Warfarin Skin Necrosis | Skin Side Effects

Warfarin induced necrosis would be one of the rare but serious complication of warfarin treatment. This normally occurs shortly after starting warfarin therapy in patients with protein C defiency. This is because Protein C is an innate anticogulant (vitamin K dependent) which play its role similar to other procogulant factors. Also, protein C requires Vitamin K for its carboxylation activity. And since warfarin initially reduces protein C levels faster than other coagulation factors, paradoxcially it would raise up blood's tendency to coagulate during starting of treatment. This may lead to skin necrosis and gangrene of limbs due to massive thrombosis. Due to this, heparin is normally given to patient for 3 to 5 days to counter this problem before warfarin full activily is achieved.
Similary, protein S deficiency may be affects in the same way as what happen to protein C deficiency.

Warfarin Mechanism of Actions | How it works

Warfarin works by inhibiting the vitamin K-dependent synthesis of calcium-dependent clotting factors (which are of active forms) include factors II, VII, IX and X (2,7,9,10). Furthermore, the regulatory factors of protein C, cofactor protein S, and protein Z would be inhibited as well. However, proteins that are not clotting factors may be influenced to a certain extent, such as osteocalcin and matrix Gla protein.

Before we go into details for mechanism of action of warfarin, we have to understand normal mechanism of clotting process. From the diagram above, we can see that the precursors of the clotting factors mentioned above (prothrombin precursor) require carboxylation of their glutamic acid residues catalyzed by gamma-glutamyl carboxylase to become active form (prothrombin), before being able to bind to phospholipid membrane on vascular endothelium of blood vessels. (The newly formed Gla residues from Glu chelate strongly and selectively with calcium ion in which the latter would form ion bridges with the anionic phosphate groups of phospholipid membrance surfaces)

However, the carboxylation process will only be able to proceed in the presence of reduced form of vitamin K (or known as vitamin K hydroquinone). The vitamin K cycle involves enzyme Vitamin KO reductase (or vitamin K epoxide reductase) which reduce oxidized vitamin K (or vitamin K epoxide) to vitamin K which would be then converted to vitamin K hydroquinone by enzyme vitamin k reductase.

Diagram for Mechanism of Action of Warfarin

Warfarin is a vitamin K antagonist which inhibits epoxide reductase step. Hence, vitamin K cannot be formed and thus would diminish availalbe vitamin K hydroquinone in the tissues, lead to the inhibition of carboxylation activity of glutamyl carboxylate. Active clotting factors no longer can be formed and the final result would be anticoagulation effect. However, the anticoauglation activity of warfarin can only be seen apparent after 3 to 5 days due to the half life of previously produced active factors which degrade over several days before replaced by new inactive actors. Furthermore, due to the inhibition of protein C and protein S (vitamin K dependent) which play their role in anticlotting as well, warfarin may cause formation of clot temporarily leading to prothrombic state. 
Hence, it is normally practised to co-administer heparin intravenously to the patient which help reduce the risk of thromosis together with warfarin therapy for 4 to 5 days, with the purpose to have heparin anticoagulation effect before the full activitly of warfarin is achieved.

Warfarin Uses | Indications

Warfarin is a blood thinning agent (anticoagulant) used to reduce the formation of blood clots (thrombosis) by inhibiting clotting factors in the body. It is indicated for prevention of disease associated with thrombosis including heart attacks, strokes, atrial fibrillation, deep vein thrombosis (DVT) and pulmonary embolism (PE). Embolism is an abnormal formation and migration of blood clots (thrombosis) where it would result in blocking supply to a vital organ. Warfarin is one of the most widely used and practised oral anticoagulant drug in North America.

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Warfarin Drug Info

Warfarin Uses | Indications
Warfarin is a blood thinning agent (anticoagulant) used to reduce the formation of blood clots (thrombosis) by inhibiting clotting factors in the body. It is indicated for prevention of disease associated with thrombosis including heart attacks, strokes, atrial fibrillation, deep vein thrombosis (DVT) and pulmonary embolism (PE). Embolism is an abnormal formation and migration of blood clots (thrombosis) where it would result in blocking supply to a vital organ. Warfarin is one of the most widely used and practised oral anticoagulant drug in North America.


Besides, warfarin is purposed for areas with slow flowing blood such as in veins and pool of blood in artificial and natural valves, and also in dysfunctional cardiac atria. Plus, warfarin may be used for secondary prevention of myocardial infarctions, though it is less effective in preventing the formation of new thromboses in coronary arteries.


