Semin Respir Crit Care Med 2004; 25(6): 645-659
DOI: 10.1055/s-2004-860979
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Hematologic Changes in Sepsis and Their Therapeutic Implications

Richert E. Goyette1 , Nigel S. Key2 , E. Wesley Ely3
  • 1Consultant, hematology and oncology, private practice, Knoxville, Tennessee
  • 2Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota Medical School, Minneapolis, Minnesota
  • 3Department of Medicine, Division of Allergy/Pulmonary/Critical Care Medicine and Center for Health Services Research and the VA Tennessee Valley Geriatric Research, Education, and Clinical Center (GRECC), all at the Vanderbilt University School of Medicine, Nashville, Tennessee
Further Information

Publication History

Publication Date:
22 December 2004 (online)

ABSTRACT

The blood and bone marrow constitute the hematologic organ system. Unlike other organ systems, hematologic organs are distributed in space and provide for a variety of seemingly unrelated functions. The hematologic system has both cellular and fluid-phase elements. Cellular elements include erythrocytes, leukocytes, and platelets; fluid phase elements include coagulation factors, natural antithrombotics, and proteins of the fibrinolytic system. The most common abnormalities of the hematologic system in patients with sepsis are anemia, leukocytosis, thrombocytopenia, and activation of the hemostatic system. Dysfunction of the hematologic organ system is an early manifestation of severe sepsis and is seen in virtually all patients with this disease. In concert with alterations in the endothelium, hematologic changes reflect both the body's reaction to an infectious insult as well as attempts to restore homeostasis. Dysfunction of the hematologic organ system can contribute to multiple organ dysfunctions and death. Recognizing these sepsis-associated changes and understanding the underlying pathophysiology are key to improving outcomes in patients with this deadly disease.

