mechanical heart valve anticoagulation guidelines Guide to Warfarin Therapy In cardiac surgery

1. Warfarin
Guide to Warfarin
Therapy
In cardiac surgery

2. Directed by
DR.Karar .A.Ali
department of cardiothoracic surgery
kararbenign@gmail.com

4. Which foods are high in vitamin K?
Foods high in vitamin K include:
* green leafy vegetables, including broccoli, spinach,
kale, cabbage and lettuce
* avocado
* olive oil
* chickpeas
* liver
* egg yolks
* wholegrain cereals
* mature cheeses
Don’t avoid foods high in vitamin K as you
need it for a healthy diet.
Aim for a healthy stable diet with:
* lots of different types of food
* roughly the same amount of dark leafy green
vegetables and other food high in vitamin K
per week
Alcohol
Alcohol can affect the way warfarin works. Avoid
heavy or binge drinking while taking warfarin.
Talk with your clinician about how much alcohol you
can drink

5. Some common signs and symptoms of unusual bleeding
include:
* unexpected bleeding or bleeding that lasts a long time (this
includes nose bleeds, bleeding from your gums, bleeding from
cuts and scrapes, and/or menstrual periods)
* severe unexplained bruising or bruising that gets bigger
* red or dark urine
* red or black bowel motions
* coughing blood
* dark or blood-stained vomit
* severe headache or dizziness
* unexplained new pain, swelling or discomfort.

6. Pregnancy
Warfarin use in the first three months of pregnancy
may cause abnormalities in the baby known
as fetal warfarin syndrome. Later in pregnancy,
exposure to warfarin can increase bleeding risk
in the baby Breastfeeding
Very low milk levels of warfarin are detected in
breastmilk. No problems have been observed
in infants whose mothers were treated with
warfarin. Warfarin is considered safe to use
with breastfeeding.

7. Warfarin can be taken before, with or after a meal.
The time you take warfarin needs to fit into
your daily routine. Taking your dose with your
evening meal is recommended. If an evening
dose doesn’t suit you, talk to your clinician

9. rapid and widespread adoption of trans- catheter valve technology has
overshadowed progress in other areas of management of patients with valvular
heart disease. This is particularly true for antithrombotic therapy for mechanical
prostheses, which have an important role for young patients with unrepairable
mitral and aortic valves, who may choose this prosthesis because of its durability
and the likelihood of improved late survival compared with outcomes with other
valve types. But, understanding the liabilities of systemic anticoagulation and risks of
thrombotic complications is confusing territory for most patients and for many
clinicians. For example, at a valve conference, an experienced cardiologist when
asked which aortic
prosthesis he would recommend for a 60-year-old patient replied that a biological
valve would be preferred over a mechanical valve because it has a
lower risk of thromboembolism. This, of course, is not true, because there is no
difference in rates of thromboembolism between patients with mechanical
prostheses receiving warfarin anticoagulation and patients with stented aortic
bioprostheses

10. Thrombotic obstruction is an uncommon but
important late complication of prosthetic heart
valves, and with older prosthesis models with a
single tilting disc, thrombosis of left-sided valves
often led to rapid hemodynamic deterioration and
acute presentation with pulmonary edema

12. Management of mechanical valve thrombosis is
complex and depends on many factors, including
valve position (right- vs left-sided), acuity of presentation, adequacy of and
compliance with anticoagulation, thrombophilia, or other conditions that
might affect the risk of thrombolytic therapy or surgery.
Thrombolytic therapy, when successful, has
obvious advantages for the patient compared with
reoperation for thrombectomy or prosthetic replacement. But
thromboembolism including embolic
stroke has been reported in as many as 15% of patients with left-sided
valve thrombosis receiving streptokinase or tissue plasminogen
activator.1,2 Further, thrombolytic therapy was associated with
hemorrhagic complications in approximately 5% of
patients

13. To address these problems, Özkan et al3 have
refined regimens for the administration of tPA, and
the essential features of their protocol include slow or
ultraslow infusion without an initial bolus, avoidance
of heparin during tPA administration, and echocardiographic
surveillance. The TROIA (Comparison of
Different TRansesophageal Echocardiography Guided
thrOmbolytic Regimens for prosthetIc vAlve Thrombosis) trial
reported equivalent success (83%) of
streptokinase and tPA with various infusion regimens, but the
overall complication rate was dramatically lower with slow
infusion of tPA compared with
other protocols (10% vs 30%-38%).

