Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Intensive Care Medicine
Published in: Intensive Care Medicine 11/2010

01-11-2010 | Experimental

Impaired microvascular perfusion in sepsis requires activated coagulation and P-selectin-mediated platelet adhesion in capillaries

Authors: Dan Secor, Fuyan Li, Christopher G. Ellis, Michael D. Sharpe, Peter L. Gross, John X. Wilson, Karel Tyml

Published in: Intensive Care Medicine | Issue 11/2010

Login to get access

Abstract

Purpose

Impaired microvascular perfusion in sepsis is not treated effectively because its mechanism is unknown. Since inflammatory and coagulation pathways cross-activate, we tested if stoppage of blood flow in septic capillaries is due to oxidant-dependent adhesion of platelets in these microvessels.

Methods

Sepsis was induced in wild type, eNOS−/−, iNOS−/−, and gp91phox−/− mice (n = 14–199) by injection of feces into the peritoneum. Platelet adhesion, fibrin deposition, and blood flow stoppage in capillaries of hindlimb skeletal muscle were assessed by intravital microscopy. Prophylactic treatments at the onset of sepsis were intravenous injection of platelet-depleting antibody, P-selectin blocking antibody, ascorbate, or antithrombin. Therapeutic treatments (delayed until 6 h) were injection of ascorbate or the glycoprotein IIb/IIIa inhibitor eptifibatide, or local superfusion of the muscle with NOS cofactor tetrahydrobiopterin or NO donor S-nitroso-N-acetylpenicillamine (SNAP).

Results

Sepsis at 6–7 h markedly increased the number of stopped-flow capillaries and the occurrence of platelet adhesion and fibrin deposition in these capillaries. Platelet depletion, iNOS and gp91phox deficiencies, P-selectin blockade, antithrombin, or prophylactic ascorbate prevented, whereas delayed ascorbate, eptifibatide, tetrahydrobiopterin, or SNAP reversed, septic platelet adhesion and/or flow stoppage. The reversals by ascorbate and tetrahydrobiopterin were absent in eNOS−/− mice. Platelet adhesion predicted 90% of capillary flow stoppage.

