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PPoS > Haemostasis #2 > Flashcards

Haemostasis #2 Flashcards

1
Q

Why is treating thrombosis a balancing act?

A
  • between clot formation + risk of haemorrhage as 1 will dom other
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2
Q

Which drugs are used in treating thrombosis?

A
  • anti-platelet drugs
  • anti-coagulant drugs
  • fibrinolytic drugs
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3
Q

What is function of anti-platelet drugs?

A
  • limit growth/dec risk of arterial thrombosis

- inhib platelet aggregation

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4
Q

List anti-platelet drugs + their action

A
  • aspirin: inhib COX enz which prod thromboxane in platelets
  • P2Y12 receptor antag: P2Y12 activation amp activates platelet activation by platelet agonists so antag inhib platelet activation by ADP + potentclass
  • GPIIb-IIIa (glycoprotein) + alpha IIb beta III (integrin) antag
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5
Q

What is thromboxane A2 (TXA2)?

A
  • potent platelet agonist
  • vasoconstrictor
  • mitogen of sm cells
  • major product of cyclo-oxegenase-1
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6
Q

When is low dose aspirin given + what it does?

A
  • 2ndary prevention of cardio-vas events

- irrev inhib of COX-1 (all other NSAID’s rev) + so TXA2 prod

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7
Q

Why doesn’t low-dose aspirin affect PGI2 syn + effect?

A
  • endo can continually syn COX-2 which can prod PGI2 which inhib platelet activation
  • prod more PGI2 which dec TXA2:PGI2 ratio so PGI2 dom
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8
Q

What does P2Y12 activation cause?

A
  • full platelet aggregation
  • amplifies aggreg initiated by P2Y1 + complete aggreg induced by all other platelet agonists (ADP, collagen, thrombin, TXA2, adrenaline, 5-HT)
  • irrev clot formation
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9
Q

What are 2 drug classes of GPIIa-IIb antag?

A
  • Fab fragments (small antibody) e.g. abciximab
  • small mol inhib e.g. eptifibatide
  • all used IV
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10
Q

What is action of GPIIb-IIIa antag?

A
  • compete with fibrinogen-vWF for binding to GPIIbIIIa receptors
  • v. potent + fast-acting
  • inhib aggreg irrespective of agonist
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11
Q

What are clinical benefits of GPIIb-IIIa antag?

A
  • improve ischaemic outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention
  • block immediate re-stenosis following coronary angioplasty
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12
Q

Why are GPIIb-IIIa antag not intended for long-term use?

A
  • cause of major thrombocytopaenia - high rates of bleeding complications
  • not for long term use but alt. treatments with improved safety
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13
Q

Is there any benefit of anti-platelet drugs for primary prevention of CV events?

A
  • diff to determine at risk patients + so don’t want to cause haemorrhage
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14
Q

What is adv + disadv of anti-platelet drugs?

A
  • block restenosis following angioplasty e.g. IV P2Y12 antag
  • multiple pathways to platelet activation limit effect of specific pathway inhib which leads to incomplete efficacy even though pharmacological inhib is complete
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15
Q

What is dual anti-platelet therapy?

A
  • more effective + synergistic
  • used in unstable angina, non-ST segment elevation, MI MI with S-T elevation
  • e.g. aspirin + clopidogrel
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16
Q

What is clopidogrel + disadv of using it?

A
  • PYP12 inhib - safer than old antag
  • can lead to adverse thrombolytic events due to non-uniform platelet inhib effects aka inter-indiv variability = indiv with high reactivity despite clopidogrel therapy at inc risk of other thrombolytic occurances
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17
Q

What led to dev of anti-thrombotic agents + new PYP12 antag?

A
  • other platelet signalling pathways continue to be activated + can contribute to fungus formation so new drugs have improved safety profiles
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18
Q

What is anticoagulant + fibrinolytic therapy for?

A
  • inhib coag cascade
  • prophylaxis + treatment of venous thrombi
  • prevent propagation of blood clot but don’t dissolve clot
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19
Q

What are the established anticoagulants?

A
  • heparin

- warfarin

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20
Q

What are novel anticoag drugs + issues?

A
  • factor X
  • thrombin inhib
  • studies required to determine replacement for short + long term anticoag therapy of heparin + warfarin
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21
Q

What are thrombolytics used for?

A
  • rapid removal of thrombus in coronary + cerebral artery thrombosis
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22
Q

What is purpose of fibrinolytic system?

A
  • acts as dynamic equ to stop over-activation of coag cascade + so is target for fibrinolytic drugs
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23
Q

What is function of heparin?

A
  • prevention + rapid treatment of venous thrombi
  • inhib serine-protease factors: XIIa, XIa, Xa, IXa + thrombin directly or potentiation plasma-serine inhib anti-thrombin III
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24
Q

What forms of heparin are there?

A
  • unfractionated heparin = lengths of sugar chains uncontrolled
  • low mol weight heparin e.g. enoxaparin
25
Q

What are pros of unfractionated heparin?

A
  • pros:
  • effective
  • cheap
  • short half life
  • rev with protamine (antidote)
26
Q

What are cons of unfractionated heparin?

