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Anticoagulation Theory
To Bleed or Not to Bleed
Coagulation Basics
• Ability of the body to control flow of blood
following vascular injury is needed for survival
• Hemostasis: process of blood clotting and
then the subsequent dissolution of the clot
following repair of injured tissue
Coagulation Basics
• Hemophilia: tendency to bleed
• Thrombophilia: tendency to clot
Hemostasis
• Maintains circulating blood in fluid state
• Disrupts blood flow due to vessel injury to
minimize anoxia and cellular death
• Facilitates maintenance of vascular integrity
following injury
Hemostasis
• Normally, there’s a balance between:
– Fibrin formation (thrombin mediated)
– Fibrin dissolution (plasmin mediated)
• Balance accomplished by interactions among:
– Blood vessels
– Platelets
– Coagulation proteins
– Fibrinolysis
Hemostasis
• Complex interaction of cellular components
and plasma proteins that once activated,
result in clot formation to plug the vessel
injury
• Has components necessary for limiting
excessive formation of clots and those
necessary for dissolving the clots over time
Hemostasis
• Balance between procoagulants and down
regulators
• Perturbation of this balance results in either
bleeding or pathologic clot formation
– You either don’t clot when you need to or clot
when you don’t need to
Hemostasis
Coagulation Fibrinolysis
Bleeding Thrombosis
Thrombosis Bleeding
Excessive Coagulation/Deficient Fibrinolysis
Coagulation
Fibrinolysis
Thrombosis
Thrombosis
Excessive Fibrinolysis/Deficient Coagulation
Coagulation
Fibrinolysis
Bleeding
Bleeding
Hemostatic Process: Five Steps
1. Vascular phase
2. Platelet phase
3. Coagulation phase
4. Clot retraction
5. Fibrinolysis
Primary Hemostasis
• Process of forming a platelet plug at the sit of
vessel injury
• Consists of vasoconstriction and platelet
adhesion
Vasoconstriction (Vascular phase)
• “Tightening” of blood vessels to divert blood
flow around the damaged vessel
• Enhances contact activation of platelets and
coagulation factors
Platelet Adhesion (Platelet phase)
• Platelets become activated and aggregate at
the site of injury, forming a temporary, loose,
platelet plug
Secondary Hemostasis
• To stabilize the initially loose platelet plug, a
sequence of enzymatic reactions is initiated
which culminates in fibrin strands forming at
the platelet plug
• Fibrin mesh (clot) is formed and entraps the
plug
Coagulation phase
• Fibrin-forming system
• Coagulation factors interact with each other
to form a fibrin clot
• Reinforces the platelet plug
Coagulation Factors
• Proteins normally present in the blood
• Most are produced by the liver
• Normally “turned off” (inactive)
• Designated by roman numerals
• Common names are significant of patients’
last names who were deficient with the factor
• “a” signals the factor in its “active” form
Coagulation Cascade
• Sequence of biochemical reactions that form
an insoluble gel (clot)
• Converts fibrinogen to fibrin
• Domino or waterfall effect
• Each factor is converted into its active form by
the preceding factor
ENDOTHELIALDAMAGE
Endothelium secretes VWF which makes platelets stick to the injured
vessel and cause platelet aggregation
Endothelium secretes Tissue Factors that
activate the Extrinsic system
EXTRINSIC SYSTEMINTRINSIC SYSTEM
Factor VII
XII CONTACT HMK
XIIa
KAL
XI XIa
IX IXa
ENDOTHELIUM
Ca++
Plasminogen
Plasmin
