Hemostasis Flashcards
What are the sites of intervention in hemostasis? (4)
- anti platelet agents
- anti-coaggulant agents
- fibrinolytic agents
(above are thrombolyrics) - anti firbinolytics (hemostatics)
What are the anti platelet agents used for and the 4 kinds?
used to disrupt or prevent platelet aggregation
1. ASA and related NSAIDs
2. dipyridamole
3. thienopyridines
4. glyciprotein IIb/IIIa inhibitors
NSAID/Aspirin (use, MOA, AE)
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
Issue with using COX-2 selective inhibitors
- 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
Dipyridamole (indication, MOA, PK, AE)
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
What is dipyridamole combined with and why?
- has little effect on its own: can be used as coronary vasodilator in cardiac imaging studies
- usually combined with ASA or warafin
What is the thienopyridine prototype?
ticlopidine
Thienopyridines (indications, MOA, PK, ADR)
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
What were thienopyridines replaced with and why?
- replaced by clopidogrel
- thienopyridines have frequent ADR and contraindications
- clopidogrel has a better safety profile and faster recovery
Clopidogrel indications
- 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
Clopidogrel MOA (4)
- 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
Clopidogrel PK & PD (5)
- 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
Clopidogrel adverse effects VS ASA
- more potent than ASA
- more bruising and haemorrhaging effects than ASA
- less GI bleeding and GI ulcers than ASA
Abciximab
- GP IIb/IIIa inhibitor
- monoclonal antibody against GP IIb/IIIa R (injected)
- binds irreversibly and inhibits fibrin crosslinking
- inhibits platelet aggregation > 12 hours
Newer synthetic GP IIb/IIIa antagonists advantages and use
- smaller molecules that can be taken orally
- reversible inhibition
- shorter half life
- used in angioplasty and stent procedures, acute coronary syndromes
ex. Eptifibatide, Tirofiban
Anticoagulant drug use
- thromboembolic disease via coagulation cascade
- inhibition of thrombin activity (MOA differs by which thrombin activity is inhibited)
Anticoagulant drug classes
- warfarin (vit K antagonist)
- heparin
- low molecular weight heparin
- specific factor 10Xa inhibitor (indirect)
- direct factor 10Xa inhibitor
(all above inhibit coagulation) - anti thrombin
- herbals
Warfarin/Coumadin MOA
- 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
Warfarin/Coumadin indication (4)
- 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
Warfarin PK (bioavail., PP, onset, reversal, metabolism)
- 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
Why does warfarin need to be closely monitored?
- inter-individual variability in dosage for therapeutic level
- narrow therapeutic index –> 99% is plasma protein bound
- monitored by prothrombin time (INR)
Warfarin adverse effects and drug interactions
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
Heparin MOA
- 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
Heparin PK
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
Heparin clinical use
- 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 - cardiac surgery
- requires very high dose
- monitor with activated clotting time (ACT)
Heparin adverse effects
- bleeding, dose related
- thrombocytopenia (decrease in platelets), only in 2-5% of patients but more common with cardiac surgery
What is the antidote for heparin and its adverse effects
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
How does heparin resistance occur (2) and how is it treated?
- congenital anti-thrombin III deficiency
- 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
Low molecular weight heparin drug names and structure
enoxaparin
dalteparin
Low molecular weight heparin structure
depolymerization of unfractionated heparin into small fragments that contain pentasaccharide with high affinity for anti-thrombin III
Low molecular weight heparin MOA
- small size means that it can’t inactivate thrombin directly
- LMWH catalyzes inactivation of factor Xa (anti-thrombin II also inhibits factor Xa)
Low molecular weight heparin PK (5) and AE (1)
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
Fondaparinux (drug type, structure, MOA, PK, AE)
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
Rivaroxaban, Apixaban
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
apixaban advantages over heparin and warfarin
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
anti-thrombin drug (name, MOA, use)
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
idarucinzumab
Dabigatran antidote
- mAB
- may cause significant bleeding/hemorraging in some individuals?????
- not used in patients with mechanical heart valve
Herbal medications with anticoagulant properties
- 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)
Fibrinolytic/thrombolytic drug classes
plasminogen activators
1. streptokinase
2. tissue plasminogen activator
3. tenecteplase
Fibrinolytic/thrombolytic drug uses
dissolve clots as a result of
- myocardial infarction
- thromboembolic stroke (CONTRAINDICATED IN HEMORRHAGIC STROKE)
- localized thrombosis via: arteriovenous fistula, prosthetic graft, catheters
Streptokinase (source, MOA, PK (4), AE (2))
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
Tissue plasminogen activator (tPA) or Alteplase (source advantage, specificity, t1/2, use)
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)
Tenecteplase
- new genetic variant of tPA
- increased fibrin specificity
- increased efficacy
- single bolus admin
- t1/2 = 90-130 min
- lower incidence of bleeding
Reteplase
- genetic variant of tPA
- longer t1/2 and fibrin specificity
- efficacy similar to tPA and tenecteplase
Anti-fibrinolytic drug use
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)
anti-fibrinolytic drugs
- aprotinin
- lysine derivatives
- tranexemic acid
- epsilon aminocaproic acid - protamine
- factor VIIa
Aprotinin
- 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
Lysine derivatives
- anti fibrolytic
- bind and inhibit plasminogen and plasmin
- used to reduce pre-op bleeding
factor VIIa
- 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
use of hemo drugs in COVID treatment
- anti-platelets and anti-coagulants
- hypothesis of COVID associated venous thromboembolism event, pulmonary emboli, and lung microcirulatory thrombotic disease –> interaction of inflammation and coagulant