14. During slow infusion, 25 mg of tPA was administered over 6 hours
without a bolus loading dose, and was repeated once 24 hours
later and up to 6 times for a maximum total
dose of 150 mg if needed. Remarkably, there were no
deaths in the initial cohort of 124 patients receiving
the slow infusion protocol.3
The low-dose slow (6-hour) infusion of tPA was also used
successfully to
manage prosthetic valve thrombosis during pregnancy, and among
24 women with 28 episodes of
valve thrombosis, thrombolytic therapy successfully
relieved thrombotic obstruction in all patients with
no mortality and 80% fetal survival

15. In a subsequent trial of 114 patients with obstructive
or nonobstructive ($10 mm) valve thrombosis, tPA
was administered even more slowly, 25 mg over 25
hours, and repeated as needed until thrombus
resolution or until the patient received a total dose of
150 mg.5 In this study, the ultraslow tPA protocol was
successful in 90% of patients, with only 1 death and a
nonfatal major complication rate of 3%.

16. The excellent results of the slow and ultraslow protocols
for thrombolysis have been seen in smaller series, and
these results inform the recommendation of American
College of Cardiology/American Heart Association
guidelines on valvular heart disease, which state that
fibrinolysis is an acceptable alternative to reoperation
in patients with valve thrombosis and mild symptoms,
small thrombus burden, and low bleeding risk and in
those patients with particularly high surgical risk.

18. The current HATTUSHA study addresses several
issues regarding the controversy of initial thrombolytic therapy or
reoperation for mechanical valve
thrombosis. The study investigated 158 patients with
obstructive PVT patients from 8 centers, and it
compared outcomes of 75 patients who had reoperation for valve
thrombectomy or replacement with 83
patients who received tPA with the slow and/or ultraslow infusion protocol.
Although nonrandomized,
the patients were considered eligible for either
treatment and had generally similar clinical characteristics. Thrombolytic
therapy was successful in 90%
of patients and was associated with a lower 3-month
mortality (2.4% vs 18.7%) and reduced risks of major
bleeding (2.4% vs 9.3%) and thromboembolism (2.4%
vs 5.3%) compared with reoperation

19. Reoperation for valve thrombectomy or replacement
will be necessary for patients with cardiogenic shock,
patients with associated pannus underlying thrombus
formation, as well as patients with contraindications
to thrombolysis including left atrial clot. However,
the data from the HATTUSHA study as well as previous
clinical reports from Dr Özkan and his team
establish the effectiveness and relative safety of slow
and/or ultraslow tPA infusion, which should be
offered to most eligible patients with thrombotic
obstruction of mechanical valves.

22. A 55 year old woman with severe aortic stenosis
underwent valvereplacement with amechanical
valve.She has been started on warfarin and is
maintaining an international normalised ratio (INR)
within the target range of 2.0-3.0. She finds
monitoring INR levels cumbersome. She has heard
about newer direct oral anticoagulants and asks if
she can switch to one of
these

23. Mechanical heart valves are preferred in patients
under 65.3 Bioprosthetic valves do not require
lifelong anticoagulation but have a greater rate of
primary failure and are associated with a higher
reoperation rate. They last only 10 to 15 years
compared with 20 to 30 years for mechanical heart
valves.

24. What is warfarin?
Warfarin is a vitamin K antagonist. Other drugs in
this group are acenocoumarol and dicoumarol.
Warfarin inhibits the synthesis of the vitamin K
dependent clotting factors II, VII, IX, and X (fig 1),
and also proteins C and S. Vitamin K antagonists are
the only anticoagulants licensed for use in patients
with mechanical heart valves. Among these, warfarin
is most commonly prescribed. Most of the available
evidence for patients with mechanical heart valves
relates to the use of warfarin.

