Warfarin (Anticoagulant) - Complete Overview

1. Classification & Background

2. Mechanism of Action

1. Vitamin K (from diet) is reduced to vitamin K hydroquinone (active form) by vitamin K reductase
2. Vitamin K hydroquinone acts as a cofactor for gamma-glutamyl carboxylase, which adds a carboxyl group to glutamic acid residues on clotting factors (gamma-carboxylation)
3. This gamma-carboxyglutamic acid modification is essential - it allows calcium-dependent binding of clotting factors to anionic phospholipid surfaces (the site of coagulation)
4. During this process, vitamin K hydroquinone is oxidized to vitamin K epoxide, which is recycled back to reduced vitamin K by vitamin K epoxide reductase (VKOR)

Key point: The onset of action is delayed (72-96 hours) because warfarin does not neutralize already-circulating clotting factors. It must wait for the existing active factors to be cleared. The antithrombotic effect specifically requires depletion of factor X (t½ = 24 h) and prothrombin (t½ = 72 h).

3. Pharmacokinetics

4. Therapeutic Uses

• Atrial fibrillation - stroke prevention
• DVT and PE - treatment and prevention of recurrence
• Prosthetic heart valves (mechanical valves require lifelong anticoagulation)
• Venous thromboembolism prophylaxis post-orthopedic surgery
• Protein C/S deficiency and antiphospholipid syndrome

5. Monitoring: INR

• Stable patients: INR every 3-4 weeks
• Any new medication added: more frequent monitoring required
• The INR reflects the extrinsic pathway (factors II, VII, X)

6. Dosing

• Typical starting dose: 2-5 mg/day orally (individual variation is large)
• Bridging therapy: Because of the delayed onset, patients with established thrombosis or high thromboembolic risk require concomitant parenteral anticoagulation (heparin, LMWH, or fondaparinux) for at least 5 days until INR is therapeutic
• Doses are adjusted based on INR response, genetics, and interacting drugs

7. Genetics and Pharmacogenomics

• CYP2C9*2 and 2C93 encode enzymes with reduced activity
• ~25% of Caucasians carry at least one variant allele
• Heterozygous carriers need 20-30% dose reduction; homozygous carriers need 50-70% reduction
• Variant carriers have ~2x higher bleeding risk

• Account for ~30% of warfarin dose variability
• Higher prevalence in Asians > Caucasians > African Americans
• A/A haplotype carriers require the lowest doses

8. Drug Interactions

• Broad-spectrum antibiotics (reduce gut vitamin K-producing bacteria)
• Fluconazole, metronidazole, amiodarone (CYP2C9 inhibitors)
• Aspirin / NSAIDs (additive bleeding risk + displace warfarin from albumin)
• Sulfonamides (displace warfarin from albumin binding site)

• Rifampicin, carbamazepine, phenytoin (CYP inducers)
• Cholestyramine (reduces warfarin absorption)

• Vitamin K-rich foods (green leafy vegetables, broccoli, spinach) reduce warfarin efficacy
• Grapefruit can inhibit CYP metabolism
• Patients should be counseled to maintain consistent dietary vitamin K intake rather than eliminate it

9. Adverse Effects

10. Management of Elevated INR / Bleeding

Note: High-dose vitamin K (5-10 mg) may cause temporary resistance to warfarin when it is restarted.

11. Reversal Agent

• Vitamin K (phytomenadione) is the primary antidote
• Oral vitamin K takes ~24 hours to work (requires degradation of existing clotting factors, then resynthesis)
• IV vitamin K acts faster (~6-12 hours)
• 4-factor PCC (factors II, VII, IX, X) provides immediate reversal for emergencies
• FFP can also be used if PCC is unavailable

12. Special Situations

13. Comparison: Warfarin vs DOACs

• Harrison's Principles of Internal Medicine, 22nd Ed. (2025), Chapter 123, p. 994-996
• Braunwald's Heart Disease, Chapter 95
• Lippincott Illustrated Reviews: Pharmacology, Chapter 13, p. 458-461
• Goodman & Gilman's Pharmacological Basis of Therapeutics

Hematinics - Complete Overview

Classification of Hematinics

I. IRON

Iron Metabolism and Physiology

• ~80% is in hemoglobin, myoglobin, and iron-containing enzymes (catalase, cytochromes)
• ~15-20% is in storage form as ferritin and hemosiderin (primarily in macrophages of liver, spleen, bone marrow)
• Transport form: iron is carried in plasma bound to transferrin (normally ~33% saturated)

