1. Warfarin inhibits vitamin K-dependent clotting factors II, VII, IX, and X, as well as anticoagulant proteins C and S. It takes 5 days for warfarin's effects to be fully realized due to the circulating clotting factors not initially being affected. 2. Warfarin is commonly used for indications like atrial fibrillation, venous thromboembolism, and mechanical heart valves. It requires careful dosing and monitoring of the INR to maintain therapeutic anticoagulation without bleeding risks. 3. Many drug and food interactions can affect warfarin levels by inhibiting or inducing its metabolism, requiring dosage adjustments based on INR monitoring. Close monitoring is

5. Coagulation cascade

6. Warfarin
Mechanism of Action of Warfarin ( VKA)
1. Inhibits vitamin K–dependent clotting factors II, VII, IX, and X
2. Inhibits anticoagulant proteins C and S
3. Racemic mixture of R- and S-isomers
a. S-isomer more potent vitamin K antagonist
b. S-isomer metabolized primarily by CYP2C9
c. R-isomer metabolized primarily by CYP3A4
It takes several days
(5 DAYS) for warfarin to
reach the therapeutic
effect since the circulating
coagulation factors are
not affected by the drug
so hospitalized patients
are usually given heparin
with warfarin initially, the
heparin covering the 3–5
day lag period and being
withdrawn after that

7. Indications

8. • TRIPLE THERAPY
• DUAL ANTIPLATELET THERAPY

10. for estimating the risk of stroke in patients with non-rheumatic atrial fibrillation

17. M.H. is a 63-year-old woman with a history of mechanical mitral valve replacement, hypertension,
and dyslipidemia. Her medications include warfarin 8 mg/day, aspirin 81 mg/day, lisinopril 20
mg/day, and atorvastatin 10 mg/day. Which one of the following best represents M.H.’s goal INR?
A. 1.5–2.5.
B. 1.8–2.6.
C. 2.0–3.0.
D. 2.5–3.5.
18. What if M.H. had an aortic mechanical valve (not a mitral valve replacement)? Which one of the
following would best represent M.H.’s goal INR?
A. 1.5–2.5.
B. 1.8–2.6.
C. 2–3.
D. 2.5–3.5.

18. A 77-year-old man has atrial fibrillation, hypertension, diabetes, and a history of transient
ischemic attack (TIA) 3 years ago. He will be undergoing major abdominal surgery in 1 week
and will need to hold his warfarin.
Which one of the following is the most appropriate LMWH bridge therapy for him?
A. No bridge LMWH is needed; just hold warfarin.
B. Enoxaparin 30 mg 2 times/day.
C. Enoxaparin 1 mg/kg 2 times/day.
D. Enoxaparin 30 mg 2 times/day or 1 mg/kg 2 times/day is an option.

19.  Overlap with heparin or therapeutic-dose LMWH for at least 5 days for acute venous
thromboembolism (VTE), to fully inhibit factor II, until INR is therapeutic for at least 24
hours.
Initial dose
a. Begin warfarin on day 1 (preferred) or day 2 of heparin or LMWH.
b. CHEST guidelines suggest initiating warfarin at 10 mg/day for the first 2 days, followed
by INR based dosing in patients healthy enough to be treated as outpatients (2C).
Otherwise, 5 mg/day is generally sufficient.
c. Specific patients may need a lower starting dose (5 mg/day or in some cases 2–3
mg/day) like elderly patient , liver disease , C.H.F, Concurrent use of drugs interacted with
warfarin
Dosing and Administration of Warfarin

20.  If INR is out of therapeutic range, increase or decrease cumulative weekly warfarin
dose by 5%–20% depending on INR; if INR is high, may hold one or two doses and
resume at a lower dose
 If INR previously stable/therapeutic and single out-of-range INR is 0.5 or less above or
below therapeutic range, current dose can be continued, and recheck INR within 1–2
weeks (2C)
 Generally, do not need to adjust if INR is within 0.1 of goal (but monitor more closely).
N.B CHEST guidelines recommend AGAINST bridging with LMWH/UFH for a single
subtherapeutic INR in a patient normally stable (2C).
 Some patients on long-term warfarin have a variable INR response that is not from
usual known causes
Dosing and Administration of Warfarin

