulate coagulation, thrombosis, thrombocytopenia, and organ damage in mice. We show that extracellular DNA and histones as well as markers of neutrophils are present in acute TMAs. Analysis of plasma from TMA patients of different clinical categories revealed elevated levels of DNA-histone complexes and myeloperoxidase (MPO) from neutrophil granules as well as S100A8/A9, a heterocomplex abundant in neutrophil cytosol. During therapy of thrombotic thrombocytopenic purpura, a subtype of TMAs often associated with severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) deficiency, plasma DNA and MPO were inversely correlated with platelet counts, and their levels indicated amelioration or exacerbation of the disease. ADAMTS13 deficiency together with increased levels of plasma DNA and MPO were characteristic for acute thrombotic thrombocytopenic purpura. A minor infection often precedes acute TMA and extracellular DNA and histones released during the inflammatory response could provide the second hit, which precipitates acute TMA in patients with pre-existing risk factors.

KW - Acute Disease

KW - Adolescent

KW - Adult

KW - Aged

KW - Case-Control Studies

KW - Cohort Studies

KW - DNA

KW - Disease Progression

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Nucleosomes

KW - Peroxidase

KW - Prognosis

KW - Remission Induction

KW - Thrombotic Microangiopathies

U2 - 10.1182/blood-2012-02-412197

DO - 10.1182/blood-2012-02-412197

M3 - SCORING: Journal article

C2 - 22611154

VL - 120

SP - 1157

EP - 1164

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 6

ER -