27. What are the harms?
The main risk is haemorrhage. Between 2% and 5% of patients on
warfarin experience major bleeding annually, which can be
potentially life threatening. The yearly incidence of intracranial
bleeding is 0.2%-0.4% and 0.5%-1.0% for fatal bleeding.8 An INR
over the therapeutic range is the most important risk factor.
Age over 75, hypertension, previous stroke, co-prescription of
antiplatelet drugs, and a history of bleeding increase this risk.9
Discontinuation and/or reversal of anticoagulation need an
individual evaluation of the risk of further bleeding against that of
clotting or embolism.9Figure 2 gives an approach for managing
bleeding or a high INR in patients with mechanical heart valves.10

29. How is warfarin given and monitored?
Warfarin is given orally once daily. Monitor INR daily until the
therapeutic target is achieved. Table 1 lists recommended INR
targets for patients with mechanical heart valves. European,
US, and NICE recommendations vary, indicating areas of
continuing uncertainty and likely reflecting a lack of high
quality evidence.11 12 Gradually increase the monitoring
interval to weekly, fortnightly, and monthly if INR is stable.
Patients with mechanical mitral valves usually require higher
doses of warfarin as the risk of embolism is higher than that
with mechanical aortic valves. Box 1 gives information
for patients on taking warfarin

32. Antiplatelet agents
The addition of low dose aspirin (less than 100 mg daily) or
dipyridamole to warfarin further reduces the risk of thromboembolic
events such as transient ischaemic attack or stroke (odds ratio (OR)
0.43, 95% confidence interval (CI) 0.32, 0.59, P<0.001) and total
mortality (OR 0.57, 95% CI 0.42, 0.78, P<0.001) in patients with
mechanical heart valves, as per a Cochrane review (13 randomised
controlled trials, 4122 participants). The risk of major bleeding is
increased by just over 50% (OR 1.58, 95% CI 1.14, 2.18, P=0.006) but
this may be lower with low dose aspirin. The quality of evidence is
low. The authors concluded that low dose aspirin could safely be
added to warfarin with an acceptable risk of bleeding.15 The US
guidelines endorse this view,2 whereas the European guidelines
only recommend the addition of antiplatelet agents in certain
clinical settings (table 1).1 NICE guidelines suggest an increase in
the INR target or adding an antiplatelet drug if an embolic event
occurs while anticoagulated at the target INR.4 The dose of warfarin
must be carefully regulated with a target INR in the lower part of
the recommended range, when an antiplatelet drug is added.

33. What are special considerations in patients undergoing
surgery?
Interrupting oral anticoagulation is not required for most minor
surgical procedures (including dental extraction and cataract
removal) where bleeding is easily controlled. Patients undergoing
major non-cardiac surgery will need transient cessation of oral
anticoagulation to allow the INR to fall to <1.5
Warfarin is usually stopped three to four days before surgery and
restarted 12-24 hours after surgery. Bridging is used to reduce
thromboembolic events during temporary interruption of oral
anticoagulation in higher risk patients, such as those with a
thromboemboliceventwithinthelastthreemonths,atrialfibrillation
with previous stroke or transient ischaemic attack, or a mitral
mechanical valve.4 Unfractionated heparin has long been the
bridging anticoagulant of choice, though observational data suggest
that low molecular weight heparin (LMWH) is as effective and no
more likely to cause bleeding (except in patients with chronic kidney
disease)

34. Bridging is started when the INR falls below the
therapeutic threshold, usually 36-48 hours before surgery. It is
stopped four to six hours (for intravenous unfractionated heparin)
or 24 hours (for LMWH) before the procedure.2
For emergency non-cardiac surgery or invasive procedures, fresh
frozen plasma or prothrombin complex concentrate may be
administered. Intravenous vitamin K can be given if surgery can be
delayed for 6-12 hours to reverse the anticoagulant effect of
warfarin

36. Conclusions
The initiation of warfarin at a 5 mg dose in MVR patients was more
efficacious than the 3 mg dose in terms of time to reach the target INR.
Moreover, the cost of enoxaparin bridging was significantly reduced with a 5
mg warfarin initiation dose. Bleeding events were comparable.

