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YAY ALMOST DONE > Hemostasis > Flashcards

Hemostasis Flashcards

1
Q

What are the sites of intervention in hemostasis? (4)

A
  1. anti platelet agents
  2. anti-coaggulant agents
  3. fibrinolytic agents
    (above are thrombolyrics)
  4. anti firbinolytics (hemostatics)
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2
Q

What are the anti platelet agents used for and the 4 kinds?

A

used to disrupt or prevent platelet aggregation
1. ASA and related NSAIDs
2. dipyridamole
3. thienopyridines
4. glyciprotein IIb/IIIa inhibitors

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3
Q

NSAID/Aspirin (use, MOA, AE)

A

use: low dose used as anti-platelet drug

MOA: inhibits COX1/2 enzymes –> which inhibit the conversion of arachidonic acid into PGH2 into thromboxane in platelets (no nucleus) –> to inhibit TX’s platelet aggregation and vasoconstriction effects, therefore it prevents thrombi formation and vasoconst.
–> aspirin irreversible inhibits this –> 7-10 days for complete recovery because platelets do not have a nucleus so they require de novo synthesis

AE: GI bleeding due to more PGI2 being released in the balance –> endothelial cells have nucleus so they can make more PGI2

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4
Q

Issue with using COX-2 selective inhibitors

A
  • selective inhibitors target COX2 which is in endothelial cells
  • this pushes the balance from the PG pathway to the TX pathway where COX1 converts AA to TX
  • more platelet aggregation and vasoconstriction
  • enhanced CV risk
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5
Q

Dipyridamole (indication, MOA, PK, AE)

A

use: anti platelet drug

MOA: inhibits platelet phosphodiesterase (PDE-3) –> causes increase in cAMP –> decreases ADP release and blocks adenoside reuptake –> reduces platelet adhesion and aggregation

PK: t1/2 = 10-12 hours, requires >1 dose daily
AE: headache, hypotension

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6
Q

What is dipyridamole combined with and why?

A
  • has little effect on its own: can be used as coronary vasodilator in cardiac imaging studies
  • usually combined with ASA or warafin
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7
Q

What is the thienopyridine prototype?

A

ticlopidine

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8
Q

Thienopyridines (indications, MOA, PK, ADR)

A

type: antiplatelet drug, prevention of coronary and cerebrovascular thrombosis (TIA or stroke)

MOA: ADP R antagonist –> irreversible inhibition of ADP binding to platelet receptor –> prevents expression of glycoprotein IIb/IIIa R –> inhibits platelet aggregation

PK: 2 days for therapeutic platelet aggregation, maximum effect in 5-10 days

ADR: frequent and many contradictions

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9
Q

What were thienopyridines replaced with and why?

A
  • replaced by clopidogrel
  • thienopyridines have frequent ADR and contraindications
  • clopidogrel has a better safety profile and faster recovery
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10
Q

Clopidogrel indications

A
  • anti platelet aggregation
  • most common use: coronary angioplasty and stenting –> during procedure the walls of the endothelium can be touched and can cause plaque release which increases platelet aggregation
  • prevention of ischemic stroke, myocardial infarction, progressive peripheral disease
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11
Q

Clopidogrel MOA (4)

A
  • specific inhibitor of ADP induced platelet aggregation
  • IRREVERSIBLY inhibits binding of ADP to P2YR (antagonist)
  • prevents expression of glycoprotein IIb/IIIa R –> inhibits platelet aggregation
  • inhibits amplification of platelet response that release ADP –> to block further ADP release
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12
Q

Clopidogrel PK & PD (5)

A
  • effect is dependent on platelet turnover
  • onset of action 2 hours
  • steady state 3-7 days, degree of inhibition 40-60%
  • prodrug activated by CYPC19 –> metabolite responsible for effects
  • no correlation between drug level and platelet aggregation inhibition
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13
Q

Clopidogrel adverse effects VS ASA

A
  • more potent than ASA
  • more bruising and haemorrhaging effects than ASA
  • less GI bleeding and GI ulcers than ASA
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14
Q

Abciximab

A
  • GP IIb/IIIa inhibitor
  • monoclonal antibody against GP IIb/IIIa R (injected)
  • binds irreversibly and inhibits fibrin crosslinking
  • inhibits platelet aggregation > 12 hours
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15
Q

Newer synthetic GP IIb/IIIa antagonists advantages and use

A
  • smaller molecules that can be taken orally
  • reversible inhibition
  • shorter half life
  • used in angioplasty and stent procedures, acute coronary syndromes
    ex. Eptifibatide, Tirofiban
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16
Q

Anticoagulant drug use

A
  • thromboembolic disease via coagulation cascade
  • inhibition of thrombin activity (MOA differs by which thrombin activity is inhibited)
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17
Q

