2. The coagulation process that leads to hemostasis involves a complex set of
reactions involving approximately 30 different proteins
These reactions convert fibrinogen, a soluble protein, to insoluble strands of
fibrin, which, together with platelets, forms a stable thrombus
7. Thrombin (factor lla) : final enzyme in the clotting cascade that
cleaves fibrinogen to fibrin and activates factor V,VIII,XI.
Direct thrombin inhibitors are able to block the action of both
circulating and clot-bound forms of thrombin because their
site of binding to thrombin is not masked by fibrin ( not
obstructed), they prevent thrombin from cleaving fibrinogen to
fibrin.
Parenteral DTIs include bivalirudin, argatroban, desirudin
The only oral DTI available for clinical use is dabigatran
8.
9. Drug Uses Monitoring
Bivalirudin PCI, HIT, NSTEMI =
(aPTT), with a target of 1.5 to
2.5 times the normal range
Argatroban PCI, HIT aPTT (target 1.5 to 3 times the
initial baseline, not >100 s)
.
Desirudin DVT prophylaxis aPTT
10. Drug C/I side effect Antidote
Bivalirudin
Major bleeding.
Bacterial endocarditis severe uncontrolled
HTN, diabetic or hemorrhagic
retinopathy.
Need renal dose adjusment
Bleeding, hypotension
Argatroban Major bleeding
Need kiver dose adjustment
Bleeding
Genitourinary tract
hemorrhage
Desirudin Major bleeding
Need renal dose adjustment
Bleeding, deep vain
thrombophlebitis,
11. Dabigatran is the only oral direct thrombin inhibitor available for
clinical use. Additional agents are under development
12. Monitoring Warning C/I S.E antidote:
(aPTT), creatinine if renal
insufficiency
*risk of thrombotic
events following
premature
discontinuation
avoidance of dabigatran
in individuals with
creatinine clearance
<15 mL/minute or in
those who are
hemodialysis dependent
dyspepsia, bleeding Idarucizumab
Uses
the prevention and management of (VTE)
disease, and in stroke prevention in
patients with (AF)
13.
14. Factor Xa upstream thrombin in clotting cascade at the convergence
point of the intrinsic and extrinsic pathway
Direct factor Xa inhibitors are able to block the action of both
circulating and clot-bound forms of factor Xa
whereas indirect factor Xa inhibitors such as heparin and
fondaparinux are only able to inactivate factor Xa in the fluid phase
via antithrombin
15. they prevent factor Xa from cleaving prothrombin to thrombin. They
bind directly to factor Xa
No parenteral direct factor Xa inhibitors in clinical use
Several oral agents are available, including rivaroxaban, apixaban,
edoxaban, betrixaban
16. Drug Uses Monitoring
Rivaroxaban used in the prevention and
treatment of (VTE) disease, and
in stroke prevention in patients
with atrial fibrillation (AF).
prior to initiating:
CBC, platelet
count, (PT),
(aPTT),(INR)
Apixaban same prior to initiating :
CBC, renal function
Platelet count, PT,
aPTT
Edoxaban same Prior to initiation:
CBC, renal function
Betrixaban prevention of VTE in
hospitalized adult medical
patients
Prior to initiation:
renal function
17. Drug C/I S.E Antidote
Rivaroxaban patients with prosthetic heart
valves or during pregnancy
bleeding ,
dizziness,
insomnia anxiety,
depression ,
fatigue, syncope ,
wound secretion,
abdominal pain
Andexanet alfa
Apixaban Same Bleeding
increased
gammaglutamyl
trasferase ,
neausea
Andexanet alfa
Edoxaban Same Bleeding, GI
bleeding,vaginal
hemorrhage
Andexanet alfa
18. Fondaparinux , Heparin, LMWH
Fondaparinux MOA:
Potentiates the antithrombin effect that inhibit Xa.
Adm.: IV,SC
20. *Heparin:
MOA: accelerate interaction of antithrombin III with both
thrombin and factor Xa.
Adm.: IV, SC
*LMWH:(enoxaparin,tinzaparin)
MOA: accelerate interaction of antithrombin with factor
Xa.
Adm.: SC, IV in acute MI.
21.
