Lecture 9: Normal Hemostasis

At baseline, __ should occur.

hemostasis

What is hemostasis?

sequence of processes that maintain blood in a fluid, clot-free state in normal vessels with the ability to rapidly form a blood clot at site of vascular injury

At baseline, what 2 things should not happen?

1. thrombosis = formation of clot in an intact vessel

2. hemorrhage when there is an inability to form a blood clot at a site of injury

What helps to maintain hemostasis?

endothelial & smooth muscle cells

platelets

coagulation factors

The endothelium maintains __ and regulates the __. Thus, it maintains the balance between the __.

blood flow; blood coagulation system; anti- and prothrombotic events

How does the endothelium maintain balance between the anti- and prothrombotic events?

various surface molecules normally inhibit the activation of platelets and the coagulation cascade, but injury exposes molecules that promote activation of platelets and the coagulation cascade

In antithrombic properties of the endothelium, the endothelium serves as a __ between platelets and highly thrombogenic extracellular matrix. This is an example of an __ effect.

barrier; antiplatelet

In antithrombic properties of the endothelium, products of __ & __ hamper platelet adhesion and aggregation and are potent __.

PGI2 (prostacyclin); NO; vasodilators

In antithrombotic properties of the endothelium, __ is elaborated, which degrades __ and inhibits platelet __.

adenosine phosphatase; adenosine diphosphate (ADP); activation

What are the 3 antiplatelet effects of antithrombotic properties in the endothelium?

1. barrier between platelets and highly thrombogenic ECM

2. produces PGI2 & NO

3. elaborates adenosine phosphatase

In antithrombotic properties of the endothelium, factors on the epithelial surface, like __ (3) produce __ effects. These factors act __ to inhibit __.

1. heparin-like molecules (cofactor for antithrombin III inhibits factors II, IX, X, XI)

2. thrombomodulin (binds to thrombin to help it activate protein C and S)

3. tissue factor pathway inhibitor (TFPI) (inhibits factor VII)

anticoagulant; indirectly; coagulation

In antithrombotic properties of the endothelium, synthesis of __, which activates __ to break down __, is an example of a __ effect.

tissue-type plasminogen activation (tPA); plasminogen to plasmin; fibrin; fibrinolytic

In prothrombotic properties of the endothelium, production of __ is an example of a platelet activator.

von Willebrand factor (vWF)

__ are proteins expressed by cells to interact with platelet glycoprotein Ib (GPIb) to help anchor platelets to the site of injury.

von Willebrand factor (vWF)

In prothrombic properties of the endothelium, production of __, which activates coagulation and down regulates thrombomodulin, is an example of a __ activator.

tissue factor; coagulation factor

What do tissue factors activate/down regulate?

activates coagulation, down regulates thrombomodulin

In prothrombic properties of the endothelium, secretion of __ limit __ much more than it favors __. This is an example of __ effects.

plasminogen activator inhibitors (PAIs); fibrinolysis; thrombosis; antifibrinolytic

How do we stop bleeding or make a clot?

• stop bleeding: vasoconstriction to decrease blood flow

• make clot: primary or secondary hemostasis

What is primary hemostasis?

activation and aggregation of platelets —> platelet plug

What is secondary hemostasis?

activation of coagulation factors —> mature fibrin clot

In response to an injury site, reflex vasoconstriction is mediated by:

endothelin release

What are the steps in primary hemostasis?

1. platelet adhesion

2. shape change

3. granule release (ADP, TXA2): recruit more platelets

4. recruitment

5. aggregation = hemostatic plug

What are the steps in secondary hemostasis?

