Oral Anticoagulants (FETT)

Blood products and modifiers

WARFARIN

Dabigatran

Vitamin K antagonist (coumarins)

• Inhibit hepatic vitamin K epoxide reductase → ↓ hepatic synthesis (recycling) of the active, reduced form of vitamin K → ↓ γ-carboxylation of glutamate residues on coagulation factors II, VII, IX, and X as well as protein C and protein S

• Mutations and polymorphisms in gene VKORC1 alter the effect of vitamin K antagonists.

• Well-known effects and side effects

• Low costs

• In cases of life-threatening bleeding:

  • Direct reversal by replacement (e.g., with prothrombin complex concentrate, FFP)

  • Indirect/delayed reversal by increasing production of coagulation factors (e.g., with vitamin K substitution)

• Difficult to manage

  • Long half-life

  • Regular monitoring of the PT/INR required (as vitamin K antagonists affect the extrinsic coagulation pathway)

  • Requires periprocedural bridging anticoagulation

• Broad range of interactions

• Not suited for acute therapy of pulmonary embolism or deep vein thrombosis

• Prophylaxis of thromboembolism following:

  • DVT and/or pulmonary embolism

  • Prolonged immobilization after surgery (e.g., especially in knee or hip surgery)

  • Nonvalvular atrial fibrillation

increased PT/INR, no change to PTT or TT (routinely monitored)

WARsaw is an EXTRaordinary Place To check out: WARfarin affects the EXTRinsic pathway; therefore, PT should be regularly checked.

WEPT: Warfarin Extrinsic pathway PT

• Dose-dependent increased risk of bleeding

  • Small wounds cease to bleed spontaneously and no additional measures are required

  • Severe cases of hemorrhage are usually retroperitoneal, intracranial, or gastrointestinal.

  • Countermeasures for extensive or life-threatening bleeding include

    • Stop coumarins

    • Administer FFP or prothrombin complex concentrate (PCC) for rapid reversal of warfarin effect

    • Vitamin K: takes longer to take effect than FFP or PCC

• Seen within the first few days of treatment with high doses of warfarin

• Warfarin inhibits all vitamin K-dependent coagulation factors: anticoagulants protein C and protein S have a relatively short half-life and are depleted more quickly than procoagulants factors II, IX, and X → increased factor V and VIII activity → initial hypercoagulable state → formation of microthrombi → vascular occlusion, tissue infarction, and blood extravasation

• Increased risk in patients with underlying hereditary protein C deficiency

• Presentation: painful purpura, hemorrhagic blisters, and large areas of necrosis; mostly affects subcutaneous adipose tissue

• Immediate management: discontinue warfarin, administer IV vitamin K, unfractionated heparin, and source of protein C (protein C concentrate, FFP); surgical debridement and grafting in therapy-refractory cases

• Prevention: temporary bridging anticoagulation with heparin until warfarin has started to act and the initial hypercoagulable state has been bridged

• Prophylaxis of thromboembolism (e.g., stroke) in patients with the following:

  • Valvular atrial fibrillation and nonvalvular atrial fibrillation

  • Heart valve replacement

  • Heart failure

• Myocardial ischemia

• Standard target INR: 2.0–3.0 (higher in mechanical heart valves or in special high-risk circumstances; usually 2.0–3.5)

• Therapy and secondary prophylaxis of:

  • Deep vein thrombosis

  • Pulmonary embolism

• Prophylaxis of thromboembolism following:

  • Total knee or hip replacement, hip fracture surgery

• General contraindications

  • Coagulopathies; hepatic dysfunction with impaired hepatic production of coagulation factors

  • Acute bleeding

  • Suspected vascular lesions, increased risk of severe bleeding

    • Severe arterial hypertension, aneurysm

    • Endocarditis

    • Recent cardiovascular events (e.g., cerebral ischemia)

    • Gastrointestinal bleeding

    • Surgery or interventional procedures (e.g., biopsy)

    • Tendency to fall

  • Severe renal insufficiency

  • Concurrent administration of several anticoagulants

  • Pregnancy and breastfeeding

    • Warfarin crosses the placenta, causing teratogenicity and fetal bleeding

    • Side effects of NOACs during pregnancy and breastfeeding are unknown. Therefore, they are currently not recommended.

• Specific contraindications

  • Dabigatran: concurrent administration of ketoconazole, itraconazole, ciclosporin, tacrolimus, or dronedarone

Warfarin crosses the placenta and is teratogenic, in contrast to heparin, which does not cross the placenta.

Warfarin is metabolized by cytochrome P450 (CYP) enzymes. Its effects can be significantly impacted by a variety of interactions; for this reason, warfarin serum levels should be monitored regularly.

• Decrease of anticoagulant effect

  • Rifampicin, carbamazepine, St. John's wort, ginger, licorice: induce metabolic breakdown of warfarin via induction of cytochrome P450

  • Foods rich in vitamin K (e.g., kale, spinach): counter effect of warfarin

  • Gastric acid inhibition (PPI use), cholestyramine treatment: impaired uptake of warfarin

• Increase of anticoagulant effect

  • Several antidepressants and antibiotics, PPIs, amiodarone, grapefruit: impair metabolic breakdown via inhibition of cytochrome P450

  • Acetaminophen: metabolite of acetaminophen interrupts vitamin K cycle via inhibition of vitamin K-dependent carboxylase

  • Sulfonamides, sulfonylureas: competitively block or displace warfarin at plasma protein binding sites

  • Damage to gut flora (e.g., antibiotic therapy): impaired bacterial vitamin K synthesis

“Chronic alcoholics Steal Phen-Phen and Never Refuse Greasy Carbs): Chronic alcohol use, St. John's wort, Phenytoin, Phenobarbital, Nevirapine, Rifampin, Griseofulvin, and Carbamazepine are P450 inducers (↓ warfarin levels).

“sickfaces.com group”: Sulfonamides, Isoniazid, Cimetidine, Ketoconazole, Fluconazole, Alcohol (binge drinking), Ciprofloxacin, Erythromycin, Sodium valproate, Chloramphenicol, Omeprazole, Metronidazole, and Grapefruit juice are P450 inhibitors.

• Bridging anticoagulation: the administration of heparin for the duration of the transient hypercoagulable state caused by warfarin therapy. Heparin prevents coagulation by activating antithrombin.

  • Reduces risk of venous thromboembolism and skin necrosis

  • May also be used during interruptions of warfarin therapy (e.g., surgery)

1. Interrupt VKAs as needed (e.g., patients with high periprocedural bleeding risk) a few days before the procedure.

2. Initiate bridging anticoagulation once the INR is in the subtherapeutic range,

3. Administer the last dose of LMWH 24 hours before the procedure (4–6 hours before the procedure for UFH).

4. Resume VKA after surgery ; consider postprocedural bridging anticoagulation as needed (e.g., patients with high periprocedural thrombotic risk.