FUNCTIONS OF THE COAGULATION SYSTEM ACTIONDESIRED RESULT Rapid formation of mechanically sound clot Stop bleeding quickly Prevent clot formation at non-injured sites Prevent thrombosis Gradual replacement of clot with viable tissue Wound healing

BLOOD COAGULATION Platelet plug Fibrin clot

PLATELETS

WHAT PLATELETS DO  Stick to damaged blood vessels requires von Willebrand factor  Spread out to cover damaged area  Activate and release contents partly blocked by aspirin  Aggregate  Cause blood vessel constriction  Cause retraction of clot to draw wound edges together

VWF IS A VERY LARGE PROTEIN ELECTRON MICROSCOPIC IMAGES OF SINGLE MOLECULES

VWF UNFOLDS UNDER SHEAR STRESS The faster the blood flow, the stickier it gets

WHAT PLATELETS DO (2)

PLATELET ADHESION TO AREA OF VESSEL INJURY

PLATELET SPREADING Patel et al, Blood 2003;101:929-36

PLATELET AGGREGATION

 Tissue damage exposes blood to tissue factor  Coagulation cascade: series of enzymatic reactions leading to thrombin formation takes place mainly on membrane surface, eg platelet membrane  Thrombin converts fibrinogen to fibrin  Fibrin polymerizes and becomes crosslinked FIBRIN CLOT FORMATION

Red blood cells trapped in a fibrin mesh

 Ubiquitous lipoprotein (part of cell membrane)  Initiates physiologic clotting process  Highest concentration in brain, mucous membranes, skin, and immediately outside blood vessels  Forms "hemostatic envelope"  Not normally found on endothelial cells lining blood vessels, or on circulating blood cells TISSUE FACTOR INITIATES FIBRIN CLOT FORMATION

TISSUE FACTOR: THE HEMOSTATIC ENVELOPE LARGE VESSEL SMALL VESSEL Am J Pathol 1989; 134:

 Fat-soluble vitamin present in many foods  Some made by bacteria in gut  Necessary for synthesis of several components of coagulation cascade  Deficiency may lead to low levels of clotting factors, causing a bleeding tendency  Warfarin (Coumadin™): a drug that interferes with vitamin K action used as an anticoagulant (prevent thrombosis) VITAMIN K IS NEEDED FOR PRODUCTION OF SEVERAL CLOTTING PROTEINS

Enzyme Proenzyme (prothrombin) Helper Phospholipid membrane Production of thrombin Vitamin K necessary to create these specialized binding regions

THROMBIN CONVERTS FIBRINOGEN TO FIBRIN Fibrinogen Fibrin Thrombin FIBRIN FORMS LARGE POLYMERS

Red blood cells trapped in a fibrin mesh

Platelet-fibrin clot Platelets Fibrin

 Degradation of fibrin clot by enzyme called plasmin  Necessary to remove clot so wound healing can proceed  Plasminogen activators from blood vessels and other cells convert plasminogen to plasmin to begin the process FIBRINOLYSIS

FIBRINOLYSIS Intact fibrin clotFibrin clot exposed to plasmin

 Antithrombin: inhibits thrombin and other enzymes  Protein C: degrades activated factors V and VIII  Protein S: cofactor for protein C  Deficiency of any of these proteins can increase risk of thrombosis REGULATION OF COAGULATION CONFINES CLOT TO INJURED AREA HELPS PREVENT THROMBOSIS

DISEASES OF PLATELETS  Thrombocytopenia = low platelet count (may cause bleeding) decreased production: bone marrow failure, leukemia increased consumption autoimmune (ITP) disseminated intravascular coagulation microangiopathy enlarged spleen - sequesters (soaks up) platelets from the bloodstream  Thrombocytosis = high platelet count myeloproliferative disorders (may cause thrombosis) inflammation, iron deficiency  Platelet dysfunction drugs (eg, aspirin)