Stable Fibrin Clot Fibrin Degradation
Products
Fibrin
XIIIa
Thrombin
+ PF3 Factor VIIa
X Xa
V + Ca++ + PF3
Prothrombin
Fibrinogen
Factor XIIIActivated Protein C
Protein C
Protein S
Ca++
Tissue Factor
VIII
VIII
Antithrombin III
Extrinsic Pathway
• Activated when endothelial cells are injured and tissue
factor is released
• Activated Factor VII and tissue factor bind to form a
complex
– This complex, plus calcium, activates Factor X
Tissue Factor
VII VIIa
Ca+
X Xa
(Protrombin) II IIa (Thrombin)
Fibrinogen Fibrin
PF3 Ca++
Intrinsic Pathway
• Requires clotting factors
VIII-XII
• Initiation occurs when
factor XII is exposed to a
negatively charged
surface
– Termed the contact
phase
• Exposure of collagen to a
vessel surface is the
primary stimulus for the
contact phase
Prekalikrein Kalikrein
XII XIIa
XI XIa
IX IXa
X Xa
PF3 Ca++
Common Pathway
• Activated by either extrinsic or intrinsic pathway
• When Factor Xa binds to the platelet surface, a complex
is formed composed of platelet phospholipid, calcium
and Factor Va
– Complex converts prothrombin to thrombin which in turn
converts fibrinogen to fibrin
X Xa
(Prothrombin) Thrombin
Fibrinogen Fibrin
PF3
Ca++
Clot Generation
• Endothelial damage  vWF  platelets stick
to endothelium (adhesion)  exposure of
collagen fibrils  stimulates platelets to stick
together (aggregation)
• Activation of coagulation
– Tissue factor on the surface of monocytes and
endothelium activate various factors that lead to
the formation of thrombin
Clot Generation
• Thrombin changes properties of fibrinogen 
polymerization  fibrin  meshwork  clot
• Fibrinolysis: dissolution of the fibrin clot
– Initiation of clot lysis begins concurrently with the
activation of the clotting cascade
• Endothelium  plasminogen  plasmin 
degrades fibrin  FDP
Fibrinolysis
• Body’s way of keeping coagulation from becoming
excessive and occluding the blood vessels
• Function of plasmin that circulates as the inactive
proenzyme plasminogen
Fibrinogen
Soluble
Fibrin
Insoluble (stable)
Fibrin Clot
FDPs Plasminogen
Plasmin
Tissue
Plasminogen
Activator
D
Regulation
• Balance between coagulation and fibrinolytic
processes must be maintained
– Otherwise, excess clotting or fibrinolysis will occur
• Body has inhibitors to regulate the system
Antithrombin
 Protein C
 Protein S
 Plasmin Inhibitor
STOP
ENDOTHELIALDAMAGE
Endothelium secretes VWF which makes platelets stick to the injured
vessel and cause platelet aggregation
Endothelium secretes Tissue Factors that
activate the Extrinsic system
EXTRINSIC SYSTEMINTRINSIC SYSTEM
Factor VII
XII CONTACT HMK
XIIa
KAL
XI XIa
IX IXa
ENDOTHELIUM
Ca++
Plasminogen
Plasmin
Stable Fibrin Clot Fibrin Degradation
Products
Fibrin
XIIIa
Thrombin
+ PF3 Factor VIIa
X Xa
V + Ca++ + PF3
Prothrombin
Fibrinogen
Factor XIIIActivated Protein C
Protein C
Protein S
Ca++
Tissue Factor
VIII
VIII
Antithrombin III
Venous Thrombotic Event (VTE)
• Thrombophilia
– Hypercoagulable state due to inherited
(hereditary/genetic) defects or acquired defects in
one or several factors of the coagulation cascade
• Thrombophilia causes DVT (deep vein
thrombosis) or PE (pulmonary embolism)
Thrombotic Alert #1
• How many patients in the US are diagnosed
with deep vein thrombosis each year?
More than 500,000
Thrombotic Alert #2
• How many pulmonary embolisms are
diagnosed each year in the US?
More than 630,000
Thrombotic Alert #3
• How many deaths are attributed to PE each
year?