Anticoagulant drug classes

A
  1. warfarin (vit K antagonist)
  2. heparin
  3. low molecular weight heparin
  4. specific factor 10Xa inhibitor (indirect)
  5. direct factor 10Xa inhibitor
    (all above inhibit coagulation)
  6. anti thrombin
  7. herbals
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18
Q

Warfarin/Coumadin MOA

A
  • inhibits VKOR to inhibit vitamin K dependent factor synthesis (II, VII, IX, X)
  • vit K is required to activate precursors
  • inactive precursors cannot bind Ca
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19
Q

Warfarin/Coumadin indication (4)

A
  • long term oral anticoagulation
  • atrial fibrillation: during turbulent blood flow cells can hit BV walls –> drug used to prevent coagulation in case of damage
  • prosthetic heart valves: after surgery to prevent thrombosis
  • DVT
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20
Q

Warfarin PK (bioavail., PP, onset, reversal, metabolism)

A
  • 100% bioavailable orally
  • peak plasma levels 2-12 hours
  • effect apparent after 30-60 hours because drug has to deplete vit K factors that have already been made
  • reversal takes 2-5 days after discontinuation, need to make new Vit K dependent factors
  • biotransformation in liver (9C9) and kidney
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21
Q

Why does warfarin need to be closely monitored?

A
  • inter-individual variability in dosage for therapeutic level
  • narrow therapeutic index –> 99% is plasma protein bound
  • monitored by prothrombin time (INR)
22
Q

Warfarin adverse effects and drug interactions

A

AE
- bleeding –> treated with Vit K of fresh frozen plasma

Drug interactions/contraindications
- Vit K deficiency
- liver disease
- platelet inhibitory drugs (ASA)
- displacement from albumin (Septra)
- enzyme induction (barbiturates)
- pharmacogenetics of CYP2C9 and VKOR affect response

23
Q

Heparin MOA

A
  • binds to anti-thrombin III (endogenous anticoagulant) and increases its activity by 1000X
  • anti-thrombin III binds to thrombin and inactivates it so thrombin can’t activate the conversion of fibrinogen to fibrin
  • it also inhibits factor Xa which would normally activate the conversion of prothrombin to thrombin
24
Q

Heparin PK

A

Admin: parentally (IV bolus/infusion or deep subcutaneous) –> highly charged and large (3-30KD) so it is not absortbed po and 1st pass metabolism

Onset: immediately with IV, 20-60 min after SC injecton

t1/2: 90 min

elimination: uptake into reticuloendothelial system (RES), endogenous hepirinases

distribution: does not cross placenta because it is so large so can be given during pregnancy

25
Q

Heparin clinical use

A
  1. prevention of deep vein thrombosis and pulmonary embolus
    - this is a common in many post surgical complications so can give heparin
    - no monitoring is required
  2. cardiac surgery
    - requires very high dose
    - monitor with activated clotting time (ACT)
26
Q

Heparin adverse effects

A
  • bleeding, dose related
  • thrombocytopenia (decrease in platelets), only in 2-5% of patients but more common with cardiac surgery
27
Q

What is the antidote for heparin and its adverse effects

A

PROTAMINE
- basic protein that binds to heparin and inactivates it
- isolated from fish sperm and contains zinc
- used when heparin dose is too high and people are at risk of bleeding

AE
- allergy to components
- intrinsic anticoagulant effect
- dyspnea, flushing, hypotension

28
Q

How does heparin resistance occur (2) and how is it treated?

A
  1. congenital anti-thrombin III deficiency
  2. acquired anti-thrombin deficiency due to previous heparin administration

treat with
- fresh frozen plasma: has coagulation cascade factors and proteins
- anti-thrombin III concentrate: high concentration to overcome heparin

29
Q

Low molecular weight heparin drug names and structure

A

enoxaparin
dalteparin

30
Q

Low molecular weight heparin structure

A

depolymerization of unfractionated heparin into small fragments that contain pentasaccharide with high affinity for anti-thrombin III

31
Q

Low molecular weight heparin MOA

A
  • small size means that it can’t inactivate thrombin directly
  • LMWH catalyzes inactivation of factor Xa (anti-thrombin II also inhibits factor Xa)
32
Q

Low molecular weight heparin PK (5) and AE (1)

A

PK
- more predictable
- no lab testing required
- onset: 2-3 hours
- t1/2: 3-5 hours sc injection
- reversal of effect within 24 hours

AE
- significant bleeding risk

33
Q

Fondaparinux (drug type, structure, MOA, PK, AE)

A

type: specific factor Xa inhibitors
Structure: synthetic analogue of pentasaccharide chain that binds anti-thrombin III
MOA: inhibits free and clot bound Xa
PK: long t1/2 (30-35hrs), 100% bioavailability (1 sc/day)
AE: significant bleeding but no heparin induced thrombocytopenia

