FUNCTIONS OF THE COAGULATION SYSTEM ACTIONDESIRED RESULT Rapid formation of mechanically sound clot...
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Transcript of FUNCTIONS OF THE COAGULATION SYSTEM ACTIONDESIRED RESULT Rapid formation of mechanically sound clot...
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