Approximately 200,000 deaths
Research Indicates…
• Approximately 100,000 of these deaths are
preventable
• Half of pulmonary emboli are not diagnosed
until…
AUTOPSY
COAGULATION DISORDERS
Hereditary/Genetic Irreversible
Factor I (Fibrinogen)
• Afibrinogenemia
– Total absence of measurable fibrinogen
– Rare congenital disorder
• Hypofibrinogenemia
– Below normal levels of fibrinogen
– Treated by cryoprecipitate or FFP
• Dysfibrinogenemia
– Altered structure of the fibrinogen molecule
– Usually asymptomatic but has been associated
with both bleeding and thrombotic events
Factor V (Proaccelerin)
Gene Defect
• Cofactor in coagulation cascade
• Deficiency causes bleeding but…
– Factor V mutation (Factor V Leiden) causes
thrombotic events due to impaired degradation of
Factor V resulting in continued thrombin
generation
• Most common cause of thrombophilia
Defects in Prothrombin Gene
• Second most common cause of thrombophilia
• Prothrombin does not break down
– Keeps on activating thrombin to convert
fibrinogen into a fibrin clot
Defects of Methyl Tetrahydrofolate
Reductase (MTHFR) Enzyme
• MTHFR breaks down homocysteine
• Deficiency of MTHFR increases homocysteine,
leading to thrombosis
• Acquired homocysteinemia is due to
deficiency of folate, vitamins B6 and B12
Less Common
• Antithrombin III deficiency
• Protein C deficiency
• Protein S deficiency
Factor VIII (Antihemophilic Factor)
• Composed of a coagulant portion and vWF
(vonWillebrand Factor)
• Acute phase reactant
– Increase in inflammation, stress, pregnancy and
infection which can lead to clot formation
• Defect or absence of coagulant portion causes
classic Hemophilia A
• Deficiency in vWF portion causes
vonWillebrand’s Disease
Acquired/Environmental Risk Factors
for VTE
• Extended bed rest
• Malignancy (cancer)
• Oral contraceptives
(estrogen)
• Hormonal replacement
therapy
• Pregnancy and recent
surgery
• Trauma
• Obesity/inactivity
• Antiphospholipid
antibodies (APA)
• Anticardiolipin
Antibodies (ACA)
• Lupus Anticoagulants
(LA)
• Inflammatory bowel
disease (IBD)
Most Commonly Requested
Coagulation Tests
• Prothrombin Time (PT)
• Activated Partial Thromboplastin Time
(aPTT/PTT)
• Fibrinogen Assay
• Factor Assays
• D-Dimer
• FDP
• Bleeding Time
Pathways/Tests
• PT monitors extrinsic pathway
– PT monitors coumadin therapy
• aPTT/PTT monitors intrinsic pathway
– aPTT/PTT monitors heparin therapy
• PT and aPTT/PTT both monitor the common
pathway

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Anticoagulation theory 2_students_

  • 2. Coagulation Basics • Ability of the body to control flow of blood following vascular injury is needed for survival • Hemostasis: process of blood clotting and then the subsequent dissolution of the clot following repair of injured tissue
  • 3. Coagulation Basics • Hemophilia: tendency to bleed • Thrombophilia: tendency to clot
  • 4. Hemostasis • Maintains circulating blood in fluid state • Disrupts blood flow due to vessel injury to minimize anoxia and cellular death • Facilitates maintenance of vascular integrity following injury
  • 5. Hemostasis • Normally, there’s a balance between: – Fibrin formation (thrombin mediated) – Fibrin dissolution (plasmin mediated) • Balance accomplished by interactions among: – Blood vessels – Platelets – Coagulation proteins – Fibrinolysis
  • 6. Hemostasis • Complex interaction of cellular components and plasma proteins that once activated, result in clot formation to plug the vessel injury • Has components necessary for limiting excessive formation of clots and those necessary for dissolving the clots over time
  • 7. Hemostasis • Balance between procoagulants and down regulators • Perturbation of this balance results in either bleeding or pathologic clot formation – You either don’t clot when you need to or clot when you don’t need to
  • 11. Hemostatic Process: Five Steps 1. Vascular phase 2. Platelet phase 3. Coagulation phase 4. Clot retraction 5. Fibrinolysis
