Fibrinolysis and Anticoagulants

the visible result of the conversion of plasma fibrinogen into a stable fibrin clot

what is clotting?

• proteolysis

• polymerization

• stabilization

what are the phases in which fibrin formation occurs in?

a protease enzyme

what is thrombin?

• cleaves fibrinogen to fibrin

• results in a fibrin monomer

  • fibrinopeptide A and fibrinopeptide B

  • fibrin monomers polymerize end-to-end due to hydrogen bonding

  • fibrin monomers are linked covalently to factor Xllla into fibrin polymers

what is the action of thrombin?

a mesh network

what do fibrin polymers form?

fibrin solution is converted to a gel after 25% of fibrinogen is converted to fibrin

what forms fibrin polymers?

as a soluble molecule

how is fibrinogen present in the plasma?

peptide bonds within the polymerized fibrin network

what does Factor Xllla introduce?

the cross-linking of Factor Xllla

what makes the fibrin more elastic and less susceptible to lysis by fibrinolytic agents?

a loose covering over the injured area, reinforces the platelet plug, and closes off the wound

what does fibrin form?

it begins to retract and becomes smaller and more dense

what happens to the clot after a short period of time?

the action of platelets trapped along with erythrocytes and leukocytes in the clot

what is thought to cause the retraction process?

the platelets send out cytoplasmic processes that attach to the fibrin and pull the fibers closer together

what happens when the fibrin filaments gather around the aggregated platelets?

temporary structures that seal off a damaged area until healing can take place

what are fibrin clots?

the physiological process that removes insoluble fibrin deposits by enzymatic digestion of the stabilized fibrin polymers

what is fibrinolysis?

the clots themselves are dissolved by plasmin

what happens as healing occurs?

a proteolytic enzyme that dissolves the clot, allowing blood to flow again

what is plasmin?

liver

where is plasmin produced?

the clot so lysis reactions begins immediately

what is plasmin bound into?

by hydrolysis to produce progressively smaller fragments

how does plasmin digest fibrin and fibrinogen?

it is the result of the activity of a number of proteolytic enzymes (kinases)—referred to as plasminogen activators

how is plasminogen activated?

endogenous and exogenous

what are the 2 types of tissue activators?

within the body

where are endogenous activators produced?

• tissue-type plasminogen activator

• urokinase plasminogen activator

what are the 2 endogenous activators?

tissue-type plasminogen activator

what is the primary activator within the vascular system?

urinary epithelial cells, monocytes, and macrophages

what secretes the urokinase plasminogen activator?

substances outside the body

what produces exogenous activators?

• streptokinase

• APSAC

what are the two exogenous activators?

the initiation of the contact phase of coagulation, factor Xla, Xlla fragments, kallikrein, and high-molecular weight kininogen, interact to yield plasminogen-activating ability

how is plasminogen activated?

contact phase of coagulation with tPA

what converts plasminogen to plasma?

breaks fibrin(ogen) down into fibrin degradation products or fibrin split products that will be eliminated by the liver or RE system

what is the function of plasmin?

the coagulation cascade

what does plasmin stop?

inactivating factors V, VIII, and XIII

how does plasmin stop the coagulation cascade?

fibrin(ogen) split products (FSP)

what are FDPs also known as?

it is broken down into an X monomer

what happens to fibrinogen or fibrin first?

D and E that are generated from one molecule of fibrinogen

what are the final split products of FDPs?

hemostasis

what do X, Y, D, E fragments interfere with?

exert an anti-thrombin effect—interferes with fibrin monomer polymerization and platelet aggregation

how do X,Y, D, E fragments interfere with hemostasis?

produces FDPs and D-dimer

how does plasmin destroy fibrinogen/fibrin?

a degradation product specifically derived from cross-linked stabilized fibrin polymer

what is D-dimer?

the action of plasmin on fibrin/fibrinogen 

what does FSP/FDP measure?

the action of plasmin on cross-linked fibrin

what does D-dimer detect?

only after factor XIII has stabilized fibrin

when are D-Dimers present?

that activation of coagulation has taken place

what do D-Dimers confirm?

• plasminogen activator inhibitor

• alpha-2 antiplasmin

what are the 2 primary inhibitors that inhibit excess formation of plasmin?

• rare abnormal condition

• plasmin attacks fibrinogen when no clotting has occurred

• excess activators often due to tumor at production site

• impaired inhibitors

what characterizes primary fibrinolysis?

• normal reaction to clot

• may be due to abnormal excess of fibrinolysis called DIC

• something activates clotting besides a vessel tear

  • tissue thromboplastin is released or

  • contact activation of XII occurs

what characterizes secondary fibrinolysis?

• an inherited condition

• hypercoagulable blood that clots if body or vessels are stressed

  • oral contraceptives

  • pregnancy

  • surgery

what characterizes antithrombin III deficiency?

• thrombomodulin/thrombin complex activates protein C

  • inhibits the coagulation cascade by inhibiting factors Va and Vllla

• protein S enhances the reaction

• if either of these proteins are deficient, will get blood clots

  • clots occur when there is no movement for several hours

what characterizes protein C or S deficiency?

a mucopolysaccharide isolated from the lung

wha tis heparin?

binds to antithrombin III and inactivates factors II, IX, X, XI, XII to turn off coagulation

what is the function of heparin?

IV or IM

how can heparin be given?

the APTT

• 1.5-2 times normal or baseline

• monitoring is critical

  • too much is critical

how is heparin monitored?

no more than 7 days

how long can heparin be given?

after a clot occurs or to precent a future clot

when is coumadin or warfarin given?

impairs the synthesis of vitamin-K dependent factors

what is the function of coumadin/warfarin?

orally

how is coumadin/warfarin given?

Prothrombin time (PT)

how is coumadin/warfarin monitored?

irreversibly inhibits thromboxane A₂ by blocking cyclooxygenase in the platelet—platelet will no longer be capable of aggregating throughout it’s lifespan

what is the function of aspirin?

inhibits thromboxane but is reversible

what is the function of ibuprofen?

break up the existing clot as compared to preventing new ones

what is the function of thrombolytic drugs?

IV or injected directly into the clot or infarct

how can streptokinase/urokinase be given?

• streptokinase/urokinase

• tissue plasminogen activator

what are the two commonly prescribed thrombolytic drugs?

urokinase

what thrombolytic drug is better but more expensive?

only on clotted surface

what does tissue plasminogen activator work on?

recombinant DNA

what produces tissue plasminogen activator?

tissue plasminogen activator

what is preferred for most cardiovascular procedures?