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

arteriole venule Vessels of Circulatory System

Blood Components

Rouleaux Pre Stasis Granular Blood Flow Cell free Plasma Rigid RBC Swelling of Endothelial Cell Obstruct 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-type sensors nerves fibres

Inflammatory Response to a Tissue Injury

Neutrophil and Endothelium in Inflammation TISSUE INJURED

Type I Activation of Endothelial Cell Nature Reviews Immunology 7, (October 2007) Stimulation- Rapid response independent of new genes expression Typically mediated by ligands P-Selectin PAF Resolves due receptor desensitization

Type II Activation of Endothelial Cell in Acute Inflammation Nature Reviews Immunology 7, (October 2007) More sustained inflammatory response Slow response dependent of new genes expression TNFα; IL-1 are derived from activated leukocytes Open gaps Leakage of fibrinogen Hard swelling Leukocytes recruitment more effective E –Selectin IL-8 VENULES (-) AP1 shut of E-Selectin >>VCAM1; ICAM-1 (+ by Cytokines) Mononuclear –cell rich infiltrates CAPILLARIES TNFα; IL-1. IFNγ EC death Favours thrombosis; apoptotic cells lose their anticoagulant sheding hepa ran sulphate ; exocytosis microparti cles Shuting off NOS3 and Trombomodulin by TNFα; TNFα; IL-1 induce Tf microparticles shed from cell surface Thrombus: fibrin +plateles wall of infe cted tissue limit spread of microbes Resolves by removal stimulus; by terminus NFk-β juxtacrine

Creates a provisional matrix to support leukocytes entry 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 Cascade Interwined Pathways Fibrin Plolymer FXIIIa colagen * TFPI

Endothelial Cell in Resting Non inflamed state Nature Reviews Immunology 2007; 7,

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

Fibrinolysis Coagulation

Recovery of Vessel Wall

Inflammation / Hemostasis Hemostatic Clot Can trap invading microbe;> vascular permeability Antimicrobial lysis Gram+ Bleeding Restore the Integrity of damaged tissues

Proinflammatory Cytokines TNFα, IL-1, IL-6 Inflammation Affects Hemostasis Brist J Haemat 2005; 131: Circulation 2004;109: J Leukoc Biol 2008; 83: 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 release PAI-1

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

Inflammation Affects Hemostasis Platelet acting as proinflammatory cell

Hematology 2011; 2011:51-61

Fibrina neutrophil TNFα CD40L IL-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 ECs IL-8; MCP-1

Monocytes IL-6 TNFα; IL-1β Blood 1996;87: Circ Res 2005;96:1217 Critical Concepts 2007 adhesion ROS leukocytes TNFα, IL-1β on monocytes IL-8; MCP-1 on ECs PAR-1, 3, 4 PAR-2 Contribute of Coagulation in Inflammation and 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