Coagulation Disorders and Anticoagulants

Coagulation Disorders

• Coagulation disorders are conditions that affect the process of blood clotting.
• The coagulation cascade is a series of reactions that lead to the formation of a blood clot.
• The intrinsic pathway and extrinsic pathway are two main pathways in the coagulation cascade.
  • Intrinsic pathway is activated by factors within the blood itself.
  • Extrinsic pathway is activated by tissue factors outside the blood.
• Heparin (LMWH) enhances antithrombin activity and thereby regulates clot formation.
• Thrombin (factor IIa) converts fibrinogen to fibrin.
• Factors like Factor Xlla (activated factor II) and Factor Xa (activated factor X) are essential steps in the cascade, leading to thrombin formation and clot formation.

Drugs that Prevent Coagulation (Anticoagulants)

• Parental Anticoagulants

  • Heparin (fractionated and unfractionated): A natural occurring substance with negative charge. Not administered orally. Cannot cross BBB and placenta. It activates antithrombin III, inhibiting clotting factor X and thrombin (factor II). Its onset and duration are immediate and short (2-4 hours).
  • Direct thrombin inhibitors (e.g., Bivalirudin): Synthetic hirudin analogue and is reversible and short acting. It's used as an alternative to heparin for treating heparin-induced thrombocytopenia.
  • Factor Xa inhibitors (e.g., Fondaparinux): Synthetic polysaccharide, acting similarly to LMWH by inhibiting factor Xa. Administered as a subcutaneous (SC) injection once daily.

• Oral Anticoagulants

  • Warfarin: A synthetic coumarin compound that inhibits the formation of active vitamin K. It reduces the synthesis of vitamin K-dependent clotting factors (II, VII, IX, and X). Onset is delayed (3-7 days). Primarily used for in vivo anticoagulation.
  • New oral anticoagulants (NOACs): These are direct thrombin inhibitors (e.g., dabigatran) or factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban).
    • NOACs are easier to control and administer, do not require regular monitoring, effective and safe.

Low-molecular-weight heparins (LMWH)

• LMWH has a low molecular weight, which makes it specific for factor X, (higher anti-Xa: Ila ratio) and minimizes effects on other factors.
• Enoxaparin is a common example of an LMWH.

Standard Heparin Vs LMWH

• Standard heparin has a higher molecular weight compared to LMWH.
• Standard heparin is less specific for factor Xa compared to LMWH.
• LMWH has higher bioavailability after SC injection compared to standard heparin.
• LMWH has a longer half-life than standard heparin.
• Standard heparin primarily cleared by the liver, while LMWH excretion is primarily through the kidneys.
• Thrombocytopenia is more common with standard heparin than LMWH.
• Bleeding risk is lower with LMWH compared to standard heparin.

IV Direct Thrombin Inhibitors

• Bivalirudin is a synthetic hirudin analog, a reversible, short-acting DTI.
• It's used as an alternative to heparin in treating heparin-induced thrombocytopenia (HIT).
• Bleeding is the major side effect; no antidote is available.

Factor Xa Inhibitors

• Fondaparinux is a synthetic polysaccharide with a similar mechanism to LMWH, inhibiting factor Xa.
• It's administered subcutaneously once daily.

Oral Anticoagulants - Warfarin

• Warfarin is a synthetic coumarin compound that prevents the production of vitamin K-dependent clotting factors (II, VII, IX, and X).
• Its action is antagonized by vitamin K administration.
• Warfarin's effects take 3-7 days to fully manifest.

Warfarin - Monitoring and Therapeutic Uses

• Warfarin's therapeutic efficacy is monitored using the prothrombin time (PT) or International Normalized Ratio (INR).
• Prevention and treatment of venous/arterial thrombosis and embolization. Prevention and treatment of artificial heart valves and AF (atrial fibrillation).

Warfarin - Adverse Effects

• Bleeding is a main side effect, with Vitamin K as the antidote.
• Warfarin can cross the placenta, posing risks to the fetus.
• CNS (central nervous system) hemorrhage is a possible side effect.
• Teratogenicity (malformation during pregnancy) is a concern.
• Sudden warfarin withdrawal can cause thrombotic issues, skin necrosis and hepatotoxicity (liver damage).

Drug Interactions of Warfarin

• Certain medications can increase or decrease warfarin's anticoagulant activity.
  • Microsomal enzyme inhibitors (e.g., cimetidine, amiodarone) decrease metabolism of Warfarin, increasing its effects.
  • Microsomal enzyme inducers (e.g., phenytoin, barbiturates) increase warfarin metabolism reducing its effects.
  • Some antibiotics also reduce the production of vitamin K in the gut, impacting warfarin action.
• Certain drugs, like liquid paraffin, can reduce vitamin K absorption.
• Aspirin and fibrates can displace warfarin from plasma protein binding sites, increasing its effect.

Changing Therapy from Heparin to Warfarin

• Warfarin therapy can be initiated concurrently with heparin, but heparin needs to be continued for a minimum of four days.
• Time to peak antithrombotic effect with Warfarin takes 96 hours.
• Discontinue heparin once warfarin's INR reaches the desired therapeutic range.

Warfarin Overdose Treatment

• Stopping warfarin may suffice in some cases.
• Fresh frozen plasma or clotting factors can rapidly reverse major bleeding but have a short duration.
• Vitamin K reverses warfarin's effects more slowly.

New Oral Anticoagulants (NOACs)

• NOACs are a newer generation of oral anticoagulants with various mechanisms, including direct thrombin inhibitors (e.g., dabigatran) and factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban).
• Generally, once daily constant doses, predictable kinetics, and fewer drug interactions are advantages of NOACs compared to warfarin.

Warfarin Problems

• Warfarin's dosage can fluctuate due to dietary or drug interactions.
• Warfarin's narrow therapeutic index dictates careful monitoring.

Advantages of New Anticoagulants

• Constant, once-daily dosage.
• Predictable kinetics and anticoagulant effect.
• Fewer drug interactions than warfarin.

Oral Direct Thrombin Inhibitors (e.g., Dabigatran)

• Dabigatran is the first oral direct thrombin inhibitor (DTI) approved by the FDA.
• It was superior to warfarin in preventing stroke and thromboses in patients with nonvalvular atrial fibrillation.
• Primarily excreted through the kidneys (80%), so contraindicated in renal failure.
• Dyspepsia, gastritis, and higher gastrointestinal bleeding rates are potential adverse effects.

Factor Xa Inhibitors (e.g., Rivaroxaban, Apixaban)

• Oral factor Xa inhibitors (e.g., rivaroxaban, apixaban) are suitable for preventing venous thromboembolism and stroke in patients with nonvalvular atrial fibrillation.
• They are metabolized by CYP3A4 and are contraindicated in hepatic or renal disease.
• Intracranial hemorrhage risk is lower than with warfarin, while gastrointestinal bleeding risk is greater.
• Andexanet alfa is the antidote.