UTAustin | Portugal Workshop on Modeling and Simulation of Physiological Systems

December 6-8, 2012, Lisbon, Portugal

“ Coagulation and Inflammation Physiological Process for Numerical Studies”

Carlota Saldanha and Ana Silva - Herdade

Instituto Superior Técnico

UTAustin | Portugal Workshop on Modeling and Simulation of Physiological Systems

December 6-8, 2012, Lisbon, Portugal

“ Coagulation and Inflammation Physiological Process for Numerical Studies”

Carlota Saldanha and Ana Silva - Herdade

Instituto Superior Técnico

InflammationHemostasis ( Platelets, Coagulation, Fibrinolysis, Anticoagulation) Interrelation between Hemostasis and Inflammation and Vice Versa

arteriole

venule

Vessels of Circulatory System

Blood Components

RouleauxPreStasis

Granular Blood Flow

Cell freePlasma

RigidRBC

Swelling ofEndothelial CellObstruct RBC flow

In: Exempla Haemorheologica Booklet 3. The Microcirculation in the terminal vascular bed

WBC

RBC and WBC Flow

Microcirculation

Intravital microscopy image of blood flow in mice venule

Acute inflammation Resulting from Infection

by leukocytes on C-typesensors nerves fibres

Inflammatory Response to a Tissue Injury

http://drugline.org/medic/term/inflammatory-response/

Neutrophil and Endothelium in Inflammation

TISSUE INJURED

Type I Activation of Endothelial Cell

Nature Reviews Immunology 7, 803-815 (October 2007)

Stimulation- Rapid response independent of new genes expression Typically mediated by ligands

P-SelectinPAFResolves due receptor desensitization

Type II Activation of Endothelial Cell in Acute Inflammation

Nature Reviews Immunology 7, 803-815 (October 2007)

More sustained inflammatory responseSlow response dependent of new genes expression

TNFα; IL-1 are derivedfrom activated leukocytes

Open gapsLeakage of fibrinogenHard swelling

Leukocytes recruitmentmore effective

E –Selectin IL-8

VENULES(-) AP1 shut of E-Selectin>>VCAM1; ICAM-1 (+ byCytokines) Mononuclear –cell rich infiltrates

CAPILLARIES TNFα; IL-1. IFNγ EC deathFavours thrombosis; apoptotic cellslose their anticoagulant sheding heparan sulphate ; exocytosis microparticlesShuting off NOS3 and Trombomodulinby TNFα; TNFα; IL-1 induce Tf microparticles shed from cell surfaceThrombus: fibrin +plateles wall of infected tissue limit spread of microbes

Resolves by removal stimulus; by terminus NFk-β

juxtacrine

Creates a provisional matrix to support leukocytesentry to tissues

Microcirculation Normal / Inflamed

Kidney International, Vol. 58, Suppl. 76 (2000), pp. S-96–S-103

Acute Phase Proteins

Plug

Clot

*

**

* Activation by Thrombin

Extrinsic and Intrinsic Coagulation CascadeInterwined Pathways

Fibrin Plolymer

FXIIIa

colagen

*

TFPI

Endothelial Cell in Resting Non inflamed state

Nature Reviews Immunology 2007; 7, 803-815

Physiological Anticoagulants

Biochemia Medica 2012;22(1):49-62.

Fibrinolysis

Coagulation

Recovery of Vessel Wall

Inflammation / Hemostasis

Hemostatic ClotCan trap invading microbe;> vascular permeabilityAntimicrobial lysis Gram+

Bleeding

Restore theIntegrity of damaged tissues

Proinflammatory Cytokines TNFα, IL-1, IL-6

Inflammation Affects Hemostasis

Brist J Haemat 2005; 131:417- 431 Circulation 2004;109:2698-2704J Leukoc Biol 2008; 83:536-545 Biochemia Medica 2012;22(1):49-62

Inflammation Affects Fibrinolytic System

•1st >> tPA•2nd >>PAI-1(ECs TN-Fα, IL-1β)<< fibrin removal•3rd endothelium dysfunction sustain <<tissue plasminogen activator (tPA)

+Platelets releasePAI-1

Inflammation Activates Coagulation

Biochemia Medica 2012;22(1):49-62

Biochemia Medica 2012;22(1):49-62

Inflammation Affects HemostasisPlatelet acting as proinflammatory cell

Platelet acting as proinflammatory cell

Hematology 2011; 2011:51-61

Fibrina

neutrophil

TNFα

CD40LIL-1β; PAF-4

GF

Tf – FVIIa-FXa

monocyte

MHC; ROS

Activated platelet

Mac-1

(PARs)

TNFα; IL-β

IL-6;IL-8; MCP-1

Contribute of Coagulation in Inflammation

IL-1β

ICAM; VCAM

P-Selectin

PSGPL

PSGPL

ECsECs

IL-8; MCP-1

Monocytes

IL-6TNFα; IL-1β

Blood 1996;87:5051-5060Circ Res 2005;96:1217Critical Concepts 2007

adhesion

adhesion

ROSleukocytes

TNFα, IL-1β on monocytes

IL-8; MCP-1 on ECs PAR-1, 3, 4

PAR-2

Contribute of Coagulation in Inflammationand Vice Versa

ECs

+

Fibg/Fibrin activate leukocyte recruitment(TLR ) Thol like receptor ; and expression

PAR-2 establish cross talk between inflammation-coagulation

UTAustin | Portugal Workshop on Modeling and Simulation of Physiological Systems

December 6-8, 2012, Lisbon, Portugal

“ Coagulation and Inflammation

Physiological Process for Numerical Studies”

Instituto Superior Técnico

Thank you