REFERENCES

  • 1 Angus D C, Linde-Zwirble W T, Lidicker J, Clermont G, Carcillo J, Pinsky M R. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.  Crit Care Med. 2001;  29 1303-1310
  • 2 Aird W C. The hematologic system as a marker of organ dysfunction in sepsis.  Mayo Clin Proc. 2003;  78 869-881
  • 3 Sporn L, Huber P. Endothelial cell biology. In Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN Hemostasis and Thrombosis Philadelphia: Lippincott; Williams & Wilkins 2001
  • 4 Hack C E, Zeerleder S. The endothelium in sepsis: source of and a target for inflammation.  Crit Care Med. 2001;  29(7 Suppl) S21-S27
  • 5 Esmon C T. The normal role of activated protein C in maintaining homeostasis and its relevance to critical illness.  Crit Care. 2001;  5 S7-12
  • 6 Leclerc J, Pu Q, Corseaux D et al.. A single endotoxin injection in the rabbit causes prolonged blood vessel dysfunction and a procoagulant state.  Crit Care Med. 2000;  28 3672-3678
  • 7 Vincent J L. Microvascular endothelial dysfunction: a renewed appreciation of sepsis pathophysiology.  Crit Care. 2001;  5 S1-S5
  • 8 Reinhart K, Bayer O, Brunkhorst F, Meisner M. Markers of endothelial damage in organ dysfunction and sepsis.  Crit Care Med. 2002;  30(5 Suppl) S302-S312
  • 9 Krafte-Jacobs B, Brilli R. Increased circulating thrombomodulin in children with septic shock.  Crit Care Med. 1998;  26 933-938
  • 10 Moss M, Gillespie M K, Ackerson L, Moore F A, Moore E E, Parsons P E. Endothelial cell activity varies in patients at risk for the adult respiratory distress syndrome.  Crit Care Med. 1996;  24 1782-1786
  • 11 Hotchkiss R S, Karl I E. The pathophysiology and treatment of sepsis.  N Engl J Med. 2003;  348 138-150
  • 12 Baskurt O K, Gelmont D, Meiselman H J. Red blood cell deformability in sepsis.  Am J Respir Crit Care Med. 1998;  157 421-427
  • 13 Langenfeld J E, Livingston D H, Machiedo G W. Red cell deformability is an early indicator of infection.  Surgery. 1991;  110 398-403 , discussion 403-404
  • 14 Baskurt O K, Temiz A, Meiselman H J. Red blood cell aggregation in experimental sepsis.  J Lab Clin Med. 1997;  130 183-190
  • 15 van Iperen C E, Gaillard C A, Kraaijenhagen R J, Braam B G, Marx J J, van de Wiel A. Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients.  Crit Care Med. 2000;  28 2773-2778
  • 16 Zimmerman J E, Seneff M G, Sun X, Wagner D P, Knaus W A. Evaluating laboratory usage in the intensive care unit: patient and institutional characteristics that influence frequency of blood sampling.  Crit Care Med. 1997;  25 737-748
  • 17 Vincent J L, Baron J F, Reinhart K et al.. Anemia and blood transfusion in critically ill patients.  JAMA. 2002;  288 1499-1507
  • 18 Smoller B R, Kruskall M S. Phlebotomy for diagnostic laboratory tests in adults: pattern of use and effect on transfusion requirements.  N Engl J Med. 1986;  314 1233-1235
  • 19 Olivares M, Walter T, Osorio M, Chadud P, Schlesinger L. Anemia of a mild viral infection: the measles vaccine as a model.  Pediatrics. 1989;  84 851-855
  • 20 Krantz S B. Pathogenesis and treatment of the anemia of chronic disease.  Am J Med Sci. 1994;  307 353-359
  • 21 Andrews N C. Disorders of iron metabolism.  N Engl J Med. 1999;  341 1986-1995
  • 22 Shurin S B, Anderson P, Zollinger J, Rathbun R K. Pathophysiology of hemolysis in infections with Hemophilus influenzae type b.  J Clin Invest. 1986;  77 1340-1348
  • 23 Su D, Roth R I, Levin J. Hemoglobin infusion augments the tumor necrosis factor response to bacterial endotoxin (lipopolysaccharide) in mice.  Crit Care Med. 1999;  27 771-778
  • 24 Corwin H L, Parsonnet K C, Gettinger A. RBC transfusion in the ICU: is there a reason?.  Chest. 1995;  108 767-771
  • 25 Gazmuri R J, Shakeri S A. Blood transfusion and the risk of nosocomial infection: an underreported complication?.  Crit Care Med. 2002;  30 2389-2391
  • 26 Goodnough L T, Brecher M E, Kanter M H, AuBuchon J P. Transfusion medicine: first of two parts-blood transfusion.  N Engl J Med. 1999;  340 438-447
  • 27 Hébert P C, Wells G, Blajchman M A et al.. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group.  N Engl J Med. 1999;  340 409-417
  • 28 Corwin H L, Gettinger A, Pearl R G et al.. Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial.  JAMA. 2002;  288 2827-2835
  • 29 Russell J A. Adding fuel to the fire: the supranormal oxygen delivery trials controversy.  Crit Care Med. 1998;  26 981-983
  • 30 Rivers E, Nguyen B, Havstad S et al.. Early goal-directed therapy in the treatment of severe sepsis and septic shock.  N Engl J Med. 2001;  345 1368-1377
  • 31 Bone R C, Balk R A, Cerra F B et al.. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine Chest 1992 101: 1644-1655
