Activated factor XIII synthesizes fibrin from these monomers. The acquired fibrin molecules then trap the platelets and eventually form the blood clot [ 27 , 28 ].
The coagulation process has both an intrinsic and an extrinsic pathway. The difference is that the intrinsic pathway only requires ionized calcium to be activated while the extrinsic pathway requires both calcium and tissue factor that is released with trauma [ 28 ]. Figure 1 gives an overview of the coagulation process along with the interference sites of warfarin. Overview of the coagulation process along with the interference sites of warfarin.
Warfarin is highly lipid soluble [ 29 , 30 , 31 ]. The half-life of the drug is generally more than 20 h, with a large individual variety [ 32 ]. Consequently, the agent has a slow onset of action and a long duration of activity [ 33 ]. In fact, the optimal effect is delayed for a few days, until all remaining activated factors II, VII, IX, and X are depleted from the liver and the circulation [ 33 ].
Warfarin accumulates in the liver where it exerts its effect and is inactivated through oxidative metabolism by cytochromes P to several isomers of water-soluble hydroxywarfarin with negligible anticoagulant activity [ 34 , 35 ]. These metabolites are almost completely cleared by the kidneys [ 36 ].
The hepatic accumulation and relative easy absorption in the intestines result in an enterohepatic circulation of the drug [ 37 ]. Enterohepatic circulation is a process in which substances are secreted by the liver with bile to the intestines and subsequently absorbed again by the latter [ 28 ].
This results in recycling of the product with very little elimination. Warfarin inhibits the enzyme vitamin K epoxide reductase that recycles oxidized vitamin K [ 38 ]. Vitamin K activates the coagulating factors prothrombin factor II and the structurally related serine proteases known as factors VII, IX, and X in the liver cells [ 27 ]. Decreasing the biological availability of vitamin K inhibits the synthesis of these essential factors and eventually leads to inhibition of the coagulation process.
This means that this compound affects both the intrinsic as well as the extrinsic cascade of coagulation since prothrombin plays a central role in both of these pathways [ 28 ] and renders it a highly effective anticoagulant drug. Hemostasis is an essential process to prevent significant external as well as internal blood loss after injury. However, under certain circumstances, it is not desirable to activate or continue this homeostatic process like in disorders with spontaneous thrombosis such as deep venous thrombosis in the legs often resulting in pulmonary embolism [ 39 ].
In addition, there are conditions that are prone to a reasonable chance of forming a blood clot during stasis of the blood circulation like in atrial fibrillation and in the limbs of patients with prolonged immobility after surgery [ 39 ]. Moreover, conditions like myocardial infarction or ischemic stroke form a preventable group of disorders with inhibition of the thrombotic process [ 5 ].
Based on its anticoagulant properties, warfarin is thus an ideal compound for the treatment and prevention of these thromboembolic conditions [ 5 ]. Based on the pharmacokinetic properties and the challenges they present, dosing of warfarin is not simple, and a careful approach is necessary.
On one hand, a low plasma concentration will not achieve the effect of sufficient anticoagulation and, on the other side of the spectrum, there is the constant chance of overdosing with potential lethal internal or external bleeding. Another problem is the great variety of absorption, body distribution, and metabolism of the agent with individual patients based on the pharmacokinetic properties of warfarin [ 30 ]. Frequent monitoring of therapeutic efficiency with adequate laboratory tools like prothrombin time PT or international normalized ratio INR is absolutely necessary [ 40 , 41 ] and a fixed or constant dose is close to impossible.
Nevertheless, warfarin is highly effective in anticoagulation regiments when carefully dosing and assessing the potential bleeding sites as well as other potential side effects. Warfarin is initially dosed at 5—10 mg daily [ 42 ].
Subsequent doses depend on the international normalized ratio, with a therapeutic value between 2 and 4. Concomitant administration of heparins like fraxiparine is necessary when fast anticoagulant activity is desirable [ 43 ].
Warfarin is not an ideal agent in conditions when immediate treatment of thromboembolism is imminent due to the long time of onset. In cases of pulmonary embolism and acute ischemic stroke, it is desirable to start with both the oral anticoagulant and fast-acting agent like heparins [ 44 ]. The long duration of action harbors another challenge. When acute termination of anticoagulation is necessary with unwanted bleeding like in menstruating women and after blunt and sharp trauma leading to hemorrhage, it could take days before the process of coagulation completely restores after quitting oral administration [ 27 , 30 ] due to the depletion of coagulant factors in liver and blood.
