Prophylaxis & acute mgt of DVT (2)
UFH/LMWH
Category & ex’s (2) of drugs for long-term DVT prevention
Oral anticoagulants: Warfarin & Rivaroxaban
Virchow’s Triad
“SHE”
Stasis: post-op/long drive or flight
Hyper coagulability: coagulation cascade problem
(ie: Factor V Leiden mutation)
Endothelial damage (i.e.: exposed collagen that triggers clotting cascade)
Imaging test of choice for DVT
Compression ultrasound w/ Doppler
Imaging test of choice for PE
CT pulmonary angiography
Factor Xa Anticoagulant w/ greatest efficacy & 2 examples
LMWH (dalteparin, enoxaparin)
Direct Xa Inhibitors (2)
Apixaban, Rivaroxaban
Factor IIa (Thrombin) Anticoagulant w/ greatest efficacy
Heparin
Direct Thrombin Inhibitors (3)
Argatroban, Dabigatran, Bivalirudin,
Prophylaxis and Acute Mgmt of DVT
UFH or LMWH (eg: enoxaparin)
Tx & Long term prevention of DVT
Oral anticoagulants (eg: warfarin, rivaroxaban)
Indirectly lowers activity of thrombin and factor Xa w/ short T1/2
UFH
Clinical Use of Heparin
Immediate anticoagulation for pulmonary embolism
acute coronary syndrome, MI, DVT
Anticoagulant that doesn’t cross placenta & monitored via PTT
Heparin
AE of Heparin
Bleeding, Thrombocytopenia (HIT), osteoporosis, hypoaldosteronism, hyperkalemia, drug-drug interactions
Rapid reversal agt vs. Heparin
Protamine Sulfate: (+) charged molecule that binds (-) charged Heparin
Heparin class that acts predominantly on Factor Xa (#1-w/ 2ex’s) and only on Factor Xa(#2)
1) LMWH (eg: enoxaparin, dalteparin)
2) Fondaparinux
MOA of Heparin-induced Thrombocytopenia (HIT)
dev of IgG ab’s vs. heparin bound PT factor 4 (PF4)
ab-Hep-PF4 complex activates PT’s->Thrombosis & Thrombocytopenia
Only PO direct thrombin inhibitor
Dabigatran
Clinical use of direct thrombin inhibitor
VTE, a fib, HIT
doesn’t require lab monitoring
What can reverse dabigatran (direct thrombin inhibitor)?
idarucizumab
MOA of Warfarin
What is its metabolism affected by?
interferes w/ Y-carboxylation of vit K dep clotting factors (II, VII, IX, X) and proteins C & S
metabolism influenced by polymorphisms in gene for vit k epoxide reductase complex (VKORC1)
What is the effect of warfarin in a laboratory assay?
effect on extrinsic pathway, ↑ PT and w/ long T1/2
Clinical Uses of Warfarin (2)
Chronic anticoagulation (eg: VTE prophylaxis) & stroke prevention in a fib
CI of Warfarin
Pregnant women bc crosses placenta; follow PT/INR
AE of Warfarin
Bleeding, teratogenic,
skin/tissue necrosis*
(due to small vessel micro thrombosis*)
Explain the early transient hyper coagulability w/ warfarin use
Factors C & S with shorter T1/2 than clotting factors II, VII, IX, X
Warfarin reversal (a) & rapid reversal (b)
Vit K (a)/FFP or PCC (b)
What is heparin “bridging” & why is it imp?
Heparin frequently used when starting warfarin
Heparin’s activation of antithrombin enables anticoagulation during initial transient hyper coagulable state caused by warfarin
Initial heparin Tx ↓ risk of recurrent VTE & skin/tissue necrosis
Compare route of admin, site of action & onset of action in Heparin vs. Warfarin
Heparin:
Parenteral (IV, SC)
Blood
Rapid (secs)
Warfarin:
PO
Liver
Slow, limited by half lives of normal clotting factors
Direct Factor Xa Inhibitors (2)
Apixaban, Rivaroxaban
Clinical use of direct Factor Xa inhibitors (2)
Tx and prophylaxis of DVT & PE , stroke paralysis in patients w/ a fib
+ of oral anticoagulant agents?
Don’t usually require monitoring
AE & limitation of direct factor Xa inhibitors
Bleeding; not easily reversible
Grade the reversibility of the heparin classes
UFH: Robust
LMWH: Moderate
FPX: Little, if any
What are HIT paradoxes?
Anticoagulant-induced thrombosis Clotting, not bleeding disorder PT transfusions can ↑ thrombosis risk Simply stopping heparin may not prevent thrombosis Warfarin CI as acute monotherapy
How might HIT present clinically?
Drop in PT count & or new thrombosis
Describe the nature of heparin exposure in HIT in terms of
a) Heparin Class
b) Dose/Duration
c) Route of admin
d) Clinical Setting
a) UFH>LMWH
b) High>Low dose
c) Long term>Short term
IV>SC, flushes, heparin coated devices
d) cardiac, orthopedic or ICU
Derivation & action of Argatroban
L arginine; Univalent inhibitor of thrombin, inhibiting clot bound & soluble thrombin
Indication of Argatroban
Anticoagulant for prophylaxis/Tx of thrombosis, or PCI in patients w/ HIT*
Anticoagulant w/o cross-reactivity w/ heparin induced antibodies
Argatroban
Limitation of Argatroban
No known antidote
Therapeutic Effect of Argatroban
Rapid, ~30 mins (IV but no bolus)
Argatroban Elimination
Hepatic metabolism; T1/2 ↑ in patients w/ mild hepatic impairment
Given the challenging transition from Argatroban, what other drug may be beneficial?
Direct Factor Xa Inhibitors
What are 2 imp points to remember during Argatroban therapy transition?
1) Don’t rely on warfarin alone until HIT is adequately controlled
2) Give several days for warfarin to attain its therapeutic effect
What are some criteria that have to be met before Argatroban is discontinued? (5)
- INR>4.0^2
- Obtain INR 4-6 hours after Argatroban discontinued
- Absence of new TEC’s
- PT recovery
- Restart Argatroban Tx if INR falls below therapeutic range
What are 2 anticoagulants that are CI in acute HIT?
a) Warfarin
b) LMWH: cross-reactive w/ heparin antibodies
What is one + of Fondaparinux?
Rarely cross reacts w/ heparin ab’s
No EBM but anecdotal support
3 +/- of Oral Xa Inhibitors
+:
PO
Easy dosing
No routine monitoring
-:
$
No antidote
Renal clearance
Why is warfarin not used in acute thrombotic settings?
Bc it requires 3-4 days to have anticoagulant effects