21. • Bleeding: Epistaxis, hematuria, gastrointestinal hemorrhage,
bleeding gums…
• Skin necrosis (rare)
• Purple toe syndrome
• Teratogenic
Adverse Effects of Warfarin

22. 1. Reduced warfarin absorption (e.g., cholestyramine, sucralfate)
2. Enzyme induction (decreases INR and warfarin effects)
• CYP3A4 (e.g., rifampin, carbamazepine, phenobarbital, St. John’s wort)
• Other (e.g., griseofulvin, nafcillin, dicloxacillin, phenytoin [inhibition; then induction])
• Delay in onset and offset
3. Enzyme inhibition (increases INR and warfarin effects)
• S-warfarin* (CYP2C9) (e.g., metronidazole, trimethoprim/sulfamethoxazole,
fluconazole,isoniazid, fluoxetine, sertraline, amiodarone, clopidogrel, lovastatin)
• R-warfarin (CYP3A3/4/5) (e.g., omeprazole, clarithromycin, erythromycin, “azole”
antifungals, nefazodone, fluoxetine, amiodarone, cyclosporine, sertraline, grapefruit juice,
ciprofloxacin,norfloxacin, protease inhibitors, diltiazem, verapamil, isoniazid, metronidazole)
4. Antiplatelet effects (e.g., gingko, garlic, aspirin, (NSAIDs),selective serotonin reuptake
inhibitors); NSAIDs and aspirin also increase the risk of ulcers, providing a site from which to
bleed.

23. 5. Reduced clearance of warfarin (e.g., propafenone)
6. Increased degradation of clotting factors (e.g., levothyroxine)
7. CHEST guidelines recommend to avoid concomitant NSAIDs (including COX-2 inhibitors)
and antibiotics (see Table 8 in main article and add list) (2C). Antibiotics with evidence of
increased risk of bleeding: trimethoprim/sulfamethoxazole, quinolones, metronidazole,
cephalosporins, doxycycline, amoxicillin, and amoxicillin/clavulanate

25. Foods with Medium-High Vitamin K Content

26. May result in increased INR and a lower warfarin dose requirement
1. Malnourished/nothing by mouth
2. Recent major surgery
3. Chronic heart failure (especially acutely decompensated)
4. Liver disease
5. Hyperthyroid state (increased clearance of clotting factors) (opposite occurs in
hypothyroid state)
6. Prolonged fever (increased clearance of clotting factors)
7. Diarrhea

27. 1. Signs and symptoms of bleeding
a. Mild: Nosebleeds, bleeding gums, easy bruising
b. More severe (evaluation needed): Hematuria, hematemesis, hemoptysis, melena,
hematochezia, bright red blood per rectum
2. INR
a. In general, check INR within 1–2 weeks after dose adjustment and every 2 weeks until 2–3
consecutive therapeutic INRs; then testing can be done less frequently.
b. Previous CHEST guidelines recommended minimum INR testing frequency of every 4 weeks
(8th edition)
c. Latest CHEST guidelines (9th edition) state that if INR is consistently stable, suggest INR
testing frequency of up to 12 weeks (2B)

28. Warfarin: Pregnancy category X
a. If a woman receiving anticoagulation for VTE becomes pregnant, she should be
switched to LMWH (not UFH). Avoid dabigatran, rivaroxaban, and apixaban.
b. If a woman with a mechanical heart valve becomes pregnant:
Use adjusted-dose twice-daily LMWH or UFH throughout pregnancy OR
Use adjusted-dose twice-daily LMWH or UFH until 13th week of pregnancy; then switch
to warfarin; then switch back to LMWH or UFH close to delivery.
c. If a pregnant woman has an acute VTE, anticoagulants should be continued for at least 6
weeks postpartum (for a minimum total therapy duration of 3 months).
Use in lactation: Warfarin, LMWH, or UFH can be safely in breastfeeding; use these
rather than dabigatran, rivaroxaban, or apixaban.

