Tissue Factor

Other names?

Where does it come from?

TF + what starts cascade

*Tissue Factor = Factor 3, thromboplastin

Exposed at site of injury, from endothelial cells

TF + Factor 7 initiate coagulation cascade → thrombin generation

Thrombin

&

Fibrin

&

Factor XIII

Cleaves fibrinogen into soluble fibrin,

Fibrin polyermization → more platelet recruitment and activation (secondary hemostatis)

Factor 13 cross links fibrin molecules

Endothelium Anti-platelet Effects

(released by endothelium)

Prostacyclin and nitric oxide impede platelet adhesion

Adenosine disphosphatase degrades ADP(therefore inhibiting aggregation)

Heparin-like molcules

&

Thrombomodulin

Heparin-like molecules bind and activate antithrombin III

Antithrombin  III inactivates thrombin, 9a, 10a

Thrombomodulin upon binding thrombin activates protein C

Protein C inactivates factors 5 and 8.

 (Protein S produced by endothelium is co-factor)

t-PA

&

Plasmin

&

α₂ plasmin inhibitor

t-PA(tissue plasmin activator) from endothelium

 t-PA is most active when bound to fibrin

Cleaves plasminogen → Plasmin

Plasmin cleaves fibrin to degrade thrombi & other coagulation factors

α₂ plasmin inhibitor prevents plasmin activity in areas away from damage

Platelets

α-Granules

Dense Granules

What triggers their release?

α-Granules

Fibrinogen, Fibronectin

Factors 5,13 PDGF, TGF-B

Dense granules

ADP, ATP

Ca++, Histamine, Serotonin, Epinephrine

Change shape and release granules upon binding c ollagen or vWF

Gp1B

&

Disease of Gp1B

Gp1B is a platelet glycoprotein.

vWF binds collagen and Gp1B(platelet adhesion)

Bernard-soulier syndrome is defect

 prolonged bleeding time & decreased platelets

GpIIb-IIa

What is it?

Disease from mutation?

GpIIb-IIa: platelet surface receptor

 binds fibrinogen(aggregation, links platelets)

Glanzmann thrombasthenia is defect

 Prolonged bleeding time

Platelet Aggregation

What compounds amplify it?

What Drug is used to stop it and how?

ADP, thromboxane A₂, and thrombin cause more aggregation of platelets.

ADP activates platelets → conformational change in GpIIb-IIa receptors

Allows GpIIb-IIa to bind fibrinogen

Clopidogrel(plavix) blocks ADP binding(stops fibrinogen cross linking)

PGI₂

vs

TxA₂

what are they released from?

what do they do?

Aspirins effect?

PGI₂(prostacyclin)

Vasodilator & inhibits platelet aggregation

From endothelial cells & Aspirin has little effect as endothelial cells can make new cyclooxygenase

TxA₂

Activates platelet aggregation & Vasoconstrictor

Aspirin blocks in synthesis in platelets

Vitamin K depedent Cofactors

Which factors?

What is Vitamin K required for?

What Drug blocks this reaction?

Factors 2(prothrombin),7, 9, 10, & protein C  are vitamin K dependent

Vitamin K is required for adding γ-carboxyl groups to glutamic acid residues on these factors. Allows binding of Ca++

Coumadin(warfarin) blocks this.

aPTT test
What pathway does it test?

Which therapy is it used to evaulate?

Evaulates 12,11, 9, 8, 10, 5, 2, 1

Intrinsic pathway Common pathway

Used for evaluating heparin therapy

(FYI, Blood sample taken, citrate added(sequesters Ca) which prevents clotting. Excess calcium added along with silica to start cascade)

PT test

What pathway does it test?

What therapy is monitered with it?

Factors 7, 10, V, II, and I(fibrinogen)

Extrinsic pathway. (tissue factor added to sample)

Evaulates coumadin therapy

TT test

What does it evaulate?

Evaulates fibrinogen.

Prolonged time with low or abnormal fibrinogen

can be used toe evaluate heparin therapy but PTT more common

Vit K defiency or Warfarin therapy

Effect on PT & PTT & platelets

Prolonged PT & PTT.

Platelets normal

Both pathways have vitamin K dependent factors(2,7,9,10)

DIC & Liver Failure

Effect on PT & PTT & platelets

Prolonged PT & PTT

Decreased Platelets

DIC results from consumption of clotting factors which leads to destruction of platelets

Liver produces clotting factors.

Hemophillia

Effect on PT & PTT & platelets

Prolonged PTT

Everything else normal

Muations in Instrinsic pathway

Hemophilia A = Factor 8 deficiency

Hemophilia B = Factor 9 deficiency

Fibrinogen Split Products(FSPs)

Which kind of FPS can be used for diagnosis?

What are they signs of?

D-dimers of FSPs are used in diagnosing

DIC

DVT(deep vein thrombosis)

Pulmonary Embolism