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Vascular > Clotting, platelet activation and their measurement > Flashcards

Clotting, platelet activation and their measurement Flashcards

1
Q

Describe process of platelet aggregation (part 1)

A

Damage to blood vessel –> Exposure of platelets to collagen and vWF in extracellular matrix and (later) exposure to thrombin –> Platelets adhere
and activate –> Release of mediators –> Vasoconstriction + aggregation of platelets –> Formation of soft platelet plug

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2
Q

Describe process of platelet aggregation (part 2)

A

Platelets adhere to sub endo collagen exposed after vessel damage
GP1b binds to VWF expressed on damaged endo cells
GPVI + A2b1 bind to collagen
Platelets adhere to collagen + activation to release mediators: thrombin, ADP, TXA2 –> vasoconstriction of vessels
Thrombin + ADP –> further platelet activation
ADP induces expression of GPIIa/IIIa which is expressed on platelets + causes cross-linking between platelets of a fibrinogen bridge –> irrev platetet agg –> stops blood loss

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3
Q

What do anti-platelet drugs do?

A

limit growth of, or decrease risk of, arterial thrombosis

act by inhibiting platelet aggregation

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4
Q

List 3 anti-platelet drugs

A

Aspirin - inhib cyclooxygenase which need for thromboxane prod
P2Y12 antagonists – stop platelet prod by ADP
GPIIb-IIIa (aIIbb3) antagonists (GPIs)

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5
Q

What is the initiation process of the clotting pathway?

A

activated by Tissue Factor (TF)

takes place on TF-expressing cells in tissues after blood, with its clotting factors, leaks out of the blood vessel

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6
Q

What is the amplification process of the clotting pathway?

A

initiated by thrombin
involves activation of many factors, including FV, FVIII, FIX, FX
takes place on activated platelets

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7
Q

Briefly describe the clotting pathway

A

TF + FVII –> FVIIa:TF –> FX –> FXa:FVa –> FII (prothrombin) –> FIIa (thrombin)
Thrombin –> fibrinogen –> fibrin which activates platelets to form a fibrin clot

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8
Q

What causes TF release?

A

Damage to blood vessels causes TF exposure of endo behind it
TF expressed on cells not normally exposed to blood e.g. fibroblasts + monocytes outside vessels

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9
Q

Describe the process of initiation (detailed)

A

TF + VII form complex which activates VII –> VIIa
X activated by TF:VIIa in presence of Ca + PLD –> Xa
Xa forms complex with Va which causes thrombin to be prod from pro-thrombin

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10
Q

Describe the process of amplification (detailed)

A

Thrombin prod can be amplified on platelet surface à activates platelets
Release of V from platelet a-granules to prod Va expressed on platelet surface
Thrombin cleaves VIII –> Vwf which prod exposed VIIIa on platelet surface

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11
Q

Describe the process of propagation (detailed)

A

IX in plasma can be converted to IX by XI

IX activated tenase (VIIIa:IXa) which convertes X à Xa which binds to V to drive IIa (thrombin) prod

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12
Q

How does heparin act on the clotting cascade?

A

activates antithrombin which inhib IX + X.

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13
Q

What’s the diff between UFH + LMWH?

A

Unfractionated (UF) heparin variable in effect (diff saccharide lengths); low molecular weight heparins (LMWH) more predictable, more effective on FXa than on thrombin
Fondaparinux is a synthetic polysaccharide that acts like LMWH – smaller chain tf easier to monitor in blood

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14
Q

How does warfarin act on the clotting cascade?

A

inhibits vitamin K reductase in liver, required for g-carboxylation of factor II (prothrombin), VII, IX & X – tf takes long time to have an effect

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15
Q

List the direct inhibitors

A

Direct thrombin inhibitors e.g. Dabigatran, Bivalirudin

Direct FXa inhibitors E.g. Rivaroxaban

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16
Q

Describe fibrin deposition

A

fibrinogen binds to GPIIb/IIIa receptors
Fibrinogen –> fibrin by thrombin which binds to fibrin
Fibrin polymerises to form stable fibrin clot
Thromcin activates XIIIa which causes crosslinking of fibrin polymers

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17
Q

What do fibrinolytics do?

A

Activate plasminogen
Used to remove (Lyse) arterial thrombi
AMI: upto 12hrs
Stroke: upto 3hrs

18
Q

What is the risk of fibrinolytics + antidote?

A

High risk of haemorrhage
I.V. Infusion
Antidote: Severe haemorrhage treated with transexamic acid (inhibits activation of plasminogen)

19
Q

Give 2 examples of fibrinolytics

A

Streptokinase
Non-enzyme protein from streptococci
Binds and activates plasminogen → plasmin
Allergenic
Alteplase (r-tPA)
Non-allergenic
Clot selective? (only activates plasminogen bound to fibrin in thrombus)

20
Q

What do screening tests for haemostasis involve?

A

Patient history
Vital: ultimately guide the extent of the laboratory evaluation
Determine how complications can be managed.
Primary haemostasis
Coagulation tests
Blood disorders
Thrombosis
Manage anti-coagulant and anti-platelet therapy

21
Q

How do you take a bleeding history (who)?