• Serum iron: ~120 µg/dL (men), ~100 µg/dL (women)
• Total iron-binding capacity (TIBC): 300-350 µg/dL

Iron Absorption

1. Ferric iron (Fe³⁺) is reduced to ferrous iron (Fe²⁺) by duodenal cytochrome B (a ferric reductase)
2. Fe²⁺ enters the enterocyte via DMT-1 (divalent metal transporter-1) on the apical membrane
3. Iron exits the enterocyte into plasma via ferroportin on the basolateral membrane
4. Iron is re-oxidized to Fe³⁺ by hephaestin/ceruloplasmin before binding transferrin

• A small peptide secreted by the liver
• Negatively regulates ferroportin - when hepcidin is high, ferroportin is degraded, trapping iron in enterocytes and macrophages
• High in inflammation (IL-6 stimulus) → explains anemia of chronic disease
• Low in iron deficiency and high erythroid demand (erythroferrone from erythroblasts suppresses hepcidin)

Iron Deficiency Anemia

• Chronic blood loss (most common in developed countries - GI: peptic ulcer, colon cancer; or menorrhagia)
• Poor dietary intake (most common in developing countries)
• Increased demand (pregnancy, infancy)
• Malabsorption (celiac disease, gastrectomy)

1. Depletion of iron stores → falling serum ferritin, absent bone marrow iron
2. Fall in serum iron + rise in TIBC (transferrin rises to compensate)
3. Microcytic hypochromic anemia

• Low serum ferritin (most sensitive early marker)
• Low serum iron, high TIBC, low transferrin saturation
• Peripheral smear: microcytic, hypochromic RBCs
• Thrombocytosis (platelet count often elevated)

Treatment: Oral Iron

• Ferrous salts (Fe²⁺) are absorbed ~3x better than ferric salts (Fe³⁺)
• Ferrous sulfate: 325 mg tablet = 65 mg elemental iron; typical dose 150-200 mg elemental iron/day
• Other ferrous salts (fumarate, gluconate, succinate) are absorbed to approximately the same extent - the dose is based on elemental iron content

Oral iron delivers at most 40-60 mg of iron/day to the erythroid marrow with tolerable doses.

• Vitamin C (ascorbic acid) - reduces Fe³⁺ to Fe²⁺
• Acidic environment (take on empty stomach if tolerated)
• Heme iron

• Phytates (grains, bran), tannins (tea, coffee)
• Calcium, antacids, proton pump inhibitors
• Tetracyclines, fluoroquinolones (form chelates)

• Reticulocytosis expected within 4-7 days
• Hemoglobin rise of 2 g/dL or more within 4 weeks = adequate response
• Treatment should continue for 3-6 months after normalization to replenish stores

Parenteral Iron

• Ferric carboxymaltose, iron sucrose, low-molecular-weight iron dextran, ferumoxytol
• Indicated for: malabsorption, chronic blood loss exceeding oral absorption capacity, non-compliance, IBD
• Risk of anaphylaxis (lower with newer preparations); always have resuscitation available
• Can deliver complete iron deficit in 1-2 infusions

II. VITAMIN B12 (Cobalamin)

Biochemical Roles

• Converts homocysteine → methionine (using methyltetrahydrofolate as methyl donor)
• This reaction is critical for folate recycling: it regenerates tetrahydrofolate (THF) for DNA synthesis
• Lack of B12 "traps" folate as methylTHF (the methyl-trap hypothesis), explaining why B12 deficiency causes megaloblastic anemia

• Converts methylmalonyl-CoA → succinyl-CoA
• Deficiency → accumulation of methylmalonic acid (MMA) - a diagnostic marker for B12 deficiency

Absorption of Vitamin B12

1. Dietary B12 is released from food protein by gastric acid and pepsin
2. B12 binds haptocorrin (R-protein) in stomach
3. In duodenum, pancreatic enzymes degrade haptocorrin
4. B12 binds intrinsic factor (IF) secreted by gastric parietal cells
5. B12-IF complex is absorbed in the terminal ileum via cubilin receptors

