Haemostasis Flashcards by Rakul Sri

what is the haemostatic response to endothelial injury [4]

vessel constriction
formation of unstable platelet plug
stabilisation of plug with fibrin
dissolution of clot and vessel repair

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what occurs with platelets in unstable plug formation?

adhesion and aggregation

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what is the function the endothelium?

Maintain barrier between blood and tissue factor.

- Synthesis of PGI2, thrombomodulin, vWF, plasminogen activators

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what is the platelet transformation process from stem cell to release from the bone marrow?

origin: bone marrow

haemopoietic stem cell precursors
myeloid stem cell
megakaryocytes precursor
undergoes nuclear replication without cytoplasmic division
matures and granulate
migrates to marrow sinusoids
megakaryocytes produce ~4000 platelets by fragmenting into circulation through the endothelial wall of the bone marrow

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what is the lifespan of a platelet?

~10 days

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how much platelets is stored/sequestered in the spleen?

1/3

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platelet features

what are the glycopeptides on the surface?

Dense granules
alpha-granules
thrombin receptors
surface glycoproteins: Glp1a, Glp1b, Glp2b/3a).

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what glycoprotein of a platelet does vWF bind to?

Glp1b

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what does Glp1a bind to?

collagen

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what needs to be released to cause enhanced aggregation?

what is the effect?

ADP (released from platelets granules) and thromboxane from other platelets

causes Glp2b/3a receptor expression on the platelets

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what do endothelial cells and platelets produce mainly

endothelial- PGI2 (prostacyclin)

platelets- TXA2

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what enzyme makes the final PGI2 product?

prostacyclin synthetase

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what enzymes makes the final TXA2 product?

thromboxane synthetase

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what effect that PGI2 have on platelets?

potent inhibitor of platelet function

remember prostacyclin is anti-thrombotic

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what are the effects of endoperoxides (PGG2 and PGH2) and thromboxanes on platelets?

potent inducer of aggregation

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what enzyme does aspirin affect in prostaglandin metabolism?

cyclo oxygenase (COX1)

[converts arachidonic acid to endoperoxides]

prevents TXA2 production so it can’t activate platelet aggregation

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examples of COX1 inhibitors

aspirin

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examples of ADP receptor antagonists

clopidogrel (P2Y12)

prasugrel

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example of Glp2b,3a antagonists

Abciximab
Tirofiban,
Eptifibatide

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drug classes used in antithrombotic therapy in the ARTERIAL system?

 COX-1 Inhibitors/antagonists
 ADP receptor antagonists
 GlpIIb/IIIa antagonists

i.e. antiplatelets

blood is too fast for coagulation due to stasis to happen

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examples of lab tests

platelet count (monitor thrombocytopenia)

bleeding time and platelet aggression

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what does ITP present with

Auto-immune Thrombocytopenia (ITP) presents with – purpura, multiple bruises, ecchymoses.

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example of when platelet count would be used in monitoring treatment?

In treatment of leukaemia’s, you can knock out platelets.

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what does bleeding time reveal?

check platelet-vessel-wall interactions, when the platelet count is normal, e.g. renal disease.

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what does platelet aggregation reveal?

measures functional defect of platelets, e.g. vWF disease, inherited defects.

what are the sites of clotting factor, fibrinolytic factor and inhibitor synthesis?

- liver (coag.proteins, antithrombin) - endothelial cells (VWF) - megakaryocytes (VWF, Factor V)

order of factors in intrinsic pathway until thrombin formation

12,11,9, 10

where does TF get involved?

in the extrinsic pathway with F7

what is tested for to show the intrinsic pathway

F12

what factors drive the positive feedback loop from the intrinsic pathway into the common pathway?

8a (for 9a) and 5a (for 10a) | phospholipids found on platelet surface membrane

what does F9a activate? | via which factor?

F10 via F8aPI

what does F10a activate? | via which factor?

F2 (prothrombin to thrombin) via F5aPI

what is the effect of thrombin apart from fibrin formation?

- drive more platelet activation - more expression of F8a and F5a PIs thrombin generation is accelerated by x10000 by F8a and F5a PI

which vitamin mediates the production of factor 2, 7, 9, 10? where is this done? what extra group do these factors have?