  • 12. Primary Hemostasis • Process of forming a platelet plug at the sit of vessel injury • Consists of vasoconstriction and platelet adhesion
  • 13. Vasoconstriction (Vascular phase) • “Tightening” of blood vessels to divert blood flow around the damaged vessel • Enhances contact activation of platelets and coagulation factors
  • 14. Platelet Adhesion (Platelet phase) • Platelets become activated and aggregate at the site of injury, forming a temporary, loose, platelet plug
  • 15. Secondary Hemostasis • To stabilize the initially loose platelet plug, a sequence of enzymatic reactions is initiated which culminates in fibrin strands forming at the platelet plug • Fibrin mesh (clot) is formed and entraps the plug
  • 16. Coagulation phase • Fibrin-forming system • Coagulation factors interact with each other to form a fibrin clot • Reinforces the platelet plug
  • 17. Coagulation Factors • Proteins normally present in the blood • Most are produced by the liver • Normally “turned off” (inactive) • Designated by roman numerals • Common names are significant of patients’ last names who were deficient with the factor • “a” signals the factor in its “active” form
  • 18. Coagulation Cascade • Sequence of biochemical reactions that form an insoluble gel (clot) • Converts fibrinogen to fibrin • Domino or waterfall effect • Each factor is converted into its active form by the preceding factor
  • 19. ENDOTHELIALDAMAGE Endothelium secretes VWF which makes platelets stick to the injured vessel and cause platelet aggregation Endothelium secretes Tissue Factors that activate the Extrinsic system EXTRINSIC SYSTEMINTRINSIC SYSTEM Factor VII XII CONTACT HMK XIIa KAL XI XIa IX IXa ENDOTHELIUM Ca++ Plasminogen Plasmin Stable Fibrin Clot Fibrin Degradation Products Fibrin XIIIa Thrombin + PF3 Factor VIIa X Xa V + Ca++ + PF3 Prothrombin Fibrinogen Factor XIIIActivated Protein C Protein C Protein S Ca++ Tissue Factor VIII VIII Antithrombin III
  • 20. Extrinsic Pathway • Activated when endothelial cells are injured and tissue factor is released • Activated Factor VII and tissue factor bind to form a complex – This complex, plus calcium, activates Factor X Tissue Factor VII VIIa Ca+ X Xa (Protrombin) II IIa (Thrombin) Fibrinogen Fibrin PF3 Ca++
  • 21. Intrinsic Pathway • Requires clotting factors VIII-XII • Initiation occurs when factor XII is exposed to a negatively charged surface – Termed the contact phase • Exposure of collagen to a vessel surface is the primary stimulus for the contact phase Prekalikrein Kalikrein XII XIIa XI XIa IX IXa X Xa PF3 Ca++
  • 22. Common Pathway • Activated by either extrinsic or intrinsic pathway • When Factor Xa binds to the platelet surface, a complex is formed composed of platelet phospholipid, calcium and Factor Va – Complex converts prothrombin to thrombin which in turn converts fibrinogen to fibrin X Xa (Prothrombin) Thrombin Fibrinogen Fibrin PF3 Ca++
  • 23. Clot Generation • Endothelial damage  vWF  platelets stick to endothelium (adhesion)  exposure of collagen fibrils  stimulates platelets to stick together (aggregation) • Activation of coagulation – Tissue factor on the surface of monocytes and endothelium activate various factors that lead to the formation of thrombin
  • 24. Clot Generation • Thrombin changes properties of fibrinogen  polymerization  fibrin  meshwork  clot • Fibrinolysis: dissolution of the fibrin clot – Initiation of clot lysis begins concurrently with the activation of the clotting cascade • Endothelium  plasminogen  plasmin  degrades fibrin  FDP
  • 25. Fibrinolysis • Body’s way of keeping coagulation from becoming excessive and occluding the blood vessels • Function of plasmin that circulates as the inactive proenzyme plasminogen Fibrinogen Soluble Fibrin Insoluble (stable) Fibrin Clot FDPs Plasminogen Plasmin Tissue Plasminogen Activator D