37. CONCLUSIONS AND RELEVANCE
Among Asian patients in this study, the incidence of
thromboembolic events in the MVR group with INRs in the range of 2.0 to
2.5 was not significantly
higher than that among those with INRs in the range of 2.5 to 3.0; in the
AVR group, the incidence for
those with INRs in 1.5 to 2.0 range was not significantly higher than for
those with INRs in the range
of 2.0 to 2.5.

38. Warfarin, sold under the brand name Coumadin
among others, is a medication that is used as an
anticoagulant (blood thinner).[6] It is commonly used
to prevent blood clots such as deep vein thrombosis
and pulmonary embolism, and to prevent stroke in
people who have atrial fibrillation, valvular heart
disease or artificial heart valves.[6] Less commonly it
is used following ST-segment elevation myocardial
infarction (STEMI) and orthopedic surgery.

39. The common side effect is bleeding.[6] Less common side
effects may include areas of tissue damage and purple
toes syndrome.[6] Use is not recommended during
pregnancy.[6] It is recommended that the effects of
warfarin typically be monitored by checking
prothrombin time (INR) every one to four weeks.[6]
Many other medications and dietary factors can interact
with warfarin, either increasing or decreasing its
effectiveness.[6][7] The effects of warfarin may be
reversed with phytomenadione (vitamin K1), fresh
frozen plasma, or prothrombin complex concentrate

40. Warfarin-
induced
purple toe
syndrome
successfull
y treated
with
apixaban

41. • Medical uses
• Warfarin is used to decrease the tendency for thrombosis, or as secondary
prophylaxis (prevention of further episodes) in those individuals who have
already formed a blood clot (thrombus). Warfarin treatment can help prevent
formation of future blood clots and help reduce the risk of embolism (migration
of a thrombus to a spot where it blocks blood supply to a vital organ).[18]
• Warfarin is best suited for anticoagulation (clot formation inhibition) in areas of
slowly running blood (such as in veins and the pooled blood behind artificial and
natural valves), and in blood pooled in dysfunctional cardiac atria. Thus, common
clinical indications for warfarin use are atrial fibrillation, the presence of artificial
heart valves, deep venous thrombosis, and pulmonary embolism (where the
embolized clots first form in veins). Warfarin is also used in antiphospholipid
syndrome. It has been used occasionally after heart attacks (myocardial
infarctions), but is far less effective at preventing new thromboses in coronary
arteries. Prevention of clotting in arteries is usually undertaken with antiplatelet
drugs, which act by a different mechanism from warfarin (which normally has no
effect on platelet function).[19] It can be used to treat people following ischemic
strokes due to atrial fibrillation, though direct oral anticoagulants (DOACs) may
offer greater benefits

42. • Contraindications
• All anticoagulants are generally contraindicated in situations in which the
reduction in clotting that they cause might lead to serious and potentially
life-threatening bleeds. This includes people with active bleeding
conditions (such as gastrointestinal ulcers), or disease states with
increased risk of bleeding (e.g., low platelets, severe liver disease,
uncontrolled hypertension). For patients undergoing surgery, treatment
with anticoagulants is generally suspended. Similarly, spinal or lumbar
puncture (e.g., spinal injections, epidurals, etc.) carry increased risk so
treatment is suspended prior to these procedures.[31][32]
• Warfarin should not be given to people with heparin-induced
thrombocytopenia until platelet count has improved or normalised.[31]
Warfarin is usually best avoided in people with protein C or protein S
deficiency as these thrombophilic conditions increase the risk of skin
necrosis, which is a rare but serious side effect associated with warfarin

