coagulation pathophysiology - dr austin

what is the purpose of hemostasis?

-keep blood fluid and clot-free in healthy vessels

-form a plug in injured vessels to heal and prevent blood loss

what is thrombosis?

inappropriate activation of hemostatic processes

what is thrombus?

solid mass of blood components that forms locally and blocks blood flow

-stays in place

what is embolus?

substance that travels through blood and causes blockage away from site of origin

-when thrombus detaches

what is a thromboembolus?

thrombus breaks free

-most common

what is an arterial thrombosis?

-small to medium vessels

-damaged vessels

-produce platelet-rich clot

what is a venous thrombosis?

-veins and venuoles

-associated with reduced blood flow (hemostasis)

-associated with inappropriate activation of coagulation cascade

-produce fibrin-rich clot

what are considered white clots?

arterial clots

what are arterial clots (contain, cause, treatment)?

-contain many platelets

-caused by atherosclerosis

-treated with antiplatelets

what are considered red clots?

venous clots

what are venous clots (contain, cause, treatment)?

-large size

-mostly fibrin and RBC components

-blood stasis and/or medications

-treated with anticoagulants

what are arterial clots treated with?

antiplatelets

what are venous clots treated with?

anticoagulants

what kind of clot are oral contraceptives associated with?

venous clots

what do antiplatelets prevent?

occurrence or growth of clot

what do anticoagulants prevent?

occurrence or growth of clot

what do thrombolytics do?

bust an existing clot

list the thromboembolic conditions

-DVT

-PE

-stroke

-MI

-disseminated intravascular coagulation

list the bleeding conditions

-vitamin K deficiency

-thrombocytopenia

-stroke

-impaired liver function

-hemophilias

what thromboembolic conditions are associated with venous clots?

-DVT

-PE

what thromboembolic conditions are associated with arterial clots?

-stroke

-MI

list the three predisposing factors of Virchow's Triad

-endothelial injury

-stasis

-hypercoaguable state

what are the three factors of thrombosis called?

Virchow's Triad

what type of thrombosis is endothelial injury usually associated with?

arterial

what type of thrombosis is stasis usually associated with?

venous

what type of thrombosis is hypercoaguable state associated with?

-arterial

-venous

which part of Virchow's triad is inadequate disease management (HTN, HLD, DM) associated with?

endothelial injury

which part of Virchow's triad is afib or atherosclerotic plaques associated with?

stasis

what does stasis do?

-increases endothelial cell activation and platelet proximity

-activated coagulation factors "overstay" their welcome

which part of Virchow's triad may be genetic or acquired?

hypercoaguable state

what are common causes of a hypercoaguable state?

-malignancy

-oral contraceptives

-HIT

what is the sequence of events of coagulation?

-vasoconstriction

-primary hemostasis

-secondary hemostasis (coagulation cascade)

-resolution

which part of coagulation is a reflex mechanism?

vasoconstriction

what does vasoconstriction respond to?

secreted vasoconstrictors (released by damaged cells and platelets)

list the vasoconstrictors

-epinephrine

-serotonin

-endothelin

-thromboxane A2

what rate does vasoconstriction occur?

-immediately

-transient (not permanent)

what is primary hemostasis?

platelets activate and adhere to subendothelial matrix

what is secondary hemostasis?

activation of coagulation cascade leads to formation of fibrin matrix

-recruitment of more platelets

what is resolution?

formation of stable plug

-activation of antithrombotic mechanisms to restrict plug to site of injury

what are the three steps of primary hemostasis?

-adhesion

-granule release and activation

-aggregation

how does platelet adhesion occur?

-damage or injury to vascular endothelium

-subendothelial collagen exposed to blood

-exposed collagen binds VWF and platelets

-binding interactions with glycoproteins

how does granule release and activation occur?

-adhering platelets change shape

-secrete alpha and dense storage granules (ADP)

-phospholipase activation

-increased synthesis and release of TxA2

-ADP AND TxA2 activate platelets

-activation of IP3-DAG pathways

-GPIIb-IIIa converted from resting to activated state (minions--> purple minions)

how does platelet aggregation occur?

-activated GPIIb-IIIa binds to fibrinogen with high affinity

-fibrinogen binds on both sides, cross-links platelets to form a mesh, becomes primary hemostatic plug

what is the purpose of secondary hemostasis?

form a stable fibrin clot at the site of injury

what are the pathways in secondary hemostasis?

-intrinsic

-extrinsic

-merge into common pathway

when does the coagulation cascade occur?

secondary hemostasis

do the two pathways of secondary hemostasis occur at the same time as eachother?

yes

same time as primary hemostasis too

what are activated in the coagulation cascade?

inactive proenzymes

once activated, what do inactive proenzymes serve as?

-cofactors

-enzymes for subsequent reactions

how do you recognize the active form of proenzymes?

a

where are proenzymes synthesized?

liver

where do the reactions that activate proenzymes occur?

phospholipid protein-protein complexes

what is required for proenzymes to be activated?

-phosphatidylserine

-Ca2+

what part of coagulation has amplification and positive feedback?

coagulation cascade (secondary hemostasis)

explain the extrinsic pathway

-initiating factor (TF) is outside of

-tissue factor (TF) is on exposed, damaged endothelium

what is the primary pathway for in vivo coagulation?

extrinsic

what initiates the extrinsic pathway?

TF-calcium complex

what coagulation pathway also plays a role in platelet activation?

extrinsic

explain the intrinsic pathway

factors are contained within blood

what is the primary pathway for in vitro coagulation?

intrinsic

what are the three key functions of thrombin?

-induction of platelet recruitment/activation

-conversion of soluble fibrinogen to insoluble fibrin

-activation of proenzymes --> amplification of coagulation cascade

what drives positive feedback?

thrombin

when does fibrin polymerization occur?

loss of solubility

what is the end result of coagulation?

erythrocytes trapped in fibrin mesh

what is fibrinolysis?

dissolution of clot begins shortly after it is formed

what is plasminogen converted to plasmin by?

tissue-type and urokinase-type plasminogen activators

are the plasminogen activators stable?

no

rapidly inactivated

what does plasmin digest?

-fibrin

-fibrinogen

-factor V

-factor VIII

-prothrombin

-factor XII

what characteristic of plasmin limits its activity to the local clot?

rapidly inactivated

what are the limitations of clot formation?

-pro-coagulant factors are often membrane-bound

-anti-coagulant factors are soluble and secreted

-Five important substances (Antihrombin III, Proteins C and S, t-PA, PGI2, TF pathway inhibitor)

why do pro-coagulant factors limit clot formation?

-membrane-bound

-localized activity

what does antithrombin III do?

inactivates thrombin and other factors

what enhances antithrombin III activity?

heparin-like molecules

what are proteins C and S?

-vitamin K-dependent proteins

-inactivate factors Va and VIIIa

what are treatment strategies for clots?

-inhibit platelet activity

-dissolve clot (clot busters)

-anticoagulants

what treatment strategy prevent clots/enhance endogenous anticlotting system?

anticoagulants

what treatment strategy always has bleeding as an ADR?

anticoagulants