Physiologic anticoagulants

• Inhibit intrinsic pathway:
  • Antithrombin (with heparin): inhibit factor 2(thrombin), 9, 10, 11, 12
  • Protein C: inhibit 5, 8; need VitK to synthesize
• Inhibit extrinsic pathway:
  • TFPI(Tissue factor pathway inhibitor): combine factor 10 to inhibit factor 8

Oral anticoagulants

Tip

• Heparin: also affects VIII and IX → intrinsic pathway → PTT
• Warfarin: affects both intrinsic and extrinsic pathway, but VII has shorter half life → extrinsic pathway → PT
  • The half-lives of the procoagulants are ∼ 2–4 days (except for factor VII, which has a short half-life), while the anticoagulants only have half-lives of 6–10 hours.
  • Intrinsic pathway remains active another 2–3 days, while extrinsic pathway and protein C are already inactive.

• Direct thrombin inhibitors: prolonged thrombin time (TT), no change to PTT or PT (not routinely monitored)
• Direct factor Xa inhibitors: prolonged PT and PTT, unchanged thrombin time (not routinely monitored)

Adverse effects

Warfarin

• Warfarin-induced skin necrosis
  • 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 (which protein C and S normally inactivate) → 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

Tip

Anticoagulants cause thrombosis, this can also be seen in HIT.

Warfarin reversal

Active hemorrhage (regardless of INR)

• Stop warfarin.
• Administer IV vitamin K PLUS 4-factor prothrombin complex concentrate (PCC)
  • If PCC is unavailable, give fresh frozen plasma (FFP)
• Monitor INR every 6 hours until warfarin has been fully reversed (INR ≤ 1.1)

Warfarin interactions

---

Warfarin is metabolized by cytochrome P450 (CYP) enzymes.

• 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

Bridging anticoagulation

• 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)
• Periprocedural bridging anticoagulation
  • Because the effect of coumarin can last several days, it is necessary to switch to heparins before surgery (preferably LMWH) to reduce the risk of intraoperative bleeding.
  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.