FUNCTIONS 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 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
FIBRIN CLOT FORMATION
 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
Red blood cells trapped in a fibrin mesh
TISSUE FACTOR INITIATES FIBRIN
CLOT FORMATION
 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:
THE HEMOSTATIC ENVELOPE
Am J Pathol 1989; 134:1087-97
LARGE VESSEL
SMALL
VESSEL
VITAMIN K IS NEEDED FOR PRODUCTION
OF SEVERAL CLOTTING PROTEINS
 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)
Production of thrombin
Proenzyme (prothrombin)
Enzyme
Helper
Phospholipid membrane
Vitamin K necessary to create these specialized binding regions
THROMBIN CONVERTS FIBRINOGEN TO FIBRIN
Fibrinogen
Thrombin
Fibrin
FIBRIN FORMS LARGE POLYMERS
Red blood cells trapped in a fibrin mesh
Platelet-fibrin clot
Platelets
Fibrin
FIBRINOLYSIS
 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
Intact fibrin clot
Fibrin clot exposed to plasmin
REGULATION OF COAGULATION
CONFINES CLOT TO INJURED AREA
HELPS PREVENT THROMBOSIS
 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
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
Lower
platelets
Prolonged bleeding
when count < 100K
Longer bleeding time
ACUTE IMMUNE THROMBOCYTOPENIC
PURPURA (ITP)
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
CHRONIC 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
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
decreased production of single clotting factor
 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
ACUTE COMPLICATIONS OF HEMOPHILIA
Hematoma
Hemarthrosis
(joint bleeding)
LONG-TERM COMPLICATIONS
OF HEMOPHILIA
Joint destruction
Nerve 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)
VITAMIN K DEFICIENCY
 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
DISSEMINATED INTRAVASCULAR
COAGULATION
 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
DIC
Soluble fibrin in the blood
MONKEY (E. COLI
INJECTION)
HUMAN (ACUTE
LEUKEMIA)
TISSUE INJURY IN DIC
ASSOCIATED WITH SEPSIS
NEJM
2001;344:1593
THROMBOSIS
 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
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