A
  • continuous infusion
  • variable bioavaliability due to diff in pharmacokinetics of diff fractions
  • monitoring required for patients
  • unpredictable pharmacokinetics
  • HIT
  • haemorrhage
27
Q

What are pros of LMWH?

A
  • inc bioavailability
  • inc half-life
  • dec risk of HIT
28
Q

What are cons of LMWH?

A
  • expensive
  • partial reversible with protoamine
  • haemorrhage
29
Q

What is heparin induced thrombocytopaenia?

A

side effect in 1% of patients

30
Q

What causes HIT?

A
  • heparin highly -ve charged mol + binds to platelet factor 4 - causes antibody prod on 1st exposure
  • PF4-heparin complex causes immune-mediated platelet activation of HIT
31
Q

What is function of vit K antag?

A
  • e.g. warfarin inhib vit K dependent epoxide reductase activity in liver
  • mod FVII, FIX, FX + FII (prothrimbin) during syn in liver
32
Q

What are features of vit K antag therapy?

A
  • long term anticoagulant therapy
  • orally active
  • takes 1-3 days for full effect as it inhib de-novo syn of CF
  • activity affected by diet + gen variation of liver
33
Q

What is disadv of vit K antag?

A
  • requires frequent monitoring for safety + efficacy

- 1-3% of warfarin patients have major bleeding events

34
Q

What are drug interactions of vit K antag?

A
  • displacement from plasma albumin

- alteration in metabolism in liver

35
Q

What is antidote to vit K antag?

A
  • vit K

- replace CF by plasma transfusion if haemorrhage severe

36
Q

What are 2 ways of giving FXa inhib?

A
  • injection e.g. fondaparinux

- orally e.g. rivaroxiban

37
Q

What are FXa inhib?

A
  • pentasacc
  • active moiety of heparin based on antithrombin binding sequence
  • act indirectly via antithrombin
38
Q

What are pros of injectable FXa inhib?

A
  • IV/SC - 100% bioavalability
  • more predictable PK than heparin
  • HIT rarely observed (doesn’t bind to PF-4)
  • sup. to LMWH pre + post operatively: 70% dec in thrombus risk, no inc bleeding risk
39
Q

How do oral FXa inhib work?

A
  • directly inhib FXa
40
Q

What are adv of oral FXa inhib?

A
  • favourable safety
  • don’t require frequent blood monitoring
  • becoming more widely used
41
Q

What are thrombin inhib?

A
  • aka FIIa inhib, direct thrombin inhib
  • block active site of thrombin
  • inhib both clot bound + free thrombin
42
Q

What is IV infused thrombin inhib used for?

A
  • e.g. hirudin (from leeches), lepirudin + desirudin
  • short acting
  • as effective as LMWH
  • used for anticoagulant therapy + treatment of patients with HIT
43
Q

What are pros of orally active thrombin inhib?

A
  • pros: as effective as warfarin

- cons: less chance of haemorrhage

44
Q

Which endogenous mol prevent inappropriate clot formation?

A
  • endo cell NO + prostacyclin
  • tissue factor pathway inhib
  • active protein C
  • antithrombin (III)
45
Q

What is function endo cell NO + prostacyclin?

A
  • inhib platelet activation + aggreg
46
Q

What is tissue factor pathway inhibitor?

A
  • from endo + other cells

- inactivates + forms complex with FXa which inactivates mem-bound TF-VIIa complex + limit process in extravas space

47
Q

What is active protein C?

A
  • activated by thrombin-thrombomodulin

- with cofactor protein S - inactivates FVa, VIIIa

48
Q

What is antithrombin?

A
  • activated by heparans on endo cells + heparin

- inactivates thrombin IXa-XIIa when not in clot/combined in prothrombinase

49
Q

Describe process of APC system

A
  1. thrombomodulin released by endo + comb with thrombin
  2. cause inactivated protein C to become activated (APC)
  3. APC comb with protein S to cause inactivation of FVa + FVIIIa
50
Q

Describe process of fibrinolysis using plasmin system

A
  1. damaged endo stim by bradykinin, thrombin + kallikrein to release tissue plasminogen activator
  2. TPA binds to plasminogen + cause release of plasmin which degrades fibrin into degradation products (FDPs + D-dimers)
51
Q

What is plasminogen activator inhib inhib by + sig?

A
  • inhib by APC

- acts as -ve feedback to inhib inhibition of PAI

52
Q

What is alpha-2 antiplasmin?

A
  • inhin role of plasmin
53
Q

What is function of fibrinolytics?

A
  • activate plasminogen-fibrin pathway to breakdown fibrin clot
  • remove arterial thrombi (MI - up to 12hrs, stroke - up to 3hrs)
54
Q

How are fibrinolytics given + disadv?

A
  • IV

- high risk of haemorrhage

55
Q

What is antidote to fibrinolytics?

A
  • severe haemorrhage treated with transexamic acid (inhib activation of plasminogen)
56
Q

List 2 e.g.s of fibrinolytics

A
  1. streptokinase

2. alteplase

57
Q

What is streptokinase?

A
  • non-enz protein from streptococci
  • binds + activates plasminogen
  • allergenic
58
Q

What is alteplase?

A
  • non-allergenic

- clot selective - only activates plasminogen bound to fibrin in thrombus

PPoS (11 decks)

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