29. 1. Discontinue warfarin around 5 days before surgery (1C), and perform the procedure
when the INR has normalized.
2. Test INR on day before surgery, if feasible. If INR is still elevated (1.5 or higher), could
administer low-dose (1–2 mg) oral vitamin K
3. Give last dose of LMWH 24 hours before surgery (2C) or intravenous UFH 4–6 hours
before surgery (2C). If once-daily LMWH is used, consider using half the dose for the last
dose before surgery.
4. Resume warfarin 12–24 hours after surgery (2C).
5. Resume subcutaneous LMWH (if using) and continue until warfarin is therapeutic;
restart LMWH in 24 hours after minor surgery and in 48–72 hours after major surgery/high
bleeding risk.

30. 6. LMWH is preferred over intravenous UFH for bridging anticoagulation. Subcutaneous
UFH was only studied in a few patients for bridging anticoagulation.
7. All bridging anticoagulation with LMWH is now full therapeutic dose; no more options
for prophylactic/low-dose LMWH for bridging
Bridging-dose subcutaneous LMWH:
i. Enoxaparin 1 mg/kg 2 times/day (1 mg/kg once daily if CrCl less than 30 mL/minute)
ii. Enoxaparin 1.5 mg/kg once daily
iii. Dalteparin 200 IU/kg once daily
iv. Dalteparin 100 IU/kg 2 times/day
v. Tinzaparin 175 IU/kg once daily
8. Decision to bridge is based on patient’s thromboembolic risk.
(Mechanical heart valve, A.F , VTE) depends on CHADS2 score
9. For most minor dental procedures (single- or multi-tooth extractions or root canal),
suggest continuing VKA, using oral pro-hemostatic agent (aminocaproic or tranexamic acid
mouthwash) or discontinuing VKA 2–3 days before procedure (2C).

31. 1. Patients with severe chronic kidney disease (CKD) (CrCl less than 30 mL/minute):
a. Enoxaparin is the LMWH best studied in CKD; preferred agent
b. If LMWH is used in patients who require LMWH, a reduction in the dose is recommended
(2C). Recommended to use 50% of the usual dose of enoxaparin (e.g., 1 mg/kg once daily for
therapeutic dose)
c. For prophylaxis, recommended enoxaparin dose is 30 mg once daily
d. Dosing uncertainties are avoided if UFH is used instead of LMWH.

32. 2. Obese patients:
a. LMWH weight-based dosing should be used, based on actual weight.
b. Has been suggested in patients with a body mass index greater than 40 kg/m2 to consider
monitoring antifactor Xa levels
c. Prophylactic enoxaparin dose in obesity is controversial: it has been suggested to consider
either giving 0.5 mg/kg subcutaneously every 12 hours or increasing the standard prophylaxis
dose by 25%.
d. Fondaparinux in obese patients (body weight more than 100 kg): dose at 10 mg
subcutaneously daily rather than the usual 7.5 mg/day (2C).

33. 1. Total hip arthroplasty or total knee arthroplasty: LMWH, fondaparinux, apixaban,
dabigatran, rivaroxaban, low-dose UFH, adjusted-dose VKA, or aspirin (all 1B) are
recommended for a minimum of 10–14 days.
 LMWH preferred over other agents. If patients decline injections, apixaban or dabigatran
(1B) are recommended over other agents. Rivaroxaban or VKA are recommended next.
2. Hip fracture surgery: LMWH, fondaparinux, low-dose UFH, adjusted-dose VKA, or aspirin
(all 1B) are recommended for a minimum of 10–14 days.
 LMWH preferred over other agents. If patients decline injections, apixaban or dabigatran
(1B) are recommended over other agents
N.B In patients undergoing major orthopedic surgery, suggest extending thromboprophylaxis in
the outpatient period for up to 35 days from day of surgery over 10–14 days (2B)

