Prothrombotic Coagulation Abnormalities Preceding the Hemolytic–Uremic Syndrome
Wayne L. Chandler, M.D., Srdjan Jelacic, B.S., Daniel R. Boster, B.S., Marcia A. Ciol, Ph.D., Glyn D. Williams, M.B., Ch.B., Sandra L. Watkins, M.D., Takashi Igarashi, M.D., Ph.D., and Phillip I. Tarr, M.D.
Background The hemolytic–uremic syndrome is a thromboticcomplication of Escherichia coli O157:H7 infection. It is notknown whether the coagulation abnormalities precede, and potentiallycause, this disorder.
Methods In 53 children infected with E. coli O157:H7, we measureda panel of markers indicating activation of the clotting cascadeand renal function within four days after the onset of illness.These markers were measured again in as many as possible ofthe 16 children in whom the hemolytic–uremic syndromedeveloped.
Results The children in whom the hemolytic–uremic syndromesubsequently developed had significantly higher median plasmaconcentrations of prothrombin fragment 1+2, tissue plasminogenactivator (t-PA) antigen, t-PA–plasminogen-activator inhibitortype 1 (PAI-1) complex, and D-dimer than children with uncomplicatedinfection. These abnormalities preceded the development of azotemiaand thrombocytopenia. When the hemolytic–uremic syndromedeveloped, the urinary concentrations of beta2-microglobulinand N-acetyl--glucosaminidase rose significantly (P=0.03 forboth increases); the plasma concentrations of t-PA antigen,t-PA–PAI-1 complex, D-dimer, and plasmin–antiplasmincomplex also increased significantly. The concentration of t-PAantigen correlated with that of the t-PA–PAI-1 complexin a linear regression model (squared correlation coefficient,0.80; P<0.001).
Conclusions In the hemolytic–uremic syndrome, thrombingeneration (probably due to accelerated thrombogenesis) andinhibition of fibrinolysis precede renal injury and may be thecause of such injury.
Source Information
From the Departments of Laboratory Medicine (W.L.C.), Anesthesiology (G.D.W.), and Pediatrics (S.L.W., P.I.T.), University of Washington School of Medicine, Seattle; Children's Hospital and Regional Medical Center, Seattle (S.J., D.R.B., M.A.C., G.D.W., S.L.W., P.I.T.); and the Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan (T.I.).
Address reprint requests to Dr. Tarr at the Division of Gastroenterology, CH-24, Children's Hospital and Regional Medical Center, 4800 Sand Point Way NE, Seattle, WA 98105, or at tarr{at}u.washington.edu.
Desch, K., Motto, D.
(2007). Is There a Shared Pathophysiology for Thrombotic Thrombocytopenic Purpura and Hemolytic-Uremic Syndrome?. J. Am. Soc. Nephrol.
18: 2457-2460
[Abstract][Full Text]
Ramos, M. V., Fernandez, G. C., Patey, N., Schierloh, P., Exeni, R., Grimoldi, I., Vallejo, G., Elias-Costa, C., del Carmen Sasiain, M., Trachtman, H., Combadiere, C., Proulx, F., Palermo, M. S.
(2007). Involvement of the fractalkine pathway in the pathogenesis of childhood hemolytic uremic syndrome. Blood
109: 2438-2445
[Abstract][Full Text]
Hingorani, S.
(2006). Chronic Kidney Disease in Long-Term Survivors of Hematopoietic Cell Transplantation: Epidemiology, Pathogenesis, and Treatment. J. Am. Soc. Nephrol.
17: 1995-2005
[Abstract][Full Text]
Stahl, A.-l., Svensson, M., Morgelin, M., Svanborg, C., Tarr, P. I., Mooney, J. C., Watkins, S. L., Johnson, R., Karpman, D.
(2006). Lipopolysaccharide from enterohemorrhagic Escherichia coli binds to platelets through TLR4 and CD62 and is detected on circulating platelets in patients with hemolytic uremic syndrome. Blood
108: 167-176
[Abstract][Full Text]
Wang, J.-Y., Wang, S.-S., Yin, P.-Z.
(2006). Haemolytic-uraemic syndrome caused by a non-O157 : H7 Escherichia coli strain in experimentally inoculated dogs. J Med Microbiol
55: 23-29
[Abstract][Full Text]
Nolasco, L. H., Turner, N. A., Bernardo, A., Tao, Z., Cleary, T. G., Dong, J.-f., Moake, J. L.
(2005). Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers. Blood
106: 4199-4209
[Abstract][Full Text]
Guessous, F., Marcinkiewicz, M., Polanowska-Grabowska, R., Kongkhum, S., Heatherly, D., Obrig, T., Gear, A. R. L.
(2005). Shiga Toxin 2 and Lipopolysaccharide Induce Human Microvascular Endothelial Cells To Release Chemokines and Factors That Stimulate Platelet Function. Infect. Immun.