Conclusion

Impaired perfusion and/or platelet adhesion in septic capillaries requires NADPH oxidase, iNOS, P-selectin, and activated coagulation, and is inhibited by intravenous administration of ascorbate and by local superfusion of tetrahydrobiopterin and NO. Reversal of flow stoppage by ascorbate and tetrahydrobiopterin may depend on local eNOS-derived NO which dislodges platelets from the capillary wall.
Appendix
Available only for authorised users
Literature
1.
Vincent JL, Martinez EO, Silva E (2009) Evolving concepts in sepsis definitions. Crit Care Clin 25:665–675 (vii)CrossRefPubMed
2.
Lam C, Tyml K, Martin C, Sibbald W (1994) Microvascular perfusion is impaired in a rat model of normotensive sepsis. J Clin Invest 94:2077–2083CrossRefPubMed
3.
Ellis CG, Bateman RM, Sharpe MD, Sibbald WJ, Gill R (2002) Effect of a maldistribution of microvascular blood flow on capillary O2 extraction in sepsis. Am J Physiol Heart Circ Physiol 282:H156–H164PubMed
4.
Bateman RM, Walley KR (2005) Microvascular resuscitation as a therapeutic goal in severe sepsis. Crit Care 9(Suppl 4):S27–S32CrossRefPubMed
5.
Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, len-Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P (2007) Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 13:463–469CrossRefPubMed
6.
Sakr Y, Dubois MJ, De Backer D, Creteur J, Vincent JL (2004) Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 32:1825–1831CrossRefPubMed
7.
Draisma A, Bemelmans R, van der Hoeven JG, Spronk P, Pickkers P (2009) Microcirculation and vascular reactivity during endotoxemia and endotoxin tolerance in humans. Shock 31:581–585CrossRefPubMed
8.
Mariscalco MM (2006) Unlocking (perhaps unblocking) the microcirculation in sepsis. Crit Care Med 34:561–562CrossRefPubMed
9.
10.
Daudel F, Kessler U, Folly H, Lienert JS, Takala J, Jakob SM (2009) Thromboelastometry for the assessment of coagulation abnormalities in early and established adult sepsis: a prospective cohort study. Crit Care 13:R42CrossRefPubMed
11.
Levi M, van der Poll T, Buller HR (2004) Bidirectional relation between inflammation and coagulation. Circulation 109:2698–2704CrossRefPubMed
12.
Lindenblatt N, Menger MD, Klar E, Vollmar B (2006) Systemic hypothermia increases PAI-1 expression and accelerates microvascular thrombus formation in endotoxemic mice. Crit Care 10:R148CrossRefPubMed
13.
Wassmer SC, de Souza JB, Frere C, Candal FJ, Juhan-Vague I, Grau GE (2006) TGF-beta1 released from activated platelets can induce TNF-stimulated human brain endothelium apoptosis: a new mechanism for microvascular lesion during cerebral malaria. J Immunol 176:1180–1184PubMed
14.
Otterdal K, Smith C, Oie E, Pedersen TM, Yndestad A, Stang E, Endresen K, Solum NO, Aukrust P, Damas JK (2006) Platelet-derived light induces inflammatory responses in endothelial cells and monocytes. Blood 108:928–935CrossRefPubMed
15.
Al-Bahrani A, Taha S, Shaath H, Bakhiet M (2007) TNF-alpha and IL-8 in acute stroke and the modulation of these cytokines by antiplatelet agents. Curr Neurovasc Res 4:31–37CrossRefPubMed
16.
Jeong YI, Jung ID, Lee CM, Chang JH, Chun SH, Noh KT, Jeong SK, Shin YK, Lee WS, Kang MS, Lee SY, Lee JD, Park YM (2009) The novel role of platelet-activating factor in protecting mice against lipopolysaccharide-induced endotoxic shock. PLoS One 4:e6503CrossRefPubMed
17.
Lou J, Donati YR, Juillard P, Giroud C, Vesin C, Mili N, Grau GE (1997) Platelets play an important role in TNF-induced microvascular endothelial cell pathology. Am J Pathol 151:1397–1405PubMed
18.
Tyml K, Li F, Wilson JX (2008) Septic impairment of capillary blood flow requires nicotinamide adenine dinucleotide phosphate oxidase but not nitric oxide synthase and is rapidly reversed by ascorbate through an endothelial nitric oxide synthase-dependent mechanism. Crit Care Med 36:2355–2362CrossRefPubMed
19.
Stamme C, Bundschuh DS, Hartung T, Gebert U, Wollin L, Nusing R, Wendel A, Uhlig S (1999) Temporal sequence of pulmonary and systemic inflammatory responses to graded polymicrobial peritonitis in mice. Infect Immun 67:5642–5650PubMed
20.
Reheman A, Gross P, Yang H, Chen P, Allen D, Leytin V, Freedman J, Ni H (2005) Vitronectin stabilizes thrombi and vessel occlusion but plays a dual role in platelet aggregation. J Thromb Haemost 3:875–883CrossRefPubMed
21.
McEver RP (2002) P-selectin and PSGL-1: exploiting connections between inflammation and venous thrombosis. Thromb Haemost 87:364–365PubMed
22.
Mannel DN, Grau GE (1997) Role of platelet adhesion in homeostasis and immunopathology. Mol Pathol 50:175–185CrossRefPubMed
23.
Westrick RJ, Winn ME, Eitzman DT (2007) Murine models of vascular thrombosis (Eitzman series). Arterioscler Thromb Vasc Biol 27:2079–2093CrossRefPubMed
24.
Wu F, Tyml K, Wilson JX (2008) iNOS expression requires NADPH oxidase-dependent redox signaling in microvascular endothelial cells. J Cell Physiol 217:207–214CrossRefPubMed
25.
Vachharajani V, Vital S, Russell J, Granger DN (2007) Hypertonic saline and the cerebral microcirculation in obese septic mice. Microcirculation 14:223–231CrossRefPubMed
26.
Bergmeier W, Chauhan AK, Wagner DD (2008) Glycoprotein Ibalpha and von Willebrand factor in primary platelet adhesion and thrombus formation: lessons from mutant mice. Thromb Haemost 99:264–270PubMed
27.
Moreau D, Timsit JF, Vesin A, Garrouste-Org, de Lassence A, Zahar JR, Adrie C, Vincent F, Cohen Y, Schlemmer B, Azoulay E (2007) Platelet count decline: an early prognostic marker in critically ill patients with prolonged ICU stays. Chest 131:1735–1741CrossRefPubMed
28.
29.
Wu F, Wilson JX, Tyml K (2004) Ascorbate protects against impaired arteriolar constriction in sepsis by inhibiting inducible nitric oxide synthase expression. Free Radic Biol Med 37:1282–1289CrossRefPubMed
30.
Krotz F, Sohn HY, Pohl U (2004) Reactive oxygen species: players in the platelet game. Arterioscler Thromb Vasc Biol 24:1988–1996CrossRefPubMed
31.
Ovechkin AV, Lominadze D, Sedoris KC, Robinson TW, Tyagi SC, Roberts AM (2007) Lung ischemia-reperfusion injury: implications of oxidative stress and platelet-arteriolar wall interactions. Arch Physiol Biochem 113:1–12CrossRefPubMed
32.
Lange M, Enkhbaatar P, Nakano Y, Traber DL (2009) Role of nitric oxide in shock: the large animal perspective. Front Biosci 14:1979–1989CrossRefPubMed
33.
34.
Fujimi S, MacConmara MP, Maung AA, Zang Y, Mannick JA, Lederer JA, Lapchak PH (2006) Platelet depletion in mice increases mortality after thermal injury. Blood 107:4399–4406CrossRefPubMed
Metadata
Title
Impaired microvascular perfusion in sepsis requires activated coagulation and P-selectin-mediated platelet adhesion in capillaries
Authors
Dan Secor
Fuyan Li
Christopher G. Ellis
Michael D. Sharpe
Peter L. Gross
John X. Wilson
Karel Tyml
Publication date
01-11-2010
Publisher
Springer-Verlag
Published in
Intensive Care Medicine / Issue 11/2010
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-010-1969-3

Other articles of this Issue 11/2010

Intensive Care Medicine 11/2010 Go to the issue

Pediatric Correspondence

Refractory agitation as a marker for pediatric delirium in very young infants at a pediatric intensive care unit

Experimental

Suspended animation inducer hydrogen sulfide is protective in an in vivo model of ventilator-induced lung injury

Original

Restoring arterial pressure with norepinephrine improves muscle tissue oxygenation assessed by near-infrared spectroscopy in severely hypotensive septic patients

Correspondence

Statistical analysis plan of PROWESS SHOCK study

Pediatric Original

Off-hours admission and mortality in two pediatric intensive care units without 24-h in-house senior staff attendance

Original

Human and experimental septic shock are characterized by depletion of lipid droplets in the adrenals