34. 1. Dabigatran (Pradaxa)
 FDA approved
 Oral direct thrombin inhibitor
 Indicated for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
 A 150-mg dose 2 times/day was superior to warfarin in preventing stroke/peripheral embolic events in
atrial fibrillation by 34% while reducing the risk of hemorrhagic stroke by 74%, with comparable major
bleeding rates; higher gastrointestinal bleeding (Connolly SJ, et al. RE-LY trial).
 (if CrCl 15–30 mL/minute: 75 mg 2 times/day). Assess renal function in all patients before starting therapy
and during therapy as clinically indicated.
 If possible, discontinue dabigatran 1–2 days (CrCl of 50 mL/minute or more) or 3–5 days (CrCl less than 50
mL/minute) before invasive or surgical procedures. Longer times should be considered for major or
spinal/epidural procedures.
 Contraindications: Active pathologic bleeding
 Drug interactions:. Avoid using dabigatran with P-glycoprotein (P-gp) inducers (e.g., rifampin), which reduce
exposure to dabigatran.

35. 2. Rivaroxaban (Xarelto)
a. FDA-approved oral direct factor Xa inhibitor
b. Indicated for the prophylaxis of VTE in patients undergoing total hip or knee replacement
surgery.
N.B studies show superiority to enoxaparin with no difference in major bleeding events.
Dose: 10 mg orally once daily; starting at least 6–10 hours after surgery
Duration: 35 days for hip replacement; 12 days for knee replacement
c. Indicated for the reduction of risk of stroke and systemic embolism in nonvalvular atrial
fibrillation. Dose: 20 mg orally once daily with evening meal; 15 mg once daily if CrCl 15–20 mL/
minute; avoid if CrCl less than 15 mL/minute
d. Contraindications: Active major bleeding, hypersensitivity, severe CKD, moderate-severe hepatic
impairment, or any hepatic disease associated with coagulopathy
Warnings and precautions: Bleeding- Moderate CKD (from CrCl 30 to less than 50 mL/minute)-
Spinal or epidural anesthesia (spacing between dosing of rivaroxaban and removal of epidural
catheter)
DDIS : avoid with P-gp and microsmal enzyme inducers & inhibitors

36. 3. Desirudin (Iprivask)
 FDA approved
 Specific inhibitor of human thrombin
 Indicated for the prophylaxis of DVT in patients undergoing elective hip replacement
surgery
 Dose: 15 mg subcutaneously every 12 hours; give initial dose 5–15 minutes before
surgery. Duration of up to 12 days has been well tolerated.
 Use with caution in patients with renal impairment (CrCl of 60 mL/minute or less).
 N.B Daily activated partial thromboplastin time (aPTT) and daily serum creatinine
monitoring are recommended in these patients.

37. Immunization
• Influenza vaccine
• Td/Tdap
• Varicella
• HPV
• Zoster
• MMR
• Pneumococcal
• Meningococcal
• Hepatitis A&B

38. Influenza vaccination
Annual vaccination against influenza is recommended for all persons 6 months of age and
older.
2 types of influenza vaccines:
1- live attenuated influenza vaccine(LAIV) – intra nasal
2- Trivalent inactivated vaccine(TIV) - intramuscular or intradermal
Persons 6 months of age and older(regardledd health conditions), pregnant women and
Health-care personnel who care for severely immunocompromised persons (i.e., those
who require care in a protected environment) should receive the trivalent inactivated
vaccine (TIV).
LAIV is licensed for use among nonpregnant persons aged 2-49 years; safety has not been
established in persons with underlying medical conditions that confer a higher risk for
influenza complications.

