FUNCTIONS OF THE COAGULATION SYSTEM ACTIONDESIRED RESULT Rapid formation of mechanically sound clot Stop bleeding quickly Prevent clot formation at non-injured.

FUNCTIONS OF THE COAGULATION SYSTEMFUNCTIONS OF THE COAGULATION SYSTEM

ACTION DESIRED 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 COAGULATIONBLOOD COAGULATION

Platelet plug

Fibrin clot

PLATELETSPLATELETS

WHAT PLATELETS DOWHAT 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 PROTEINVWF IS A VERY LARGE PROTEINELECTRON MICROSCOPIC IMAGES OF SINGLE MOLECULESELECTRON MICROSCOPIC IMAGES OF SINGLE MOLECULES

VWF UNFOLDS UNDER SHEAR STRESSVWF UNFOLDS UNDER SHEAR STRESSThe faster the blood flow, the stickier it gets

WHAT PLATELETS DO (2)

PLATELET ADHESION TOPLATELET ADHESION TOAREA OF VESSEL AREA OF VESSEL INJURYINJURY

PLATELET PLATELET SPREADINGSPREADING

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

PLATELET AGGREGATIONPLATELET 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 FORMATIONFIBRIN 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 TISSUE FACTOR INITIATES FIBRIN CLOT FORMATIONCLOT FORMATION

TISSUE FACTOR:TISSUE FACTOR:THE HEMOSTATIC ENVELOPETHE HEMOSTATIC ENVELOPE

LARGE VESSEL SMALL VESSEL

Am J Pathol 1989; 134:1087-97

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 VITAMIN K IS NEEDED FOR PRODUCTION OF SEVERAL CLOTTING PROTEINSOF SEVERAL CLOTTING PROTEINS

Enzyme

Proenzyme (prothrombin)

Helper

Phospholipid membrane

Production of thrombinProduction of thrombin

Vitamin K necessary to create these specialized binding regions

THROMBIN CONVERTS FIBRINOGEN TO FIBRINTHROMBIN CONVERTS FIBRINOGEN TO FIBRIN

Fibrinogen

Fibrin

Thrombin

FIBRIN FORMS LARGE POLYMERSFIBRIN FORMS LARGE POLYMERS

Red blood cells trapped in a fibrin mesh

Platelet-fibrin clotPlatelet-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

FIBRINOLYSISFIBRINOLYSIS

FIBRINOLYSISFIBRINOLYSIS

Intact fibrin clot Fibrin 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 COAGULATIONREGULATION OF COAGULATIONCONFINES CLOT TO INJURED AREACONFINES CLOT TO INJURED AREA

HELPS PREVENT THROMBOSISHELPS PREVENT THROMBOSIS

DISEASES OF PLATELETSDISEASES 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 BLEEDING TAKES LONGER TO STOP WHEN THE PLATELET COUNT IS LOWWHEN THE PLATELET COUNT IS LOW

Prolonged bleedingwhen count < 100K

Lower platelets

Longer bleeding time

Mainly in childrenOften associated with viral infection1. Antigen (virus?) sticks to platelet2. Antibody in blood sticks to antigen on

platelet surface3. Macrophages (immune cells in spleen,

elsewhere) consume antibody-coated platelets

4. Platelet number in blood drops5. Platelet count usually returns to normal

when infection resolves

ACUTE IMMUNE THROMBOCYTOPENIC ACUTE IMMUNE THROMBOCYTOPENIC PURPURA (ITP)PURPURA (ITP)

Mainly in adults1. Immune system makes antibody against

molecule on platelet surface (auto-antibody)2. Antibody sticks to platelet3. Macrophages (immune cells in spleen,

elsewhere) ingest antibody-coated platelets4. Platelet number in blood drops5. Often chronic, treated with immune

suppression or splenectomy

CHRONIC IMMUNE THROMBOCYTOPENIC CHRONIC IMMUNE THROMBOCYTOPENIC PURPURA (ITP)PURPURA (ITP)

Childhood (acute) ITPUsually goes away when virus eliminated

Adult (chronic) ITPDoes not go away on its own; usually requires immune

suppressive medication or splenectomy

PURPURA IN ITPPURPURA IN ITP

PETECHIAE IN ITPPETECHIAE IN ITP

INHERITED BLEEDING DISORDERSINHERITED 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 HEMOPHILIAACUTE COMPLICATIONS OF HEMOPHILIA

Hematoma Hemarthrosis (joint bleeding)

LONG-TERM COMPLICATIONS OF HEMOPHILIA

Joint destruction Nerve damage

ACQUIRED BLEEDING DISORDERSACQUIRED BLEEDING DISORDERSpartial 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 DEFICIENCYVITAMIN 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 DISSEMINATED INTRAVASCULAR COAGULATIONCOAGULATION

DICDICSoluble fibrin in the bloodSoluble fibrin in the blood

MONKEY (E. COLI INJECTION)

HUMAN (ACUTE LEUKEMIA)

TISSUE INJURY IN DIC TISSUE INJURY IN DIC ASSOCIATED WITH SEPSISASSOCIATED 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

THROMBOSISTHROMBOSIS

DEEP VENOUS THROMBOSIS

PULMONARY EMBOLISM

Arrow points to large clot in pulmonary

artery

Clot dissolved after administration of fibrinolytic drug

CAUSES OF THROMBOSISCAUSES 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