In these cases, intravenous administration of prothrombin complex, fresh frozen plasma with coagulation factors, and high doses of vitamin K may be helpful [ 45 ]. Warfarin readily passes the placenta and may result in spontaneous abortion due to retroplacental bleeding [ 46 ], as well as prematurity [ 47 ], fetal deformity [ 48 ], stillbirth [ 48 ], and fetal cranial bleeding [ 49 ].
Administration during the first trimester of pregnancy has a high risk of embryopathy [ 50 ]. This is accompanied by deformities of bone and cartilage [ 51 ], blindness, mental retardation, and other neurologic abnormalities [ 52 ]. The occurrence of these complications and defects seem to be dose dependent [ 47 , 53 ] and are most probably the result of the interference with vitamin K-dependent coagulation [ 38 ] and bone formation [ 54 ].
The effects of the central nervous system and the blindness are probably the result of microhemorrhages in the developing brain as a result of the anticoagulant activity [ 55 ]. Clotting factors are easily depleted in the fetus due to the immature liver and small circulating volume [ 46 ]. Warfarin does not enter breastmilk and is thus completely safe during lactation [ 56 ]. In conclusion, warfarin must be administered with great caution to women in their child-bearing age [ 57 ].
Therapy with this agent must be ceased immediately when it becomes clear that the patient is pregnant. Low-molecular weight heparins are a good alternative, since they do not cross the placenta and have been proven to be safe for mother, embryo, and fetus [ 58 ].
To say that anticoagulant coumarins have only a few side effects is an absolute understatement. Warfarin is one of the leading drugs with adverse effects requiring hospital admission [ 59 ].
Most of all, there is the constant chance of severe bleeding [ 60 ]. This can include internal hemorrhagic conditions in the head, gastrointestinal tract, female genitalia, the bladder and urethra or skeletal joints and muscles [ 40 , 61 ]. They generally present as severe headache, stomach pain, and black or bloody stool, heavier than normal menstrual bleeding, discoloration of urine, and pain and swelling of the joints or muscles.
Prolonged bleeding from external sharp or blunt wounds is always present [ 61 ]. All these conditions are the result of inability of the affected tissues to initiate and continue the process of hemostasis after damage to the epithelial barrier [ 62 ]. Patients suffering from hypertension, disorders of the liver, bleeding lesions, and the elderly and patients using drugs and substances that affect coagulation are at higher risk to suffer from bleeding when using warfarin [ 63 ].
Hypertension poses mechanical defects in the blood vessels, especially the arteries. In the long term, patients using phenprocoumon have more often international normalised ratio INR values in the therapeutic range, requiring fewer monitoring visits.
This leads us to conclude that in the absence of pharmacogenetic testing, phenprocoumon seems preferable for use in long-term therapeutic anticoagulation. Pharmacogenetic testing before initiating coumarin oral anticoagulants may add to the safety of all coumarin anticoagulants especially in the elderly receiving multiple drugs.
Abstract Coumarin oral anticoagulant drugs have proven to be effective for the prevention of thromboembolic events. In desperation, Ed Carlson, a Wisconsin farmer, drove a dead cow miles to an agricultural experimental station, where he presented biochemist Karl Link with a milk can of unclotted blood.
Link and colleagues set about identifying and isolating the active compound that caused the haemorrhagic disease. They adopted a new in vitro clotting assay using plasma from rabbits to guide chemical fractionation of compounds found in the hay.
In , Link considered using a coumarin derivative as a rodenticide. Dicoumarol acted too slowly to be a practical poison. Link and colleagues worked through a list of variations of coumarin, and number 42 was found to be particularly potent.
The compound was named 'warfarin' after the funding agency, and was successfully marketed in as a rodenticide. In , a US Army inductee attempted suicide with multiple doses of warfarin in rodenticide, but fully recovered after being treated with vitamin K in hospital. Studies then began on the use of warfarin as a therapeutic anticoagulant.
Clinical anticoagulants were available at this time, but heparin required parenteral administration, and dicoumarol had a long lag period before onset of a therapeutic effect. The main advantages of warfarin were high oral bioavailability and high water solubility; it was more potent than dicoumarol, but its effect could still be reversed by vitamin K. Therefore, warfarin transitioned into clinical use under the trade name Coumadin, and was approved for use in humans in An early recipient of warfarin was US president Dwight D.
Eisenhower, who was prescribed the drug after a myocardial infarction in Despite its widespread use, the mechanism of action of warfarin was not discovered until , when John W. Suttie and colleagues demonstrated that warfarin disrupts vitamin K metabolism by inhibiting the enzyme epoxide reductase.
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