39. Tdap taken only once while Td could be taken several times
Administer a one-time dose of Tdap to adults younger than age 65 years who have not
received Tdap previously or for whom vaccine status is unknown
Tdap is specifically recommended for the following persons:
— pregnant women more than 20 weeks’ gestation,
— adults, regardless of age, who are close contacts of infants younger than age 12 months
(e.g., parents, grandparents, or child care providers), and
— health-care personnel.
Tdap can be administered regardless of interval since the most recent tetanus or
diphtheria-containing vaccine.
Pregnant women not vaccinated during pregnancy should receive Tdap immediately
postpartum.
Adults 65 years and older may receive Tdap.
Tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccination

40. Varicella vaccination
All adults without evidence of immunity to varicella (as defined below) should receive 2
doses of single-antigen varicella vaccine or a second dose if they have received only 1
dose.
Special consideration for vaccination should be given to those who
— have close contact with persons at high risk for severe disease (e.g., health-care personnel
and family contacts of persons with immunocompromising conditions)
— are at high risk for exposure or transmission (e.g., teachers; child care employees;
residents and staff members of institutional settings, including correctional institutions;
college students; military personnel; adolescents and adults living in households with
children; nonpregnant women of childbearing age; and international travelers).
 Pregnant women who do not have evidence of immunity should receive the first dose of
varicella vaccine upon termination of pregnancy and before discharge from the
healthcare facility

41. Human papillomavirus (HPV) vaccination (inactive)
Two vaccines are licensed for use in females, bivalent HPV vaccine (HPV2) and
quadrivalent HPV vaccine (HPV4),
HPV vaccine only for use in males (HPV4).
For females, either HPV4 or HPV2 is recommended in a 3-dose series for routine
vaccination at 11 or 12 years of age, and for those 13 through 26 years of age, if not
previously vaccinated.
For males, HPV4 is recommended in a 3-dose series for routine vaccination at 11 or 12
years of age, and for those 13 through 21 years of age, if not previously vaccinated.
HPV vaccines are not live vaccines and can be administered to persons who are
immunocompromised.
Although HPV vaccination is not specifically recommended for health-care personnel
(HCP) based on their occupation, HCP should receive the HPV vaccine if they are in the
recommended age group.

42. Zoster vaccination
A single dose of zoster vaccine is recommended for adults ≥60 years, regardless
of whether they report a prior episode of herpes zoster.
Could be used concomitant with pneumococcal vaccine (no interactions)
Although zoster vaccination is not specifically recommended for health-care
personnel (HCP), HCP should receive the vaccine if they are in the recommended
age group.

43. Measles, mumps, rubella (MMR) vaccination
2 doses : A routine second dose of MMR vaccine, administered a minimum of 28 days
after the first dose, is recommended for adults who are:
— students in postsecondary educational institutions.
— work in a health-care facility.
— plan to travel internationally.
Rubella:
• For women of childbearing age, regardless of birth year, rubella immunity should be
determined. If there is no evidence of immunity, women who are not pregnant should be
vaccinated.
• Pregnant women who do not have evidence of immunity should receive MMR vaccine
upon completion or termination of pregnancy and before discharge from the health-care
facility.

44. Taken for
— age ≥ 65 years and older without a history of PPSV vaccination
— adults younger than 65 years with certain criteria
 chronic lung disease (including chronic obstructive pulmonary disease, emphysema, and
asthma); chronic cardiovascular diseases;
 diabetes mellitus;
 chronic liver disease (including cirrhosis);
 alcoholism;
 cochlear implants;
 cerebrospinal fluid leaks;
 immunocompromising conditions;
 and functional or anatomic asplenia
 residents of nursing homes or long-term care facilities
 adults who smoke cigarettes.
Pneumococcal polysaccharide (PPSV) vaccination

45. Persons with asymptomatic or symptomatic HIV infection should be vaccinated as soon as
possible after their diagnosis.
When cancer chemotherapy or other immunosuppressive therapy is being considered,
the interval between vaccination and initiation of immunosuppressive therapy should be
at least 2 weeks.
Vaccination during chemotherapy or radiation therapy should be avoided.
One-time revaccination 5 years after the first dose is recommended for persons 19
through 64 years of age with chronic renal failure or nephrotic syndrome; functional or
anatomic asplenia (e.g., sickle cell disease or splenectomy); and for persons with
immunocompromising conditions.
Persons who received PPSV before age 65 years for any indication should receive another
dose of the vaccine at age 65 years or later if at least 5 years have passed since their
previous dose.
No further doses are needed for persons vaccinated with PPSV at or after age 65 years.