43. • Pregnancy
• Further information: Fetal warfarin syndrome and
Anticoagulation in pregnancy
• Warfarin is contraindicated in pregnancy, as it passes
through the placental barrier and may cause bleeding in the
fetus; warfarin use during pregnancy is commonly
associated with spontaneous abortion, stillbirth, neonatal
death, and preterm birth.[34] Coumarins (such as warfarin)
are also teratogens, that is, they cause birth defects; the
incidence of birth defects in infants exposed to warfarin in
utero appears to be around 5%, although higher figures (up
to 30%) have been reported in some studies.[35] Depending
on when exposure occurs during pregnancy, two distinct
combinations of congenital abnormalities can arise

44. • First trimester of pregnancy
• Usually, warfarin is avoided in the first trimester, and a low molecular weight
heparin such as enoxaparin is substituted. With heparin, risk of maternal
haemorrhage and other complications are still increased, but heparins do not
cross the placental barrier, so do not cause birth defects.[35] Various solutions
exist for the time around delivery.
• When warfarin (or another 4-hydroxycoumarin derivative) is given during the
first trimester—particularly between the sixth and ninth weeks of pregnancy—a
constellation of birth defects known variously as fetal warfarin syndrome (FWS),
warfarin embryopathy, or coumarin embryopathy can occur. FWS is characterized
mainly by skeletal abnormalities, which include nasal hypoplasia, a depressed or
narrowed nasal bridge, scoliosis, and calcifications in the vertebral column,
femur, and heel bone, which show a peculiar stippled appearance on X-rays. Limb
abnormalities, such as brachydactyly (unusually short fingers and toes) or
underdeveloped extremities, can also occur.[34][35] Common nonskeletal features
of FWS include low birth weight and developmental disabilities.

45. • Second trimester and later
• Warfarin administration in the second and third trimesters is much less
commonly associated with birth defects, and when they do occur, are
considerably different from fetal warfarin syndrome. The most common
congenital abnormalities associated with warfarin use in late pregnancy
are central nervous system disorders, including spasticity and seizures,
and eye defects.[34][35] Because of such later pregnancy birth defects,
anticoagulation with warfarin poses a problem in pregnant women
requiring warfarin for vital indications, such as stroke prevention in those
with artificial heart valves.
• According to the American College of Chest Physicians (ACCP), warfarin
may be used in lactating women who wish to breast-feed their infants.[36]
Available data does not suggest that warfarin crosses into the breast milk.
Similarly, INR levels should be checked to avoid adverse effects

46. • Adverse effects
• Bleeding
• The only common side effect of warfarin is bleeding. The risk of severe bleeding is small but definite (a
typical yearly rate of 1–3% has been reported),[24] and any benefit needs to outweigh this risk when warfarin
is considered. All types of bleeding occur more commonly, but the most severe ones are those involving the
brain (intracerebral hemorrhage/hemorrhagic stroke) and the spinal cord.[24] Risk of bleeding is increased if
the INR is out of range (due to accidental or deliberate overdose or due to interactions).[37] This risk
increases greatly once the INR exceeds 4.5.[38]
• A number of risk scores exist to predict bleeding in people using warfarin and similar anticoagulants. A
commonly used score (HAS-BLED) includes known predictors of warfarin-related bleeding: uncontrolled high
blood pressure (H), abnormal kidney function (A), previous stroke (S), known previous bleeding condition
(B), previous labile INR when on anticoagulation (L), elderly as defined by age over 65 (E), and drugs
associated with bleeding (e.g., aspirin) or alcohol misuse (D). While their use is recommended in clinical
practice guidelines,[39] they are only moderately effective in predicting bleeding risk and do not perform well
in predicting hemorrhagic stroke.[40] Bleeding risk may be increased in people on hemodialysis.[41] Another
score used to assess bleeding risk on anticoagulation, specifically Warfarin or Coumadin, is the ATRIA score,
which uses a weighted additive scale of clinical findings to determine bleeding risk stratification.[42] The risks
of bleeding are increased further when warfarin is combined with antiplatelet drugs such as clopidogrel,
aspirin, or nonsteroidal anti-inflammatory drugs