Vitamin K in the liver extra carboxyl group

what is the effect of the extra carboxyl group on the factors?

allow adherence to the platelet membranes phospholipids

what is the extra carboxyl unit on the factors?

gamma-carboxyglutamic acid

what enzyme does warfarin inhibit? what is the effect of this?

vitamin K epoxide reductase reduced secretion of clotting factors and their binding e.g. f10 interactions to membrane PL is reduced as they can't bind with Ca2+

what is the indication for warfarin?

long-term anticoagulation following venous thrombosis treatment of atrial fibrillation stroke prophylaxis DVT treatment

what is the effect of Heparin?

binds to antithrombin and speeds it up 3000x

what is the indication for heparin?

immediate/ acute anticoagulation in peripheral oedema and DVT MI unstable angina pulmonary embolism

what factors does antithrombin affect?

F11a, F10a, F9a, F2a(thrombin)

how does antithrombin have its anticoagulation effect

binds to factors irreversibly by altering their tertiary structure e.g. bind to active site [9a, 10a, 2a]

structure of heparin

negatively charged string-like structure

what are the forms of heparin that can be used? when are they used

1) low MW 2) high MW both can be used to inhibit F10a only high MW can be used to inhibit F2a (thrombin) as It anchors the antithrombin to it better

which lab test detects abnormality in the intrinsic (and common) pathways? how does it do this?

Activated Partial Thromboplastin Time (APTT) - initiates coag. via F12

what lab test detects abnormality in the extrinsic (and common) pathways? how does it do this?

Prothrombin Time (PT) - initiates coag. via TF

what lab test detects abnormality in fibrinogens conversion to fibrin?

Thrombin Clotting Time (TCT/TT) - add thrombin (activated thrombin facilitates the conversion)

what tests are used to detect bleeding disorders?

APTT | PT

what test is used to monitor heparin therapy in thrombosis?

APTT as intrinsic pathway needs to be monitored

what test is used to monitor warfarin therapy in thromboses?

PT as extrinsic pathway and common pathway need to be monitored

what is required for the production of plasmin from plasminogen?

Tissue Plasminogen Activator (TPA) and a fibrin clot without the clot, the plasminogen (zymogen) does not interact to create plasmin

what is the role of plasmin?

fibrin degradation (fibrinolysis) activated from plasminogen by tPA

what components of fibrinolysis are used therapeutically for thrombolysis in MI?

TPA (alteplase) | bacterial activator streptokinase

what factors are inhibited by antithrombin in the coag. inhibition mechanism?

F9a F10a F2a (thrombin)

what factors are inhibited by Protein S and C in the coag. inhibition mechanism?

F8a and F5a

how is protein S and C activated?

when thrombin binds to platelets to create thrombomodulin which then activates protein S and C

how does the prothrombin time change in haemophilia?

prolonged i.e. clotting time has increased

which factors does the anticoagulants warfarin inhibit the activation of?

2,7,9,10 all them key players

why is prothrombin time used to measure the effect of warfarin?

warfarin impacts factor 7 factor 7 is part of the extrinsic pathway involving tissue factor the tissue factor/extrinsic pathway is best measured using prothrombin time

how are the effects of heparin measured?

using activated partial thromboplastin time (APTT) - intrinsic pathway and common pathway measurement - heparin enhances the actions antithrombin (an enzyme inhibitor glycoprotein produced in the liver) - antithrombin can deactivate thrombin, f10 etc

what are 3 examples of antiplatelets?

1) aspirin--> COX-1 therefore TXA2 reduced 2) clopidogrel--> ADP receptor 3) tirofiban--> GlpIIb/IIIa inhibitor in acute management of MI nb warfarin and heparin are antiCOAGULANTS (efficacy in secondary haemostasis)

what is the role of TXA2?

expression of GlpIIb/IIIa released by platelet activation

what is the function of the haemostatic plug?

prevent blood loss from intact vessels arrest bleeding from injured vessels

what is the first response to injury?

vessel constriction temporarily restrict blood loss

what molecules activate platelets leading to formation of unstable plug?

ADP thrombin TXA2 (made from membrane phospholipids)

how is the unstable plug stabilised?

by coagulation (initiated by Tissue Factor) this produces the fibrin clot

what vessels disorders arise due to impaired interaction of platelets with the injured vessels?

- scurvy - senile purpura - allergic vasculitis (acquired) - haemorrhagic telangiectasia - Ehlers-Danlos syndrome (inherited).