  • 32 Medzhitov R, Janeway Jr C. Innate immunity.  N Engl J Med. 2000;  343 338-344
  • 33 Funke A, Berner R, Traichel B, Schmeisser D, Leititis J U, Niemeyer C M. Frequency, natural course, and outcome of neonatal neutropenia.  Pediatrics. 2000;  106(1 Pt 1) 45-51
  • 34 Root R K, Lodato R F, Patrick W et al.. Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis.  Crit Care Med. 2003;  31 367-373
  • 35 Bernard G R, Vincent J L, Laterre P F et al.. Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med. 2001;  344 699-709
  • 36 Warren B L, Eid A, Singer P et al.. Caring for the critically ill patient: high-dose antithrombin III in severe sepsis: a randomized controlled trial.  JAMA. 2001;  286 1869-1878
  • 37 Baughman R P, Lower E E, Flessa H C, Tollerud D J. Thrombocytopenia in the intensive care unit.  Chest. 1993;  104 1243-1247
  • 38 Stephan F, Hollande J, Richard O, Cheffi A, Maier-Redelsperger M, Flahault A. Thrombocytopenia in a surgical ICU.  Chest. 1999;  115 1363-1370
  • 39 Vanderschueren S, De Weerdt A, Malbrain M et al.. Thrombocytopenia and prognosis in intensive care.  Crit Care Med. 2000;  28 1871-1876
  • 40 Nijsten M W, ten Duis H J, Zijlstra J G, Porte R J, Zwaveling J H, Paling J C. The TH: blunted rise in platelet count in critically ill patients is associated with worse outcome.  Crit Care Med. 2000;  28 3843-3846
  • 41 Long M W. Thrombopoietin stimulation of hematopoietic stem/progenitor cells.  Curr Opin Hematol. 1999;  6 159-163
  • 42 Cramer E M. Megakaryocyte structure and function.  Curr Opin Hematol. 1999;  6 354-361
  • 43 Shibazaki M, Kawabata Y, Yokochi T, Nishida A, Takada H, Endo Y. Complement-dependent accumulation and degradation of platelets in the lung and liver induced by injection of lipopolysaccharides.  Infect Immun. 1999;  67 5186-5191
  • 44 Tsujikawa A, Kiryu J, Yamashiro K et al.. Interactions between blood cells and retinal endothelium in endotoxic sepsis.  Hypertension. 2000;  36 250-258
  • 45 Salat A, Murabito M, Boehm D et al.. Endotoxin enhances in vitro platelet aggregability in whole blood.  Thromb Res. 1999;  93 145-148
  • 46 Stephan F, Thioliere B, Verdy E, Tulliez M. Role of hemophagocytic histiocytosis in the etiology of thrombocytopenia in patients with sepsis syndrome or septic shock.  Clin Infect Dis. 1997;  25 1159-1164
  • 47 Francois B, Trimoreau F, Vignon P, Fixe P, Praloran V, Gastinne H. Thrombocytopenia in the sepsis syndrome: role of hemophagocytosis and macrophage colony-stimulating factor.  Am J Med. 1997;  103 114-120
  • 48 Stephan F, Cheffi M A, Kaplan C et al.. Autoantibodies against platelet glycoproteins in critically ill patients with thrombocytopenia.  Am J Med. 2000;  108 554-560
  • 49 Brieger D B, Mak K H, Kottke-Marchant K, Topol E J. Heparin-induced thrombocytopenia.  J Am Coll Cardiol. 1998;  31 1449-1459
  • 50 Warkentin T E, Hayward C P, Boshkov L K et al.. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia.  Blood. 1994;  84 3691-3699
  • 51 Warkentin T E, Elavathil L J, Hayward C P, Johnston M A, Russett J I, Kelton J G. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia.  Ann Intern Med. 1997;  127 804-812
  • 52 Berkman N, Michaeli Y, Or R, Eldor A. EDTA-dependent pseudothrombocytopenia: a clinical study of 18 patients and a review of the literature.  Am J Hematol. 1991;  36 195-201
  • 53 Gaydos L A, Freireich E J, Mantel N. The quantitative relation between platelet count and hemorrhage in patients with acute leukemia.  N Engl J Med. 1962;  266 905-909
  • 54 Rinder H M, Arbini A A, Snyder E L. Optimal dosing and triggers for prophylactic use of platelet transfusions.  Curr Opin Hematol. 1999;  6 437-441
  • 55 Drews R E. Critical issues in hematology: anemia, thrombocytopenia, coagulopathy, and blood product transfusions in critically ill patients.  Clin Chest Med. 2003;  24 607-622
  • 56 Triulzi D. Optimizing Platelet Transfusion Therapy. Baltimore, MD: Institute for Transfusion Medicine. 1997
  • 57 Osterud B, Bjorklid E. The tissue factor pathway in disseminated intravascular coagulation.  Semin Thromb Hemost. 2001;  27 605-617
  • 58 Taylor Jr F B, Chang A, Ruf W et al.. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody.  Circ Shock. 1991;  33 127-134
  • 59 Creasey A A, Chang A C, Feigen L, Wun T C, Taylor Jr F B, Hinshaw L B. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock.  J Clin Invest. 1993;  91 2850-2860
  • 60 Taylor F B, Chang A C, Peer G, Li A, Ezban M, Hedner U. Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin-6 and -8, but not tumor necrosis factor, responses of the baboon to LD100 Escherichia coli .  Blood. 1998;  91 1609-1615