47. • Warfarin necrosis
• Main article: Warfarin necrosis
• A rare but serious complication resulting from treatment with
warfarin is warfarin necrosis, which occurs more frequently
shortly after commencing treatment in patients with a deficiency
of protein C. Protein C is an innate anticoagulant that, like the
procoagulant factors whose synthesis warfarin inhibits, requires
vitamin K-dependent carboxylation for its activity. Since warfarin
initially decreases protein C levels faster than the coagulation
factors, it can paradoxically increase the blood's tendency to
coagulate when treatment is first begun (many patients when
starting on warfarin are given heparin in parallel to combat this),
leading to massive thrombosis with skin necrosis and gangrene
of limbs. Its natural counterpart, purpura fulminans, occurs in
children who are homozygous for certain protein C mutations

48. • Osteoporosis
• After initial reports that warfarin could reduce bone mineral density,
several studies demonstrated a link between warfarin use and
osteoporosis-related fracture. A 1999 study in 572 women taking warfarin
for deep venous thrombosis, risk of vertebral fracture and rib fracture was
increased; other fracture types did not occur more commonly.[45] A 2002
study looking at a randomly selected selection of 1,523 patients with
osteoporotic fracture found no increased exposure to anticoagulants
compared to controls, and neither did stratification of the duration of
anticoagulation reveal a trend towards fracture.[46]
• A 2006 retrospective study of 14,564 Medicare recipients showed that
warfarin use for more than one year was linked with a 60% increased risk
of osteoporosis-related fracture in men; there was no association in
women. The mechanism was thought to be a combination of reduced
intake of vitamin K (a vitamin necessary for bone health) and inhibition by
warfarin of vitamin K-mediated carboxylation of certain bone proteins,
rendering them nonfunctional

49. • Purple toe syndrome
• See also: Blue toe syndrome
• Another rare complication that may occur early during
warfarin treatment (usually within 3 to 8 weeks of
commencement) is purple toe syndrome. This condition is
thought to result from small deposits of cholesterol
breaking loose and causing embolisms in blood vessels in
the skin of the feet, which causes a blueish-purple colour
and may be painful.[48]
• It is typically thought to affect the big toe, but it affects
other parts of the feet as well, including the bottom of the
foot (plantar surface). The occurrence of purple toe
syndrome may require discontinuation of warfarin

50. • Calcification
• Several studies have also implicated warfarin use
in valvular and vascular calcification. No specific
treatment is available, but some modalities are
under investigation

51. • Overdose
• The major side effect of warfarin use is bleeding. Risk of bleeding is increased if the INR is
out of range (due to accidental or deliberate overdose or due to interactions).[37] Many
drug interactions can increase the effect of warfarin, also causing an overdose.[21]
• In patients with supratherapeutic INR but INRless than 10 and no bleeding, it is enough to
lower the dose or omit a dose, monitor the INR and resume warfarin at an adjusted lower
dose when the target INR is reached.[51] For people who need rapid reversal of warfarin –
such as due to serious bleeding – or who need emergency surgery, the effects of warfarin
can be reversed with vitamin K, prothrombin complex concentrate (PCC), or fresh frozen
plasma (FFP).[7] Generally, 4-factor PCC can be given more quickly than FFP, the amount
needed is a smaller volume of fluid than FFP, and does not require ABO blood typing.
Administration of PCCs result in rapid hemostasis, similar to that of FFP; namely, with
comparable rates of thromboembolic events, but with reduced rates of volume overload.
Blood products should not be routinely used to reverse warfarin overdose, when vitamin
K could work alone.[7] While PCC has been found in lab tests to be better than FFP, when
rapid reversal is needed,[52] as of 2018, it was unclear whether there is a difference in
outcomes such as death or disability.[53]
• When warfarin is being given and INR is in therapeutic range, simple discontinuation of
the drug for five days is usually enough to reverse the effect and cause INR to drop below
1.5

