Anticoagulant Reversal

Complex process where multiple components of the blood clotting system are activated in response to
vessel injury to control bleeding

Steps
▪ Primary hemostasis
▪ Formation of platelet plug and vasoconstriction at the site of injury
▪ Secondary hemostasis
▪ Initiation of the intrinsic and extrinsic pathways within the coagulation cascade
▪ Fibrin clot formation and stabilization
▪ Inhibition of coagulation
▪ Inhibition of thrombin generation
▪ Fibrinolysis

Warfarin

Dabigatran (Pradaxa)

•Rivaroxaban(Xarelto®)
•Apixaban (Eliquis®)
•Edoxaban (Savaysa™)

•Unfractionated heparin
•Low molecularweight heparin (Lovenox®)

VTE (PE/DVT)
Stroke (A fib)
MI (Post-Op Surgery)

Age > 75 years
Previous bleeding
Malignancy
Renal failure
Liver failure (responsible for making coagulation factors)
Thrombocytopenia
Antiplatelet therapy/NSAIDS
Previous stroke
Anemia
Recent surgery
Frequent falls
Alcohol abuse
Poor anticoagulant control
Uncontrolled Hypertension

Monitoring parameters

Upcoming invasive procedure

Bleeding (major vs non major)

Inhibits vitamin K epoxide reductase complex → depletes factors II, VII, IX, X and protein C & S

Only effective in an ACUTE ingestion-NOT FOR INCREASED INR!

Adsorbs toxic substances, thus inhibiting GI absorption and preventing systemic toxicity

Multiple doses may interrupt enteroenteric, enterohepatic, and enterogastric circulation of some drugs

May also adsorb any unabsorbed drug which remains in the gut

Single Dose: 25-100g

Neutralizes the anticoagulation activity of warfarin to allow for endogenous activation of coagulation
factors

Promotes liver synthesis of clotting factors (II, VII, IX, X); however, the exact mechanism as to this stimulation is unknown

Contains factors II, V, VII, VIII, IX, X

Manufactured from whole blood
▪ Must be ABO compatible

Frozen components must be thawed

Risk of infectious transmission (not a huge concern anymore)
▪ Human Immunodeficiency Virus (HIV)
▪ Hepatitis B
▪ Hepatitis C

Risk of transfusion-associated circulator y overload
▪ ~ one “unit” of FFP=200-250mL
▪ Initial dose=15ml/kg

INR of FFP = 1.4-1.6 (this is the lowest INR you can get)
Anaphylactoid-like reactions

Derived from pooled human plasma

PCC contains:
▪ Factors II, VII (responsible for lowering INR), IX, and X
▪ Protein C and S
▪ Antithrombin III
▪ Heparin

Both products (3 and 4) contain clotting factors in their inactivated form

Works super fast

Rate of administration: PCC >>> FFP
Rate of INR correction: PCC >>> FFP
Time for preparation: PCC >>> FFP
Hemostasis: PCC ≈ FFP
Complications: Thrombosis with PCC versus pathogenic transmission and transfusion-associated events with FFP
Fluid >>FFP
Cost: PCC >>> FFP

AKA as Activated PCC

Contains mainly activated therapeutic levels of factors II, IX, and X and mainly activated factor VII (VIIa)

FEIBA does not contain heparin
- Should be used in patients who have a history of HIT and cannot receive 4F-PCC

Higher risk of thromboembolic complications compared to FFP
- Lack of anticoagulant (heparin, protein C, or protein S) to balance procoagulant effect

Novoseven® (rFVIIa) is approved for patients with hemophilia
Most pronounced clotting ability of all products available to promote coagulation

Shown to successfully reverse VKA toxicity
▪ Off-label

Higher risk of thrombotic events ( 5 -10%)
▪ FDA’s Adverse Event Reporting System database found that the majority of these complications arose in patients who received rFVIIa for off-label purposes

DOAC

Indication
Treatment of DVT and PE
Reduction in the risk of recurrent DVT and PE following initial therapy
Atrial Fibrillation
Prophylaxis of DVT and PE Following Hip Replacement Surgery

Hemodialysis removes ~57% over 4 hours

“Rebound phenomenon”: reflects large volume of distribution and redistribution of the drug from the tissues into the plasma

Correction of coagulation parameters may not reflect cessation of bleeding

Indication
Reversal of the anticoagulant effects of dabigatran for
• emergency surgery/urgent procedures or
• life-threatening or uncontrolled bleeding

Indication
Treatment of DVT and PE
Reduction in the risk of recurrent DVT and PE following initial therapy
Atrial Fibrillation
Prophylaxis of DVT and PE Following Hip and Knee Replacement Surgery

Indication
Treatment of DVT and PE
Reduction in the risk of recurrent DVT and PE following initial therapy
Atrial Fibrillation
Prophylaxis of DVT and PE Following Hip and Knee Replacement Surgery

Indication
Treatment of DVT and PE
Atrial Fibrillation

Activated Charcoal - if within 2 hours
4F-PCC
Andexanet alfa (recombinat Fxa) - approved for apixaban and rivoroxaban; off-label for edoxaban

Binds and sequesters the factor Xa inhibitors
IV infusion

1-2 days; can be longer if kidney or liver function has worsened

Potentiates the action of antithrombin III and thereby inactivates thrombin (as well as activated
coagulation factors IX, X, XI, XII, and plasmin) and prevents the conversion of fibrinogen to fibrin

Binds to antithrombin to form a complex that irreversibly inactivates clotting factor Xa

LMWH

Indication
Treatment of DVT and PE
Thromboprophylaxis
Prophylaxis of DVT and PE Following Hip and Knee Replacement Surgery

Indication
for heparin overdose

Mechanism
• When administered alone, protamine has an anticoagulant effect
• When given in the presence of heparin, a stable salt is formed which results in the loss of anticoagulant activity of both drugs

Incomplete neutralization of LMWH with protamine may occur when used for reversal (partial neutralization (~ 60%)
• Due to the lower molecular weight of these products