1. tissue factor

2. phospholipid complex expression (on platelets)

3. thrombin generation

4. fibrinpolymerization

What occurs in antithrombotic counterregulation?

expression of t-PA (—> fibrinolysis) and thrombomodulin (blocks coagulation cascade) will counter excess clotting

__ are anucleuated disc-shaped cell fragments released from the bone marrow by megakaryocytes.

platelets

__ are a critical component of hemostasis and clot formation.

platelets

Platelets accumulate at the site of endothelial injury by: (3)

• adhering

• activating

• aggregating

Platelets interact with endothelial cells to: (2)

1. facilitate clot formation

2. prevent clot formation

Platelets adhere to __ within the ECM via interactions with: (2)

exposed collagen; vWF & platelet surface receptors (glycoproteins)

Platelets can undergo __ shape change.

irreversible

Platelets activate by secretion of their __

granules

• alpha granules: fibrinogen, factors V and VIII, platelet factor 4

• gamma granules: ADP, Ca2+, serotonin, epinephrine

Platelets synthesize __ when they are activated.

thromboxane A2 (TXA2)

Platelets aggregate to transform __ into __

temporary hemostatic plug —> more definitive thrombus

__ and __ are stimulators of platelet aggregation.

ADP; TXA2 (stimulate formation of primary hemostatic plug)

__ induces conformational change of GPIIb-IIIa receptors, allowing for binding of __, which connects multiple platelets together to form __.

ADP; fibrinogen; larger aggregates

Primary hemostatic plugs are converted into a larger definitive secondary plug via: (3)

• ADP

• TXA2

• thrombin

__ deposition stabilizes and anchors aggregated platelets

fibrin

Activation of platelets results in: (2)

secretion of granules (ADP) and synthesis of TXA2

Platelets have surface expression of __.

phospholipid complexes

• facilitates platelet aggregation and thrombus formation

Injured or activated endothelial cells expose __, which triggers the extrinsic coagulation cascade.

tissue factor

What does this image show?

activated platelets aggregating

What does this image show?

activated platelets aggregating

__ are a series of enzymatic conversions from inactive proenzymes into their active state. Each reaction results from the formation of enzyme-proenzyme-cofactor complex assembled at the __ complex held together by Ca2+.

coagulation factors; phospholipid

Coagulation factors’ prothrombotic goal is to:

activate thrombin and form fibrin to be cross linked

What are the 2 coagulation cascade pathways in the laboratory? How are they measured?

1. intrinsic pathway- measured by aPTT

2. extrinsic pathway- measured by PT/INR

The two coagulation cascade pathways converge on a common pathway because they both activate __. Thus, cascade can be separated into __ (3) pathways.

factor X; intrinsic, extrinsic, common

Most factors are made in the __. The exceptions are factors __ & __.

liver; VIII (made by endothelial cells); IV (Ca2+)

Factors __ (4) are also vitamin K dependent.

II, VII, IX, X

In fibrinolysis, __ activates plasminogen to plasmin.

tissue plasminogen activator (tPA)

__ cleaves fibrinogen and fibrin into fibrinogen/fibrin degradation products (FDPs). This removes the __ that is no longer necessary when the endothelial damage is fully __ by new endothelial cells restoring the integrity of the blood vessel.

plasmin; mature clot; repaired

Things that help you form a clot or prevents a clot from breaking down are: (5)

• coagulation factors

• platelets

• vWF

• PF4

• plasminogen activator inhibitor

Things that prevent you from forming or helps break down clots are:

• AT-III (antithrombin III)

• thrombomodulin

• protein C/S

• tPA

• plasmin

What are basic lab tests to screen for coagulopathy? (5)

• complete blood count (CBC)

• activated partial thromboplastin time (aPTT)

• prothrombin time (PT/INR)

• vWF antigen/activity

• platelet aggregometry testing

Describe the coagulation cascade.

sequence of proenzymes converted to activated enzymes —> formation of thrombin —> converts fibrinogen to fibrin

• activation of factors require calcium and phospholipid membranes

Natural anticoagulants include: (4)

• antithrombin III

• proteins S and C

• thrombomodulin

• tissue factor pathway inhibitor

What does the fibrinolytic cascade involve?

tPA —> converts plasminogen to plasmin —> breaks down fibrin to fibrin split products

__ occurs when there is an imbalance of prothrombotic vs antithrombotic mechanisms.

coagulopathy

Coagulopathy may be due to a __ or __ defect.

quantitative; qualitative

In coagulopathy, taking a good __ is paramount.

clinical history