A

Who:
Who is the patient, sex, age, race and family history?
Abnormal bleeding in both parents, maternal grandparents, aunts, uncles,
and siblings as well as any history of consanguineous marriage (or among relatives)

22
Q

How do you take a bleeding history (when)?

A

When:
History of blood transfusion or other blood components
Review of PMHx and PSHx history.
Information on all operations including tooth extractions are to be listed together with any abnormal bleeding during or after surgery or poor wound healing.
Drug history: wide variety of drugs affect haemostasis.
Childhood history of epistaxis, umbilical stump bleeding, bleeding after circumcision, the answers to any of which would suggest inherited bleeding disorders.

23
Q

How do you take a bleeding history (where)?

A

sites of bleeding, skin, muscle etc.
Skin (cutaneous) and mucous membranes i.e. petechiae, purpura, bruises, epistaxis, gingival bleeding, menorrhagia and/or hematuria which would suggest a platelet and/or vascular abnormality.
Bleeding into deep tissue, joints and muscles suggest a coagulation factor defect.

24
Q

How do you take a bleeding history (what)?

A

description of the type of bleeding.
Is bleeding spontaneous or follows trauma?
A history of easy bruising or bleeding excessively after injury suggests an inherited bleeding problem.
Information on the duration must also be sought. This would indicate whether symptoms have been lifelong (since childhood) or of recent onset.

25
Q

What are the benefits of a bleeding history?

A

1) the bleeding is the result of a local anatomic defect or part of a systemic defect in haemostasis
(2) the bleeding is due to a vascular defect, platelet abnormality or coagulation disorder
or (3) the haemostatic defect is inherited or acquired

26
Q

What is the bleeding assessment tool?

A

Developed quantitative questionnaires to record bleeding symptoms and stratify bleeding manifestation/ risk
Self reporting requires clinical judgement, as frequency of haemorrhagic symptoms
can be high
Severity trumps frequency

27
Q

List 4 Tests of Primary Haemostasis

A 
Bleeding time: Assessment of platelet count and function. 2-8 minutes considered normal
Platelet function: 
PFA-100, Platelet aggregometer
Platelet count: 
150,00-400,000 cells/uL normal.
<100,000 cells/uL: thrombocytopaena
Blood smear: 
Quantitative and morphological 
abnormalities of platelets
28
Q

Why is testing clotting important?

A

Required to establish bleeding disorders, and PD of anticoagulant drugs

29
Q

What is prothrombin time?

A

measures the integrity of the extrinsic system as well as factors common to both systems

30
Q

What is Partial Thromboplastin Time(PTT)?

A

measures the integrity of the intrinsic system and the common components.

31
Q

What is Thrombin Time(TT)?

A

measures the time it takes for a clot to form in anticoagulated blood plasma, after an excess of thrombin is added

32
Q

What are D-dimers?

A

fibrin degradation products. Measured

In patients to test suspected thrombotic disorders

33
Q

What is International Normalised Ratio(INR)?

A

International Normalised Ratio(INR), used to normalise PT, since this will be affected by manufacturer’s TF

34
Q

Describe the PT test

A 
Source of TF (e.g. thromboplastin) 
added to patient’s plasma
37°C for one to two minutes 	
Calcium Chloride added to counteract 
sodium citrate (start of timing)
35
Q

What does the PT test do?

A 
Evaluates the extrinsic pathway
Specifically the presence of FVII, V, X, prothrombin, and fibrinogen
A PT of 11-15 seconds is normal 
A prolonged PT indicates deficiency in 
these factors
	Vitamin K deficiency?
	Test Warfarin PD?	
       	FX inhibitors (anti-FX assay 
	more specific)
36
Q

How is INR used in the PT test?

A

INR: required to normalise due to operational differences.
INR = (PT test/PT normal) ISI
0.8-1.2: normal
2-3: Desired target for warfarin, up to 3.5 if more intense strategy required.

37
Q

Describe the aPTT test

A

Calcium and activating substances are added to de-calcified plasma:
Kaolin: activates contact dependent FXII
Cephalin: mimics platelet phospholipids.

38
Q

What does the aPPT test do?

A

Evaluates the intrinsic pathway
Specifically the integrity of FXII, XI, VIII,
IX, and final common clotting pathway
A aPPT by 35 seconds is normal
A prolonged aPPT indicates:
Test Heparin PD?
(Heparin activates anti-thrombin III)
Liver disease?
If increased in a person with a bleeding
disorder, further investigation to
use assays for specific coagulation factors

39
Q

Describe the TT test

A

Bovine thrombinadded to plasma.
Clot formation is detected optically or mechanically.
The thrombin time compares the rate of clot formation to that of a sample of normal pooled plasma.

40
Q

What does the TT test do?

A 
A measure of the fibrin  pathway
A TT of 12-14 seconds is normal 
Batrotoxin instead of thrombin not 
affected by heparin
A prolonged TT indicates:
	Fibrinogen deficiency? 
	(quantitative measurement)
	Fibrinogen dysfunction?
	(qualitative measurement)
	Heparin PD
	Direct Thrombin inhibitor PD
41
Q

How are D-Dimers used?

A

D-Dimer concentration determined via specific bioassay.
Used to detect suspected thrombotic disorders.
Main use is to exclude thromboembolic disease.
Used in diagnosis of disseminated intravascular coagulation.

Vascular (2 decks)

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