Haemostasis (clotting) Flashcards
1
Q
What happens when blood moves along the vasculature (3)
A
- Blood flows along vasculature that is intact
- The vascular Endothelial Cell (vEC) mechanism prevails to inhibit platelet (plt) activation/adhesion
- The vascular Endothelial Cell (vEC) mechanism prevails to also inhibit blood factor activation, which therefore remains non-catalytic and soluble (sol’).
2
Q
What does injury do the the basement membrane (4)
A
- Injury makes the basement membrane extracellular matrix of connective tissue (collagen) available for platelet GlycoProtein Receptors to bind
- this activates platelets to flatten and recruit other platelets and to bind fibrinogen
- Smooth muscle cells spasm in response to platelet mediators
- this promotes stagnation/promote local clot formation over digestion/washing effects of flow.
3
Q
What happens with thromboembolic disease with age (2)
A
- Thromboembolic Disease (TED) increase with age
- is the major cause of death in developed countries
4
Q
What is thromboembolism (3)
A
- Too thick
- Clotting
- e.g. Ischaemic stroke
5
Q
What is INR (6)
A
- International Normalised Ration (of blood clotting time)
- Prothrombin (f II) clotting time of patient/normal time = INR
- High = thin blood (Haemmorage risk)
- Low = thick blood (Thromboembolism risk)
- An INR of 2 to 3.5 in patients prone to Thrombo-embolic disorder (TED) indicates need for anticoagulant therapy.
- Normal = 1
6
Q
How does prothrombin work (8)
A
- The liver produces many plasma proteins including the serine protease family of clotting factors.
- Several of these require vitamin K in order to be synthesised: II, VII, IX, X.
- Prothrombin is the inactive factor, fII.
- When activated as Thrombin, it determines the production of the fibrous clot (fibrin, fIa)
- The time taken for prothrombin to clot (PT) is a diagnostic Liver Function Test.
- However, need to test 24 hours after vitamin-K administration to rule out vitamin deficiency.
- Bleeding from the gut is a common cause of death in patients with hepatic failure.
- The vitK-dependent clotting factors from liver have been a therapeutic target of “blood thinner therapy” for years.
7
Q
What is the intrinsic activation enzymatic path underlying clot formation (5)
A
- Surface contact
- Factor XII, XI, IXa, VIII, X
- Factor Xa turning prothrombin into thrombin
- Fibrinogen
- Fibrin
8
Q
What is the extrinsic activation enzymatic path underlying clot formation (5)
A
- Vessel injury
- Factor VII
- Factor Xa turning prothrombin into thrombin
- Fibrinogen
- Fibrin
9
Q
What treatments are there for Haemorrhage (2)
A
- Vit K (phytomenadione)
- Factor IX (II, VII, X)
10
Q
What treatments are there for thromboembolism (3)
A
- Oral Anti Coagulant (Warfarin (S))
- Heparin (surgical prophylaxis)
- New / Direct / Non-vitKdept OAC
11
Q
What homeostatic mechanisms are there for the blood (3)
A
- Vascular (non-thrombogenic/Fibrinolytic (Thrombolytic))
- Platelet (Thrombogenic)
- Coagulation (Thrombogenic) “blood clotting factors“ incl PT (f II)
12
Q
What blood thinning drug interventions are there (3)
A
- Anti-coagulant(chronic avoidance of clots)
- Anti-platelet
- Fibrinolytic (Thrombolytic - acute lysis of clots)
13
Q
What blood-thickening drug interventions are there (3)
A
- Anti-fibrinolytic
- Vitamin K
- Factor VIII; Factor(s) IX (incl. II; VII; X)
14
Q
What are the haemostatic agents in blood plasma (3)
A
- Sera (IgG) used in passive immunisation
- Clotting factors (pro-haemostatic agent)
- Albumin proteins
15
Q
What are the haemostatic agents in blood cells/particles from cells (3)
A
- Erythrocytes
- Leukocytes
- Platelets (thrombocytes) (pro-haemostatic agent)
16
Q
What is the haemostatic agent in vascular cells
A
Endothelia (cells lining vessels) (anti-haemostatic agent)
17
Q
What is the other haemostatic agent (3)
A
- Smooth muscle cells around vessels
- Arteriole - surrounded by smooth muscle cells (SMC);
- Venule - Endothelial cells (EC) & few SMC
18
Q
What are the opposing haemostatic mechanisms (4)
A
- Vascular endothelial (inhibitor or “non-thrombogenic”) mechanisms
- Adaptive “value”: To limit the initiation of clot formation (response) to ‘appropriate’ stimuli and location - to prevent clot propagation beyond site of vascular injury.
- Vasoconstriction (permissive) – local response of smc to platelet thromboxane TxA2; stagnation of blood promotes clot formation.
- Non-thrombogenic (non-permissive of platelets/coagulation mechs). Endothelial cell linings of blood vessels resist thrombus formation
19
Q
How do repel platelets work (5)
A
- Release prostacyclin, PGI2;
- Maintain transmural –ve charge.
- Release tissue plasminogen activators, tPA–activate fibrinolysis(PTO)
- Activation of Protein C – degrades coagulation factors (slide 18).
- Produce heparin-like proteoglycans that inhibit coagulation.
20
Q
What is the fibrinolytic (“anti-clotting”) system in blood vessels (4)
A
- Endothelia normally release tissue Plasminogen Activators, tPA;
- tPA (“Alteplase”) converts inactive Plasminogen to active Plasmin.
- Plasmin is the fibrinolytic enzyme that digests clots.