Warfarin Mechanism of Actions | How it works
Warfarin works by inhibiting the vitamin K-dependent synthesis of calcium-dependent clotting factors (which are of active forms) include factors II, VII, IX and X (2,7,9,10). Furthermore, the regulatory factors of protein C, cofactor protein S, and protein Z would be inhibited as well. However, proteins that are not clotting factors may be influenced to a certain extent, such as osteocalcin and matrix Gla protein.


Before we go into details for mechanism of action of warfarin, we have to understand normal mechanism of clotting process. From the diagram above, we can see that the precursors of the clotting factors mentioned above (prothrombin precursor) require carboxylation of their glutamic acid residues catalyzed by gamma-glutamyl carboxylase to become active form (prothrombin), before being able to bind to phospholipid membrane on vascular endothelium of blood vessels. (The newly formed Gla residues from Glu chelate strongly and selectively with calcium ion in which the latter would form ion bridges with the anionic phosphate groups of phospholipid membrance surfaces)


However, the carboxylation process will only be able to proceed in the presence of reduced form of vitamin K (or known as vitamin K hydroquinone). The vitamin K cycle involves enzyme Vitamin KO reductase (or vitamin K epoxide reductase) which reduce oxidized vitamin K (or vitamin K epoxide) to vitamin K which would be then converted to vitamin K hydroquinone by enzyme vitamin k reductase.


Warfarin is a vitamin K antagonist which inhibits epoxide reductase step. Hence, vitamin K cannot be formed and thus would diminish availalbe vitamin K hydroquinone in the tissues, lead to the inhibition of carboxylation activity of glutamyl carboxylate. Active clotting factors no longer can be formed and the final result would be anticoagulation effect. However, the anticoauglation activity of warfarin can only be seen apparent after 3 to 5 days due to the half life of previously produced active factors which degrade over several days before replaced by new inactive actors. Furthermore, due to the inhibition of protein C and protein S (vitamin K dependent) which play their role in anticlotting as well, warfarin may cause formation of clot temporarily leading to prothrombic state. 
Hence, it is normally practised to co-administer heparin intravenously to the patient which help reduce the risk of thromosis together with warfarin therapy for 4 to 5 days, with the purpose to have heparin anticoagulation effect before the full activitly of warfarin is achieved.


Warfarin Side Effects
Hemorrhage
The most common side effects of warfarin due to its blood thinning effect would be hemorrhage (bleeding). However, mild bleeding is commonly reported and most of them can be managed and controlled well while the risk of severe bleeding is small (estimate of 0.9% to 2.7% has been reported annually). Hence, it is important to evaluate the beneifts over risk ratio before starting any warfarin therapy. The common bleeding side effects associated would be hemoptysis (coughing or spitting blood), excessive or unusual bleeding, gums or nose bleeding, bleeding from vagina or rectum, bloody / black urine or stool.


The risks of bleeding would be higher if warfarin is concurrently taken with other antiplatelet or anticoauglant (fibrinolytic) agents which include aspirin, clopidogrel or NSAIDs (eg. ibuprofen, indomethacin). Also, The risk of bleeding would be higher in elderly patients or patients undergoing hemodialysis while on warfarin therapy.


Skin Necrosis
Warfarin induced necrosis would be one of the rare but serious complication of warfarin treatment. This normally occurs shortly after starting warfarin therapy in patients with protein C defiency. This is because Protein C is an innate anticogulant (vitamin K dependent) which play its role similar to other procogulant factors. Also, protein C requires Vitamin K for its carboxylation activity. And since warfarin initially reduces protein C levels faster than other coagulation factors, paradoxcially it would raise up blood's tendency to coagulate during starting of treatment. This may lead to skin necrosis and gangrene of limbs due to massive thrombosis. Due to this, heparin is normally given to patient for 3 to 5 days to counter this problem before warfarin full activily is achieved.
Similary, protein S deficiency may be affects in the same way as what happen to protein C deficiency.


Osteoporosis
Long-term use of warfarin is associated witth osteoporosis-related fractured. Study of 572 women in 1999 showed that risk of vertebral fracture and rib fracture was increased in patients taking warfarin for deep vein thrombosis. Also, retrospective study of 14564 Medicare recipients for more than 1 year demonstrated 60% increased risk of osteoporosis-related fracture in men, however, there was no association in women. The mechanism was thought due to the reduced intake of vitamin K responsible for bone health.


Purple toe syndrome
This is a rare side effects of warfarin which may occur during 3 to 8 weeks after starting of warfarin treatment. The mechanism was thought to result from cholesterol embolism that flow into the blood vessels in the skin of feet and obstruct it, leading to blueish purple color which may be painful.