46. Meningococcal vaccination
MCV4 is preferred for adults with any of the preceding indications who are 55 years old
and younger; meningococcal polysaccharide vaccine (MPSV4) is preferred for adults 56
years and older.
Administer 2 doses of (MCV4) at least 2 months apart to adults with functional asplenia
or persistent complement component deficiencies.
HIV-infected persons who are vaccinated should also receive 2 doses.
Administer a single dose of meningococcal vaccine to microbiologists routinely exposed
to isolates of Neisseria meningitidis, military recruits, and persons who travel to or live in
countries in which meningococcal disease is hyperendemic or epidemic.
First-year college students up through age 21 years who are living in residence halls
should be vaccinated if they have not received a dose on or after their 16th birthday.
Revaccination with MCV4 every 5 years is recommended for adults previously vaccinated
with MCV4 or MPSV4 who remain at increased risk for infection (e.g., adults with
anatomic or functional asplenia or persistent complement component deficiencies).

47. Vaccinate any person seeking protection from hepatitis A virus (HAV) infection and
persons with any of the following indications:
— men who have sex with men and persons who use injection drugs;
— persons working with HAV-infected primates or with HAV in a research laboratory setting;
— persons with chronic liver disease and persons who receive clotting factor concentrates;
— persons traveling to or working in countries that have high or intermediate endemicity of
hepatitis A
— unvaccinated persons who anticipate close personal contact (e.g., household or regular
babysitting) with an international adoptee during the first 60 days after arrival in the United
States from a country with high or intermediate endemicity.
Hepatitis A vaccination

48. Vaccinate persons with any of the following indications and any person seeking
protection from hepatitis B virus (HBV) infection:
- sexual relations or HCP with STD patients
- health-care personnel and public-safety workers who are exposed to blood or other
potentially infectious body fluids;
- persons with diabetes younger than 60 years as soon as feasible after diagnosis;
- persons with diabetes who are 60 years or older increased need for assisted blood glucose
monitoring in long term care facilities, likelihood of acquiring hepatitis B infection
- persons with end-stage renal disease, including patients receiving hemodialysis; persons
with HIV infection; and persons with chronic liver disease;
- international travelers to countries with high or intermediate prevalence of chronic HBV
infection
- If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, give 3 doses at 0, 1,
and 6 months
Hepatitis B vaccination

49. Notes
• Varicella, zoster, MMR
contraindicated in pregnancy & immunocompromising
patients including HIV (CD4< 200)
• Meningococcal vaccine
For first-year college students, specific ages for vaccination
were added: those through age 21 years who are living in
residence halls should be vaccinated if they have not received
a dose on or after their 16th birthday.
• Human papillomavirus (HPV) vaccine.
HPV4 is now recommended for routine vaccination of males
at age 11–12, or at age 13–21 if not previously vaccinated,
and for ages 22–26 in certain high-risk groups if not
previously vaccinated (HIV-positive, immunocompromised, or
in men who have sex with men).

50. E.V. is a 71-year-old woman with COPD. Her only drug is tiotropium (Spiriva) inhaled 1
capsule/day. She received the influenza vaccine last October, her last Td vaccine was at age
65, and her pneumococcal polysaccharide vaccine (PPSV) was at age 60. She has a new
grandson (3 months old), whom she cares for while her daughter is at work. Which one of
the following is the most appropriate choice for vaccine(s) that should
be given at her October internal medicine clinic appointment?
A. Only the influenza vaccine should be given.
B. Influenza and PPSV vaccines should be given.
C. Influenza, PPSV, and zoster vaccines should be given.
D. Influenza, PPSV, zoster, and Tdap vaccines should be given.