- Plasmin digests both: Fibrinogen (f I, soluble precursor) and Fibrin (f Ia, fibrous clot) that was formed by the enzymatic action of Thrombin (activated “prothrombin” coagulation factor II, f IIa).
21
Q
ACTIVATORS (+) OF FIBRINOLYTIC SYSTEM (2)
A
- tPA (Urokinase, recombinant Alteplase)
- Streptokinase
22
Q
CLINICAL USES – acute remedy of thromboembolic disorder (5)
A
- Acute myocardial infarction
- Pulmonary embolism (PE)
- Deep vein Thrombosis (DVT)
- Acute arterial thromboembolism
- Thrombosed arteriovenous shunts
23
Q
INHIBITORS (-) OF FIBRINOLYTIC SYSTEM (5)
A
- US: Aminocaproic acid (Amicar) inhibits the conversion of plasminogen to plasmin, so inhibits plasmin-dep’t fibrinolysis.
- UK: Tranexamic acid; Desmopressin; Etamsylate; Aprotinin suspended
24
Q
CLINICAL USES – prevent bleeding (5)
A
- Transplant
- Prostectamy
- Dental extraction
- Haemophilia
- Menorrhagia (heavy periods)
25
How do platelets promote a cross-linked fibrous scaffold at sites of vessel injury (7)
1. bind exposed matrix
2. PGI2 (inhibits aggregation)
3. flatten & release ADP (P2YRs), TXA2, 5HT
4. Fibrinogen (f I)
5. ADP (P2YRs), TXA2, 5HT are attracted, stimulated to release & express GPIIb/IIIa receptors
6. amplified release, accumulation and cross-linking with blood clotting factor (f I) fibrinogen
7. platelet phospholipid (PL) surface (PF3) becomes a co-factor for clotting
26
How do antiplatelet drugs work (2)
1. “Antiplatelet” drugs decrease platelet aggregation
2. They may inhibit thrombus formation in the arterial circulation, where “anticoagulants” have little effect.
27
What are the clinical applications of low dose aspirin (3)
1. Given for secondary prevention of thrombotic cerebrovascular disease
2. ie. given after ischemic event; myocardial infarction; ischemic stroke (BUT NOT haemorrhagic stroke !).
3. Given following coronary bypass surgery.
28
What are the clinical applications of glycoprotein IIb/IIIa (Fibrinogen receptor) inhibitor (3)
1. Anciximab
2. monoclonal antibodies that block binding to fibrinogen
3. as an adjunct to heparin & aspirin for prevention of ischemic complications in coronary surgery.
29
What are the clinical applications of clopidogrel (P2Y-receptor antagonist of ADP) (3)
1. Anti-platelet
2. reduces risk of blood clot
3. may be given together with aspirin.
30
How are clotting factors inhibited (11)
1. VIIa, IXa, Xa, IIa = inhibited by heparin
2. XIa, VIIIa, Va = inhibited by oral anticoagulants
3. VII, IX, X, II = degraded by endothelial activity via protein C
31
What are the clinical uses of anticoagulants (3)
1. mainly used to prevent thrombosis formation or growth of existing clots in the slower-moving venous circulation
2. here clots consist of fibrin web enmeshed with platelets and red cells
3. Appropriate for prevention of Deep Vein Thrombosis (DVT) - eg. from sedentary posture (vascular stagnation) or liver disease.
32
What are the clinical uses of parenteral anticoagulants (3)
1. antagonise clotting factors
2. Heparin initiates rapid/short-duration anticoagulation.
3. Low Molecular Weight Heparins (Certoparin) have longer duration than unfractionated heparin.
33
What are the clinical uses of oral anticoagulants (vit-K-dependent class) (2)
1. antagonise the vitamin K-dependent synthesis of clotting factors (VII, IX, X & II)
2. are therefore slow (48-72 hours) and opposed by vitamin K in the diet (or administered).
34
What is the use of warfarin in animals (4)
1. Warfarin is used as a "rat poison".
2. Rats regularly eat sharp objects and injure their gut; but haemostasis contributes to natural, rapid repair.
3. They will readily consume warfarin (and do not have a vomit reflex).
4. Poisoned rats tend to bleed to death.
35
What is the note on warfarin in humans (4)
1. Aged humans suffer disorders in the liver's provision in coagulant factors such as PT (factor II); putting them at risk of bleeding or clotting.
2. Warfarin ("anticoagulant") is effective in the avoidance of thrombo-embolic disorder in old patients
3. but a long time is needed to reverse the effects.
4. Warfarin treatment needs monitoring of INR, blood loss via bruising & ulcers
36
What are the clinical applications of “New” or “Direct” Oral Anticoagulants, NOACs or DOACs (non-vit-K-dep’t) (8)
1. Inhibit different clotting factor activities to Warfarin
2. Rivaroxaban is a competitive reversible antagonist of activated factor X (f Xa).
3. Dabigatran etexilate is a competitive reversible non-peptide antagonist of thrombin (f IIa).
4. Like warfarin, New Oral Anticoagulents (NOACs) aim to prevent clots from forming & so protect from ischemic stroke
5. Used in the management of venous thromboembolism
6. Prevent strokes in people with non-valvular AF
7. Less influenced by diet and other medications
8. does not require close monitoring of INR (lacks narrow TI of warfarin; more quickly reversed by synthesis of new factors).
37
What are the clinical applications of NOACs/DOAC ((Novel Oral Anti Coagulants (Not Vit-K-dep’t; but direct acting)) (2)
1. Rivaroxaban: competitive reversible antagonist of activated factor X (f Xa).
2. Dabigatran etexilate: competitive reversible non-peptide antagonist of thrombin (f IIa); “direct thrombin inhibitor”