34
Q

Rivaroxaban, Apixaban

A

direct factor Xa inhibitors
- orally active
- maximum inhibition four hours after dose, lasts 8-12 hours, activity returns to normal after 24 hours
- no reversal of anticoagulant effect in event of major bleeding

35
Q

apixaban advantages over heparin and warfarin

A

apixaban
- orally active, no injections necessary
- as effective/better than LMWH, almost as effective as heparin
- no laboratory monitorting required
- 1st OAC to lower all risk mortality

but: no reversal of anticoagulant effect

36
Q

anti-thrombin drug (name, MOA, use)

A

dabigatran

direct thrombin inhibitor –> binds to free and clot bound thrombin –> stops permanent fibrin clot formation

used to substitute heparin in patients with heparin induced thrombocytopenia, can replace warfarin in some cases - is not currently monitored

37
Q

idarucinzumab

A

Dabigatran antidote
- mAB
- may cause significant bleeding/hemorraging in some individuals?????
- not used in patients with mechanical heart valve

38
Q

Herbal medications with anticoagulant properties

A
  • ginseng (inhibit platelet aggregation but can decrease warfarin effects)
  • gingko, dong quai (inhibit platelet aggregation)
  • ginger (inhibit thromboxane synthesis)
  • st john’s wort (enzyme induction)
  • garlic and feverfew (inhibit COX)
39
Q

Fibrinolytic/thrombolytic drug classes

A

plasminogen activators
1. streptokinase
2. tissue plasminogen activator
3. tenecteplase

40
Q

Fibrinolytic/thrombolytic drug uses

A

dissolve clots as a result of
- myocardial infarction
- thromboembolic stroke (CONTRAINDICATED IN HEMORRHAGIC STROKE)
- localized thrombosis via: arteriovenous fistula, prosthetic graft, catheters

41
Q

Streptokinase (source, MOA, PK (4), AE (2))

A

source: protein isolated from hemolytic streptococcus

MOA: binds plasminogen to form 1:1 complex –> exposes active site of plasminogen to increase plasmin formation

PK
- bolus and infusion
- anticoagulant effect lasts 12-24 hours
- measured by thrombin time
- inactivated by binding to naturally occurring antibodies at high doses

AE
- bleeding
- allergic reaction due to antibody binding

42
Q

Tissue plasminogen activator (tPA) or Alteplase (source advantage, specificity, t1/2, use)

A

source: isolated from endothelial cells and synthesized by recombinant DNA (no allergic reaction or antibody binding!!)
- more specific for fibrin bound plasminogen
- short t1/2 = 3-4 min
- efficacy in myocardial infarction (from occlusion from a clot, used to break up the clot to increase blood flow)

43
Q

Tenecteplase

A
  • new genetic variant of tPA
  • increased fibrin specificity
  • increased efficacy
  • single bolus admin
  • t1/2 = 90-130 min
  • lower incidence of bleeding
44
Q

Reteplase

A
  • genetic variant of tPA
  • longer t1/2 and fibrin specificity
  • efficacy similar to tPA and tenecteplase
45
Q

Anti-fibrinolytic drug use

A

used to increase clot formation in bleeding disorders
- inhibit fibrinolytic system
- bind plasminogen and prevent its adsorption to fibrin
- more stable clot is formed in absence of fibrinolysis

  • clinical use with hyperfibirnolysis: enhance release of plasminogen activator (bypass, prostate or liver surgery, cancer)
46
Q

anti-fibrinolytic drugs

A
  1. aprotinin
  2. lysine derivatives
    - tranexemic acid
    - epsilon aminocaproic acid
  3. protamine
  4. factor VIIa
47
Q

Aprotinin

A
  • anti fibrolytic
  • inhibits plasmin –> degraded to small peptides and cleared by kidneys
  • half life 2.5 hours, bolus plus infusion
  • hypersensitivity reaction common –> isolated from bovine lung
48
Q

Lysine derivatives

A
  • anti fibrolytic
  • bind and inhibit plasminogen and plasmin
  • used to reduce pre-op bleeding
49
Q

factor VIIa

A
  • anti fibrolytic
  • produced by recombinant technology
  • induces thrombin generation by tissue factor dependent and independent pathways –> increases colloting cascade

use
- congenital factor VII deficiency
- acquired deficiency of factor VIII, IX, vWF
- warfarin OD
- investigational use in uncontrolled hemorrhage

50
Q

use of hemo drugs in COVID treatment

A
  • anti-platelets and anti-coagulants
  • hypothesis of COVID associated venous thromboembolism event, pulmonary emboli, and lung microcirulatory thrombotic disease –> interaction of inflammation and coagulant

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