73: 8306-8316
[Abstract][Full Text]
Dixon, B., Santamaria, J., Campbell, D.
(2005). Coagulation Activation and Organ Dysfunction Following Cardiac Surgery. Chest
128: 229-236
[Abstract][Full Text]
Ake, J. A., Jelacic, S., Ciol, M. A., Watkins, S. L., Murray, K. F., Christie, D. L., Klein, E. J., Tarr, P. I.
(2005). Relative Nephroprotection During Escherichia coli O157:H7 Infections: Association With Intravenous Volume Expansion. Pediatrics
115: e673-e680
[Abstract][Full Text]
Noris, M., Remuzzi, G.
(2005). Hemolytic Uremic Syndrome. J. Am. Soc. Nephrol.
16: 1035-1050
[Full Text]
Korcheva, V., Wong, J., Corless, C., Iordanov, M., Magun, B.
(2005). Administration of Ricin Induces a Severe Inflammatory Response via Nonredundant Stimulation of ERK, JNK, and P38 MAPK and Provides a Mouse Model of Hemolytic Uremic Syndrome. Am. J. Pathol.
166: 323-339
[Abstract][Full Text]
Schneemann, M., Cathomas, R., Laidlaw, S.T., El Nahas, A.M., Theakston, R.D.G., Warrell, D.A.
(2004). Life-threatening envenoming by the Saharan horned viper (Cerastes cerastes) causing micro-angiopathic haemolysis, coagulopathy and acute renal failure: clinical cases and review. QJM
97: 717-727
[Abstract][Full Text]
Tzipori, S., Sheoran, A., Akiyoshi, D., Donohue-Rolfe, A., Trachtman, H.
(2004). Antibody Therapy in the Management of Shiga Toxin-Induced Hemolytic Uremic Syndrome. Clin. Microbiol. Rev.
17: 926-941
[Abstract][Full Text]
Wolf, G.
(2004). Not known from ADAM(TS-13)--novel insights into the pathophysiology of thrombotic microangiopathies. Nephrol Dial Transplant
19: 1687-1693
[Full Text]
Hertig, A., Rondeau, E.
(2004). Role of the Coagulation/Fibrinolysis System in Fibrin-Associated Glomerular Injury. J. Am. Soc. Nephrol.
15: 844-853
[Abstract][Full Text]
Tsai, H.-M.
(2003). Advances in the Pathogenesis, Diagnosis, and Treatment of Thrombotic Thrombocytopenic Purpura. J. Am. Soc. Nephrol.
14: 1072-1081
[Abstract][Full Text]
Tsai, H.-M.
(2003). Platelet Activation and the Formation of the Platelet Plug: Deficiency of ADAMTS13 Causes Thrombotic Thrombocytopenic Purpura. Arterioscler. Thromb. Vasc. Bio.
23: 388-396
[Abstract][Full Text]
Tarr, P. I., Tsai, H.-M., Chandler, W. L., Nzerue, C. M., Moake, J. L.
(2002). Thrombotic Microangiopathies. NEJM
347: 2171-2173
[Full Text]
Darling-Hammond, L., Youngs, P.
(2002). Defining "Highly Qualified Teachers": What Does "Scientifically-Based Research" Actually Tell Us?. EDUCATIONAL RESEARCHER
31: 13-25
Moake, J. L.
(2002). Thrombotic Microangiopathies. NEJM
347: 589-600
[Full Text]
Eddy, A. A.
(2002). Plasminogen activator inhibitor-1 and the kidney. Am. J. Physiol. Renal Physiol.
283: F209-F220
[Abstract][Full Text]
Debourdeau, P., Zammit, C., Guerard, S., Chandler, W. L., Watkins, S. L., Tarr, P. I., Grabowski, E. F.
(2002). The Hemolytic-Uremic Syndrome. NEJM
346: 1332-1334
[Full Text]
Tarr, P. I.
(2002). Basic Fibroblast Growth Factor and Shiga Toxin-O157:H7-Associated Hemolytic Uremic Syndrome. J. Am. Soc. Nephrol.
13: 817-820
[Full Text]
Grabowski, E. F.
(2002). The Hemolytic-Uremic Syndrome -- Toxin, Thrombin, and Thrombosis. NEJM
346: 58-61
[Full Text]
A correction has been published: N Engl J Med 2002;346(9):715.
-glucosaminidase rose significantly (P=0.03 for both increases); the plasma concentrations of t-PA antigen, t-PA–PAI-1 complex, D-dimer, and plasmin–antiplasmin complex also increased significantly. The concentration of t-PA antigen correlated with that of the t-PA–PAI-1 complex in a linear regression model (squared correlation coefficient, 0.80; P<0.001). 
Previous
