The Role of Coagulation and Fibrinolysis in the Pathogenesis of Diarrhea-Associated Hemolytic Uremic Syndrome

ABSTRACT

The hemolytic-uremic syndrome (HUS) is a frequent cause of acute renal failure in childhood. It comprises acute acquired hemolysis, thrombocytopenia, and renal dysfunction. Very many disease processes can lead to this constellation, the most frequent one in childhood being an infection by bacteria that produce Shiga toxin or Shiga-like toxins (SLTs) . In industrialized countries, the first identified human pathogen to cause HUS was Escherichia coli O157H7, and this organism remains the most common one. The mechanisms by which these bacteria cause hemorrhagic colitis and HUS are incompletely understood. The bacteria are able to adhere to the mucosa of the colon. The local and systemic effects that follow the intestinal invasion are responsible for the bloody diarrhea. In a further step, the SLTs reach the blood stream and attach to the endothelium of the small arterioles mainly in the kidney but also in other organs. The endothelial cells express a toxin-specific receptor that enables the contact between toxin and cells. Damage to the endothelium causes platelet aggregation and activation, which trigger fibrin deposition. Although thrombotic changes in the microcirculation have been recognized in many histological studies, it is only recently that coagulation studies have been able to demonstrate clearly localized intravascular coagulation. The finding that the fibrinolytic system is inhibited in HUS has been challenged. By using specific and sensitive tests to measure the active moiety of plasminogen activator inhibitor type 1 (PAI-1) and comparing the findings in HUS patients and appropriate controls, it has become clear that in diarrhea-associated HUS the fibrinolytic system is rather stimulated. In this contribution the pathophysiology of diarrhea-associated HUS is discussed with special emphasis on coagulation and fibrinolysis.

KEYWORD

Hemolytic-uremic syndrome - diarrhea-associated hemolytic-uremic syndrome in childhood - coagulation - fibrinolysis

REFERENCES

• 1 Gordjani N, Sutor A H, Zimmerkhackl L B, Brandis M. Hemolytic uremic syndromes in childhood.  Semin Thromb Hemost . 1997;  23 281-293
• 2 Karmali M A, Steele B T, Petric M, Lim C. Sporadic cases of haemolytic-uraemic syndrome associated with faecal verotoxin and cytotoxin producing Escherichia coli in stools.  Lancet . 1983;  8325 619-620
• 3 Karmali M A, Petric M, Lim C. The association between idiopathic hemolytic uremic syndrome and infection by verocytotoxin producing Escherichia coli J Infect Dis .  1985;  151 775-782
• 4 Furlan M, Robles R, Galbusera M. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.  N Engl J Med . 1998;  339 1578-1584
• 5 Tsai H M, Lian E CY. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.  N Engl J Med . 1998;  339 1585-1594
• 6 Habib R. Pathology of the hemolytic uremic syndrome. In: Kaplan BS, Trompeter RS, Moake JL, eds. Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura New York: Marcel Dekker 1992: 315-353
• 7 Kisker C T, Rush R A. Absence of intravascular coagulation in the hemolytic uremic syndrome.  Am J Dis Child . 1975;  129 223-226
• 8 Van Damme Lombaert R, Proesmans W, Van Damme B. Heparin plus dipyridamole in childhood hemolytic uremic syndrome. A prospective, randomized study.  J Pediatr . 1988;  113 913-918
• 9 Loirat C, Beaufils F, Sonsino E. Traitement du syndrome hémolytique et uremique de l'enfant par l'urokinase. Essai controlé coopératif (Treatment of childhood hemolytic uremic syndrome with urokinase).  Arch Fr Pediatr . 1984;  41 15-19
• 10 Gordjani N, Sutor A H. Coagulation changes associated with the hemolytic uremic syndrome.  Semin Thromb Hemost . 1998;  24 577-582
• 11 Nevard C HF, Jurd K M, Lane D A. Activation of coagulation and fibrinolysis in childhood diarrhoea-associated haemolytic uraemic syndrome.  Thromb Haemost . 1997;  78 1450-1455
• 12 Van Geet C, Proesmans W, Arnout J, Vermylen J, Declerck P J. Activation of both coagulation and fibrinolysis in childhood hemolytic uremic syndrome.  Kidney Int . 1998;  54 1324-1330
• 13 Bergstein J M. Glomerular fibrin deposition and removal.  Pediatr Nephrol . 1990;  4 78-87
• 14 Bergstein J M, Kuederli U, Bang N U. Plasma inhibitor of glomerular fibrinolysis in the hemolytic uremic syndrome.  Am J Med . 1982;  73 322-327
• 15 Bergstein J M, Riley M, Bang N U. Role of plasminogen-activator inhibitor type 1 in the pathogenesis and outcome of the hemolytic uremic syndrome.  N Engl J Med . 1992;  327 755-759
• 16 Walters M S, Matthei I U, Kay R, Dillon M J, Barratt T M. The polymorphonuclear leukocyte count in childhood haemolytic uraemic syndrome.  Pediatr Nephrol . 1989;  3 120-134
• 17 Fitzpatrick M M, Shah V, Trompeter R S, Dillon M J, Barratt T M. Interleukin-8 and polymorphoneutrophil leukocyte activation in hemolytic uremic syndrome of childhood.  Kidney Int . 1993;  42 951-956
• 18 van de Kar N A J C, Sauerwein R W, Demacker P NM. Plasma cytokine levels in hemolytic uremic syndrome.  Nephron . 1995;  71 309-313
• 19 Upadyaya K, Barwick K, Fishaut M, Kashgarian M, Siegel N. The importance of nonrenal involvement in hemolytic uremic syndrome.  Pediatrics . 1980;  65 115-120
• 20 Kelles A, Van Dyck M, Proesmans W. Childhood haemolytic uraemic syndrome: long-term outcome and prognostic features.  Eur J Pediatr . 1994;  153 38-42
• 21 Hüseman D, Gellerman J, Vollmer I. Long-term prognosis of hemolytic uremic syndrome and effective plasma flow.  Pediatr Nephrol . 1999;  13 672-677