BLEEDING TAKES LONGER TO STOP WHEN THE PLATELET COUNT IS LOW Prolonged bleeding when count < 100K Lower platelets Longer bleeding time

Mainly in children Often associated with viral infection 1.Antigen (virus?) sticks to platelet 2.Antibody in blood sticks to antigen on platelet surface 3.Macrophages (immune cells in spleen, elsewhere) consume antibody-coated platelets 4.Platelet number in blood drops 5.Platelet count usually returns to normal when infection resolves ACUTE IMMUNE THROMBOCYTOPENIC PURPURA (ITP)

Mainly in adults 1.Immune system makes antibody against molecule on platelet surface (auto-antibody) 2.Antibody sticks to platelet 3.Macrophages (immune cells in spleen, elsewhere) ingest antibody-coated platelets 4.Platelet number in blood drops 5.Often chronic, treated with immune suppression or splenectomy CHRONIC IMMUNE THROMBOCYTOPENIC PURPURA (ITP)

Childhood (acute) ITP Usually goes away when virus eliminated Adult (chronic) ITP Does not go away on its own; usually requires immune suppressive medication or splenectomy

PURPURA IN ITP

PETECHIAE IN ITP

INHERITED BLEEDING DISORDERS  Hemophilia: complete absence of factor VIII (hemophilia A) or factor IX (hemophilia B) sex-linked inheritance (99.99% of patients male) moderate or severe bleeding  von Willebrand disease: partial absence of von Willebrand factor dominant inheritance mild or moderate bleeding decreased production of single clotting factor

ACUTE COMPLICATIONS OF HEMOPHILIA Hematoma Hemarthrosis (joint bleeding)

LONG-TERM COMPLICATIONS OF HEMOPHILIA Joint destructionNerve damage

ACQUIRED BLEEDING DISORDERS partial absence of several clotting factors  Liver disease  Vitamin K deficiency  Disseminated Intravascular Coagulation & fibrinolysis (DIC)  Anticoagulant drugs: warfarin or heparin  Thrombolytic drugs (plasminogen activators)

 Newborn/premature infants  Poor intake  Defective absorption generalized malabsorption biliary disease  Diminished production by bacteria in gut (antibiotic treatment)  Vitamin K antagonists warfarin (Coumadin) certain antibiotics VITAMIN K DEFICIENCY

 Associated with many serious/lifethreatening diseases  Circulating blood exposed to excessive amount of tissue factor or other procoagulant  Breakdown of normal regulatory processes  Formation of circulating (soluble) fibrin  Consumption of clotting proteins and platelets  Accelerated fibrinolysis – clots break down too quickly  Bleeding and/or intravascular clotting in severe cases DISSEMINATED INTRAVASCULAR COAGULATION

DIC Soluble fibrin in the blood MONKEY (E. COLI INJECTION) HUMAN (ACUTE LEUKEMIA)

TISSUE INJURY IN DIC ASSOCIATED WITH SEPSIS NEJM 2001;344:1593

 Venous thrombosis Blockage of blood return and associated inflammation causes swelling, pain May become chronic If clot is dislodged from vein can travel to right ventricle and then lungs (pulmonary embolism)  Arterial thrombosis Clot prevents inflow of blood, causing ischemic tissue damage or death (infarction) Examples: myocardial infarction, stroke THROMBOSIS

DEEP VENOUS THROMBOSIS

PULMONARY EMBOLISM Arrow points to large clot in pulmonary artery Clot dissolved after administration of fibrinolytic drug

CAUSES OF THROMBOSIS  Abnormal or damaged blood vessels  Stasis of blood  Inherited lack of protein which regulates coagulation antithrombin, protein C, protein S  Resistance to effect of regulatory protein Factor V "Leiden" = mutation causing resistance to protein C; found in approx 5% of US population  Too many red cells or platelets (thick blood) polycythemia, thrombocythemia  Thrombosis most likely when several factors present at once