22. Uses Monitoring
Anticoagulation ,in PCI, interstitial
cystitis, mechanical prosthetic
valve, STEMI, NSTEMI, VTE
therapeutic aPTT
1-aPTT of 1.5 to 2.5 times
Warning C/I S.E Antidote
hyperkalemia, thrombocytopenia (HIT), thrombocytopenia, HIT,
uncontrolled active
bleeding
thrombocytopenia (HIT) protamine sulfate
23. Drug Uses Monitoring
Enoxaparin DVT prophylaxis, DVT,PE treatment, PCI, NSTEMI, unstable angina. initial :(PT) and
(aPTT), anti Xa level
Tinzaparin DVT,PE treatment ,mechanical prosthetic heart valve to bridge
anticoagulant,
initial :(PT) and
(aPTT)
anti Xa level
24. Drug Warning C/I S.E Antidote
Enoxaparin ]hyperkalemia,
thrombocytopenia,
Hypersensitivity to enoxaparin or heparin,
history of HIT in the past 100days, active
major bleeding
Need renal dose adjustment
Anemia, hemorrhage,
peripheral edema,
confusion
1 mg protamine
per 1 mg of
enoxaparin.
Tinzaparin hyperkalemia,
thrombocytopenia
Hypersensitivity to it or other LMWH or
heparin, active bleeding, History of HIT,
endocarditis, severe uncontrolled pressure,
Spinal/epidural anesthesia
Increase ALT, hematoma
at injection site, chest
pain
1 mg protamine
per 100 anti-
factor Xa units of
LMW heparin.
28. Drug C/I S.E Antidote
Warfarin Hypersensitivity to warfarin or any
component of formulation, hemorrhagic,
recent or potential surgery of the eye or
CNS, major regional lumbar block
anesthesia, pericardial effusion, malignant
HTN, bacterial endocarditis, eclampsia,
preeclampsia, pregnancy
Hemorrhage, ,systemic
cholestrol micro-embolism.
Vit. K
Anticoagulants : Variety of agents that inhibit one or more steps in the coagulation cascade
DTIs can bind to the active site or to two sites (active and exosite) of thrombin directly
In contrast to heparins that can bind to circulating thrombin only ( antthrombin lll)
another oral agent, ximelagatran which was withdrawn from the market in 2006 due to hepatotoxicity and cardiovascular events
Bivalirudin: ACT : rapid action and can be tested within minutes of adminsitration
Half life :25 minutes, return to normal after 1 hr of D/C .
Argatroban prolongs the prothrombin time/international normalized ratio (PT/INR). Thus, when patients receiving argatroban are transitioned to warfarin, it is necessary to use an adjusted INR target during overlap, and repeat the INR upon discontinuation of argatroban. Institutional guidelines regarding the appropriate INR target should be followed
Half life: 40-50 min
Dose adjust. In hepatic impairment
Desirudin: half life 2 hours
Half life 12-17 hours
Inhibition of factor Xa can prevent amplified thrombin generation because one molecule of factor Xa can cleave over 1000 molecules of prothrombin to thrombin
brand names respectively : xarelto , eliquis, lixiana, bevyxxa
Direct factor Xa inhibitors lack antidote
Settings in which coagulation testing for rivaroxaban effect may be helpful include the following:
1-Bleeding in a patient receiving rivaroxaban, or with suspected rivaroxaban overdose
2-Need for emergent or urgent surgery in a patient receiving rivaroxaban
In such cases, monitoring is best done by measuring anti-factor Xa activity using an assay specifically calibrated for rivaroxaban. If an anti-factor Xa assay calibrated to rivaroxaban is not available, it may be possible to use an anti-factor Xa assay calibrated to another anticoagulant such as low molecular weight (LMW) heparin. Other assays such as the PT and aPTT are not very reliable
Settings in which coagulation testing for apixaban effect may be helpful include the following:
●Bleeding in a patient receiving apixaban, or with suspected apixaban overdose
●Need for emergent or urgent surgery in a patient receiving apixaban
In such cases, monitoring can be accomplished through the measurement of anti-factor Xa activity
*apixaban : least dependence on renal clearance
Rivaroxaban interacts with potent dual inhibitors of CYP 3A4 and P glycoprotein eg ketoconazole… concurrent use in C/I
*VTE prophylaxis: 2500u 1-2h before surgery. Then 2500-5000u/d after day of surgery to7days.
Hyperkalemia: suppress aldosterone production
HIT :serious antibody- mediated reaction resulting from irreversible aggregation of platelets
Heparin and vitamin k antagonists may be preferable incase of: prosthetic heart valves, pregnancy, renal impairement, antiphospholipid syndrome , compliance (DOACs have short half lives), GI diseases, dosing convenience ,cost
Direct thrombin inhibitors and direct factor Xa inhibitors are not used during pregnancy (lack of clinical experience)