Deficiency - Causes

• Pernicious anemia (PA) - autoimmune destruction of gastric parietal cells → no IF → B12 malabsorption (most common cause in adults >40 yrs; 90% have anti-parietal cell antibodies, 60% anti-IF antibodies)
• Total or partial gastrectomy
• Terminal ileum disease (Crohn's, ileal resection)
• Strict vegan diet (no animal products)
• Medications: metformin, PPIs, nitrous oxide (oxidizes B12)
• Bacterial overgrowth, tapeworm (Diphyllobothrium latum)
• Pancreatic insufficiency

Clinical Features of B12 Deficiency

• Hematological: Macrocytic (megaloblastic) anemia, hypersegmented neutrophils (>5 lobes), macroovalocytes, pancytopenia
• Neurological (unique to B12, not folate):
  • Subacute combined degeneration of the spinal cord (posterior columns + lateral corticospinal tracts)
  • Peripheral neuropathy, paresthesias, ataxia, cognitive impairment
  • Neurological damage may be irreversible if not treated promptly
• Other: Glossitis, jaundice, hyperpigmentation of skin creases

Diagnosis

• Low serum B12 (<200 pg/mL)
• Elevated methylmalonic acid (MMA) - most sensitive and specific
• Elevated homocysteine (also elevated in folate deficiency)
• Anti-IF antibodies (specific for pernicious anemia)

Key distinction: MMA is elevated only in B12 deficiency; homocysteine is elevated in BOTH B12 and folate deficiency.

Treatment

• IM cyanocobalamin 1000 µg/day x 7 days, then 1000 µg/week x 4 weeks, then 1000 µg/month for life

• High-dose oral cyanocobalamin 1000-2000 µg/day (passive absorption bypasses need for IF)

Warning: Do NOT treat B12 deficiency with folic acid alone - it will correct the anemia but allow neurological damage to progress undetected.

III. FOLIC ACID

Biochemical Roles

• Thymidylate synthesis: 5,10-methyleneTHF donates a methylene group to dUMP → dTMP (rate-limiting step in DNA synthesis)
• Purine synthesis: formyl-THF donates carbon atoms to the purine ring
• Methionine synthesis: with B12 as cofactor (homocysteine → methionine)

Sources and Requirements

• Rich dietary sources: fresh green vegetables (spinach, broccoli), liver, yeast, citrus fruits
• Daily requirement: ~200 µg/day (400 µg/day in pregnancy)
• Body stores: ~3-5 months (depleted much faster than B12, which lasts 3-5 years)
• Cooking destroys up to 90% of dietary folate

Deficiency - Causes

• Malnutrition (alcoholism, poverty, elderly, psychiatric patients)
• Pregnancy/lactation (3-4x increased daily requirements)
• Malabsorption (celiac disease, bariatric surgery)
• Drugs that block folate: methotrexate, trimethoprim, pyrimethamine, phenytoin, sulfasalazine, ethanol
• Increased demand: hemolytic anemia (sickle cell, thalassemia), rapid cell turnover

Clinical Features

• Macrocytic megaloblastic anemia (identical to B12 deficiency on blood film)
• Hypersegmented neutrophils
• Glossitis
• No neurological involvement (this is the key distinguishing feature from B12 deficiency)
• Neural tube defects in the fetus (if mother deficient in early pregnancy)

Treatment

• Folic acid 1 mg/day PO (5 mg/day in malabsorption)
• Duration: until deficiency corrected (usually 4 months)
• Prevention of neural tube defects: 400-800 µg/day before conception and during first trimester
• High-risk groups (hemolytic anemia, dialysis): ongoing supplementation

IV. ERYTHROPOIESIS-STIMULATING AGENTS (ESAs)

• Anemia of chronic kidney disease (CKD)
• Chemotherapy-induced anemia
• Anemia in HIV patients on zidovudine
• Low-grade myelodysplastic syndrome

• Always ensure adequate iron stores before/during ESA therapy (functional iron deficiency is a common cause of ESA resistance)
• Target hemoglobin: < 11 g/dL - treatment to higher levels increases risk of cardiovascular events and stroke
• Common adverse effects: hypertension, thromboembolic events, bone pain (with G-CSF)

Summary Comparison Table

• Goodman & Gilman's Pharmacological Basis of Therapeutics, Chapter 45
• Robbins & Kumar Basic Pathology, Chapter 10
• The Washington Manual of Medical Therapeutics
• Harrison's Principles of Internal Medicine, 22nd Ed.