  • 26. Regulation • Balance between coagulation and fibrinolytic processes must be maintained – Otherwise, excess clotting or fibrinolysis will occur • Body has inhibitors to regulate the system Antithrombin  Protein C  Protein S  Plasmin Inhibitor STOP
  • 27. ENDOTHELIALDAMAGE Endothelium secretes VWF which makes platelets stick to the injured vessel and cause platelet aggregation Endothelium secretes Tissue Factors that activate the Extrinsic system EXTRINSIC SYSTEMINTRINSIC SYSTEM Factor VII XII CONTACT HMK XIIa KAL XI XIa IX IXa ENDOTHELIUM Ca++ Plasminogen Plasmin Stable Fibrin Clot Fibrin Degradation Products Fibrin XIIIa Thrombin + PF3 Factor VIIa X Xa V + Ca++ + PF3 Prothrombin Fibrinogen Factor XIIIActivated Protein C Protein C Protein S Ca++ Tissue Factor VIII VIII Antithrombin III
  • 28. Venous Thrombotic Event (VTE) • Thrombophilia – Hypercoagulable state due to inherited (hereditary/genetic) defects or acquired defects in one or several factors of the coagulation cascade • Thrombophilia causes DVT (deep vein thrombosis) or PE (pulmonary embolism)
  • 29. Thrombotic Alert #1 • How many patients in the US are diagnosed with deep vein thrombosis each year? More than 500,000
  • 30. Thrombotic Alert #2 • How many pulmonary embolisms are diagnosed each year in the US? More than 630,000
  • 31. Thrombotic Alert #3 • How many deaths are attributed to PE each year? Approximately 200,000 deaths
  • 32. Research Indicates… • Approximately 100,000 of these deaths are preventable • Half of pulmonary emboli are not diagnosed until… AUTOPSY
  • 34. Hereditary/Genetic Irreversible Factor I (Fibrinogen) • Afibrinogenemia – Total absence of measurable fibrinogen – Rare congenital disorder • Hypofibrinogenemia – Below normal levels of fibrinogen – Treated by cryoprecipitate or FFP • Dysfibrinogenemia – Altered structure of the fibrinogen molecule – Usually asymptomatic but has been associated with both bleeding and thrombotic events
  • 35. Factor V (Proaccelerin) Gene Defect • Cofactor in coagulation cascade • Deficiency causes bleeding but… – Factor V mutation (Factor V Leiden) causes thrombotic events due to impaired degradation of Factor V resulting in continued thrombin generation • Most common cause of thrombophilia
  • 36. Defects in Prothrombin Gene • Second most common cause of thrombophilia • Prothrombin does not break down – Keeps on activating thrombin to convert fibrinogen into a fibrin clot
  • 37. Defects of Methyl Tetrahydrofolate Reductase (MTHFR) Enzyme • MTHFR breaks down homocysteine • Deficiency of MTHFR increases homocysteine, leading to thrombosis • Acquired homocysteinemia is due to deficiency of folate, vitamins B6 and B12
  • 38. Less Common • Antithrombin III deficiency • Protein C deficiency • Protein S deficiency
  • 39. Factor VIII (Antihemophilic Factor) • Composed of a coagulant portion and vWF (vonWillebrand Factor) • Acute phase reactant – Increase in inflammation, stress, pregnancy and infection which can lead to clot formation • Defect or absence of coagulant portion causes classic Hemophilia A • Deficiency in vWF portion causes vonWillebrand’s Disease
  • 40. Acquired/Environmental Risk Factors for VTE • Extended bed rest • Malignancy (cancer) • Oral contraceptives (estrogen) • Hormonal replacement therapy • Pregnancy and recent surgery • Trauma • Obesity/inactivity • Antiphospholipid antibodies (APA) • Anticardiolipin Antibodies (ACA) • Lupus Anticoagulants (LA) • Inflammatory bowel disease (IBD)
  • 41. Most Commonly Requested Coagulation Tests • Prothrombin Time (PT) • Activated Partial Thromboplastin Time (aPTT/PTT) • Fibrinogen Assay • Factor Assays • D-Dimer • FDP • Bleeding Time
  • 42. Pathways/Tests • PT monitors extrinsic pathway – PT monitors coumadin therapy • aPTT/PTT monitors intrinsic pathway – aPTT/PTT monitors heparin therapy • PT and aPTT/PTT both monitor the common pathway