Anticoagulation theory 2_students_

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 componentsand 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

ENDOTHELIAL DAMAGEEndothelium 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 VIIXII CONTACT HMK

XIIaKAL

XI XIa

IX IXa

ENDOTHELIUM

Ca++

Plasminogen

Plasmin

Stable Fibrin Clot Fibrin Degradation Products

FibrinXIIIa

Thrombin

+ PF3 Factor VIIa

X Xa

V + Ca++ + PF3

Prothrombin

Fibrinogen

Factor XIIIActivated Protein C

Protein C

Protein S

Ca++Tissue Factor

VIIIVIII

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

PF3Ca++

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 fibrinogenpolymerization fibrinmeshwork clot

• Fibrinolysis: dissolution of the fibrin clot

– Initiation of clot lysis begins concurrently with the activation of the clotting cascade

• Endothelium plasminogen plasmindegrades 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

SolubleFibrin

Insoluble (stable)Fibrin Clot

FDPs Plasminogen

Plasmin

TissuePlasminogen

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

ENDOTHELIAL DAMAGEEndothelium 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 VIIXII CONTACT HMK

XIIaKAL

XI XIa

IX IXa

ENDOTHELIUM

Ca++

Plasminogen

Plasmin

Stable Fibrin Clot Fibrin Degradation Products

FibrinXIIIa

Thrombin

+ PF3 Factor VIIa

X Xa

V + Ca++ + PF3

Prothrombin

Fibrinogen

Factor XIIIActivated Protein C

Protein C

Protein S

Ca++Tissue Factor

VIIIVIII

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 IrreversibleFactor 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