  • 61 Pixley R A, De La Cadena R, Page J D et al.. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia: in vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons.  J Clin Invest. 1993;  91 61-68
  • 62 van der Poll T, de Jonge E, Levi M. Regulatory role of cytokines in disseminated intravascular coagulation.  Semin Thromb Hemost. 2001;  27 639-651
  • 63 Drake T A, Cheng J, Chang A, Taylor Jr F B. Expression of tissue factor, thrombomodulin, and E-selectin in baboons with lethal Escherichia coli sepsis.  Am J Pathol. 1993;  142 1458-1470
  • 64 Taylor Jr F B, Chang A C, Peer G T et al.. DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage.  Blood. 1991;  78 364-368
  • 65 Mesters R M, Helterbrand J, Utterback B G et al.. Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications.  Crit Care Med. 2000;  28 2209-2216
  • 66 Yan S B, Helterbrand J D, Hartman D L, Wright T J, Bernard G R. Low levels of protein C are associated with poor outcome in severe sepsis.  Chest. 2001;  120 915-922
  • 67 Yan S B, Dhainaut J F. Activated protein C versus protein C in severe sepsis.  Crit Care Med. 2001;  29(7 Suppl) S69-S74
  • 68 Cheng T, Liu D, Griffin J H et al.. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective.  Nat Med. 2003;  9 338-342
  • 69 Faust S N, Levin M, Harrison O B et al.. Dysfunction of endothelial protein C activation in severe meningococcal sepsis.  N Engl J Med. 2001;  345 408-416
  • 70 Dhainaut J F, Yan S B, Margolis B D et al.. Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in patients with severe sepsis.  Thromb Haemost. 2003;  90 642-653
  • 71 Liaw P, Ferrell G, Loeb M, Foley R, Weitz J, Esmon C T. Patients with sepsis vary markedly in their ability to generate activated protein C [abstract].  Blood. 2001;  98 445a
  • 72 Hermans P W, Hibberd M L, Booy R et al.. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group.  Lancet. 1999;  354 556-560
  • 73 Westendorp R G, Hottenga J J, Slagboom P E. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock.  Lancet. 1999;  354 561-563
  • 74 Raaphorst J, Johan Groeneveld A B, Bossink A W, Erik Hack C. Early inhibition of activated fibrinolysis predicts microbial infection, shock and mortality in febrile medical patients.  Thromb Haemost. 2001;  86 543-549
  • 75 Tomashefski Jr J F. Pulmonary pathology of the adult respiratory distress syndrome.  Clin Chest Med. 1990;  11 593-619
  • 76 Hasegawa N, Husari A W, Hart W T, Kandra T G, Raffin T A. Role of the coagulation system in ARDS.  Chest. 1994;  105 268-277
  • 77 Taylor Jr F B, Toh C H, Hoots W K, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation.  Thromb Haemost. 2001;  86 1327-1330
  • 78 Mammen E F. Coagulation abnormalities in liver disease.  Hematol Oncol Clin North Am. 1992;  6 1247-1257
  • 79 Clarke B J, Sridhara S, Woskowska Z, Blajchman M A. Consumption of plasma factor VII in a rabbit model of nonovert disseminated intravascular coagulation.  Thromb Res. 2002;  108 329-334
  • 80 Feinstein D I. Diagnosis and management of disseminated intravascular coagulation: the role of heparin therapy.  Blood. 1982;  60 284-287
  • 81 Dellinger R P, Carlet J M, Masurtt et al.. Surviving sepsis campaign management guidelines committee. Surviving sepsis campaign guidelines for management of severe repsis and saptic shock.  Crit Care Med. 2004;  32 858-873
  • 82 Laterre P F, Heiselman D. Management of patients with severe sepsis, treated by drotrecogin alfa (activated).  Am J Surg. 2002;  184(6A Suppl) S39-S46
  • 83 Aoki N, Matsuda T, Saito H et al.. A comparative double-blind randomized trial of activated protein C and unfractionated heparin in the treatment of disseminated intravascular coagulation.  Int J Hematol. 2002;  75 540-547
  • 84 Joyce D, Yan B, Basson B R et al.. Disseminated intravascular coagulation in severe sepsis patients treated with recombinant human activated protein C [abstract].  Blood. 2001;  98 445a
  • 85 Ely E W, Angus D C, Williams M D, Bates B, Qualy R, Bernard G R. Drotrecogin alfa (activated) treatment of older patients with severe sepsis.  Clin Infect Dis. 2003;  37 187-195
  • 86 Mari D, Mannucci P M, Coppola R, Bottasso B, Bauer K A, Rosenberg R D. Hypercoagulability in centenarians: the paradox of successful aging.  Blood. 1995;  85 3144-3149
  • 87 Cohen H J, Harris T, Pieper C F. Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly.  Am J Med. 2003;  114 180-187
  • 88 Yamamoto K, Shimokawa T, Yi H et al.. Aging accelerates endotoxin-induced thrombosis: increased responses of plasminogen activator inhibitor-1 and lipopolysaccharide signaling with aging.  Am J Pathol. 2002;  161 1805-1814

E. Wesley ElyM.D. M.P.H. 

Center for Health Services Research

#6109 MCE, Vanderbilt University Medical Center

Nashville, TN 37232-8300

Email: wes.ely@vanderbilt.edu

    >