53. • Interactions
• Warfarin interacts with many commonly used drugs, and the metabolism of warfarin varies greatly between
patients.[21] Some foods have also been reported to interact with warfarin.[21] Apart from the metabolic
interactions, highly protein bound drugs can displace warfarin from serum albumin and cause an increase in
the INR.[55] This makes finding the correct dosage difficult, and accentuates the need of monitoring; when
initiating a medication that is known to interact with warfarin (e.g., simvastatin), INR checks are increased or
dosages adjusted until a new ideal dosage is found.
• When taken with nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin increases the risk for
gastrointestinal bleeding. This increased risk is due to the anti-platelet effect of NSAIDs as well as the
possible damage to the gastrointestinal mucosa.[56]
• Many commonly used antibiotics, such as metronidazole or the macrolides, will greatly increase the effect of
warfarin by reducing the metabolism of warfarin in the body. Other broad-spectrum antibiotics can reduce
the amount of the normal bacterial flora in the bowel, which make significant quantities of vitamin K1, thus
potentiating the effect of warfarin.[57] In addition, food that contains large quantities of vitamin K1 will
reduce the warfarin effect.[21][24] Thyroid activity also appears to influence warfarin dosing requirements;[58]
hypothyroidism (decreased thyroid function) makes people less responsive to warfarin treatment,[59] while
hyperthyroidism (overactive thyroid) boosts the anticoagulant effect.[60] Several mechanisms have been
proposed for this effect, including changes in the rate of breakdown of clotting factors and changes in the
metabolism of warfarin

54. • Excessive use of alcohol is also known to affect the metabolism of warfarin and can
elevate the INR and thus increase the risk of bleeding.[62] The U.S. Food and Drug
Administration (FDA) product insert on warfarin states that alcohol should be avoided.[5]
The Cleveland Clinic suggests that when taking warfarin one should not drink more than
"one beer, 6 oz of wine, or one shot of alcohol per day".[63]
• Warfarin also interacts with many herbs and spices,[64] some used in food (such as ginger
and garlic) and others used purely for medicinal purposes (such as ginseng and Ginkgo
biloba). All may increase bleeding and bruising in people taking warfarin; similar effects
have been reported with borage (starflower) oil.[65] St. John's Wort, sometimes
recommended to help with mild to moderate depression, reduces the effectiveness of a
given dose of warfarin; it induces the enzymes that break down warfarin in the body,
causing a reduced anticoagulant effect.[66]
• Between 2003 and 2004, the UK Committee on Safety of Medicines received several
reports of increased INR and risk of haemorrhage in people taking warfarin and cranberry
juice.[67][68][69] Data establishing a causal relationship is still lacking, and a 2006 review
found no cases of this interaction reported to the FDA;[69] nevertheless, several authors
have recommended that both doctors and patients be made aware of its possibility.[70]
The mechanism behind the interaction is still unclear.

55. When warfarin is newly started, it may promote clot formation temporarily.
This is because the level of protein C and protein S are also dependent on
vitamin K activity. Warfarin causes decline in protein C levels in first 36 hours.
In addition, reduced levels of protein S lead to a reduction in activity of
protein C (for which it is the co-factor) and therefore reduced degradation of
factor Va and factor VIIIa. Although loading doses of warfarin over 5 mg also
produce a precipitous decline in factor VII, resulting in an initial prolongation
of the INR, full antithrombotic effect does not take place until significant
reduction in factor II occurs days later. The haemostasis system becomes
temporarily biased towards thrombus formation, leading to a prothrombotic
state. Thus, when warfarin is loaded rapidly at greater than 5 mg per day, it is
beneficial to co-administer heparin, an anticoagulant that acts upon
antithrombin and helps reduce the risk of thrombosis, with warfarin therapy
for four to five days, in order to have the benefit of anticoagulation from
heparin until the full effect of warfarin has been achieved

57. •

58. •

60. •

61. •

62. •

63. •