Drug-Drug Interactions
Increase INR value which increases risk of bleeding
Analgesics (acetaminophen, aspirin, topical salicylates, tramadol)
Antiarrhythimics (amiodraone, propafenone)
Antibiotics (examples include amoxicillin, cephalosporins, isoniazid, fluoroquinolones, macrolides, metronidazole, sulfonamides, telithromycin, tetracyclines)
Anticonvulsants (phenytoin which is biphasic, increase initially and decrease in long term, sodium valproate)
Antidepressants (duloxetine, venlafaxine, SSRI e.g. fluoxetine, fluvoxamine, setraline, paroxetine and citalopram)
Antifungals (itraconazole, fluconazole, ketoconazole, miconazole, voriconazole)
Antihyperlipidemics (fenofibrate, ezetimibe, fluvastatin, gemfibrozil, simvastatin)
Others include allopurinol, cimetidine, oral corticosteroids, proton pump inhibitors and thyroid supplements


Decrease INR value which increase risk of blood clotting
Antibiotics (rifampin)
Antidepressants (trazodone)
Antiepileptics (phenytoin, carbamazepine, phenobarbitone, primodone)
Other include antithyroid agents,cholestyramine


Drug Foods Interactions / herbs & supplements
Increase INR value
Alcohol (excessive), Dansh, glucosamine (with or without chondroitin), Birch, Dong Quai, grapefruit, Chitosan, fish oil, mango, cranberry juice, garlic supplement, papaya extract
Decrease INR value
Alcohol (chronic), smoking, coenzyme q10, ginseng, St. John's Wort, high dose of Vitamin C, Vitamin K (greeny vegetables)


Warfarin Dosage
Initial dose (loading dose) would be 5 mg/day for 3 to 5 days. For rapid anticoagulation effect, 10 mg/day for 2 days. After INR value is obtained, warfarin dose should be adjusted based on the INR or prothrombin time. Usual maintenance dose would be 2-10 mg daily depending on INR. Lower initial dose should be given to elderly patient, or to the patient concurrently taking medications / supplement that would increase INR value.

Warfarin Education | Counselling Information

Warfarin Use / Purpose
Patient should be well educated regarding warfarin before starting the therapy. Warfarin is a blood thinning agent used to treat heart disease or disorders associated with blood clotting in the body, including heart attack, deep vein thrombosis and pulmonary embolism.


Warfarin INR
INR (Internation Normalised Ratio) is monitored to evaluate blood thickness in the body. High INR value indicates that blood is thin and has tendency of bleeding while Low INR value shows that therapeutic objective is not achieved where the blood is thick and has tendency to clot. INR value for a normal individual (before starting warfarin therapy) should be 1.0 and desired INR is different for different disease to be treated. Normally, INR value of 2-3 is indicated for most type of disease while value of 2.5-3.5 or higher is indicated for mechanical heart valves.


Sign of Bleeding
Warfarin has been known for its blood thinning activity that would predispose patient to bleeding tendency if not well controlled. For example, different patient has different warfarin sensitivity to warfarin therapy and before stable INR is achieved, patient may be more susceptible to warfarin side effects of bleeding. Hence, patient should be advised and educated regarding sign of bleeding and appropriate actions that should be taken. 
- Easy bruising / Skin discoloration or slow wound healing
- Hemotypsis / Cough or spitting of blood
- Gum bleeding
- Bloody urine or stool / black stool or dark urine
- Pale skin, light-headed feeling
- Sudden or severe leg pain / foot ulcer or purple toes or fingers
- Unsual bleeding either from nose, mouth, vagina or rectum
Depending on the severity of bleeding, patient should inform their doctor or pharmacist immediately.


Before undergoing any surgery including dental surgery like tooth extraction, patient should inform his practitioner so that warfarin therapy can be withold prior to the surgery.


Warfarin Diet
Patient should be educated to maintain consistent diet to optimize warfarin therapy. Vitamin K high containing food (reduce INR) should be reduced to minimize inteference with warfarin therapy. Examples of vitamin K high content food include leafy green vegetables, certain vegetable oils such as canola or soybean. 
Besides, patient should let their doctor or pharmacist know any supplement or medications taken including herbal products. Products such as coenzyme Q10, cranberry products, dong quai, garlic, Ginkgo biloba, ginseng, and St. John's wort would have affected warfarin therapy.
Furthermore, some medications like NSAID (ibuprofen, acetaminophen) and Aspirin would have increase INR value leading to higher risk of bleeding. Warfarin dose would be adjusted if patient is concurrently taking these medications. 
Also, certain antibiotics including azole group of antifungals (Fluconazole, Itraconazole), Metronidazole, Bactrim, Amiodarone would have lead to a significant increase in INR and should be taken into consideration before starting warfarin therapy.

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