Blood Anti-coagulants

2007/10/17

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Blood Anti-coagulants One of the most remarkable properties of blood is its ability to clot, or coagulate. Normally, within the blood vessels, blood remains in a fluid condition. Within the body, blood may clot in response to tissue injury, such as a muscle tear, a cut, or a sharp blow. When exposed to air, blood becomes sticky and sets into a firm, jellylike mass. This mass then separates into two portions: a firm red clot floating free in a transparent, straw-colored fluid called serum.
A clot consists almost entirely of red blood cells entangled in a network of fine fibrils, or threads, composed of a substance called fibrin . Fibrin does not exist as such in blood but is created by the action of thrombin , an enzyme that promotes the conversion of fibrinogen , one of the plasma proteins, to fibrin in the clotting process. Thrombin is not present in circulating blood; it is formed from prothrombin , another of the plasma proteins, by a complex process involving blood platelets , certain calcium salts , substances produced by injured tissue, and contact with rough surfaces. If any of these factors is deficient, clot formation is defective . The addition of sodium citrate removes calcium ions from the blood and thus prevents a clot from forming. Lack of Vitamin k makes impossible the maintenance of the proper amount of prothrombin in the blood. Certain diseases may lower the concentration of the various clotting proteins or of the platelets of the blood.
Although clot formation is a normal process, it sometimes occurs inappropriately and constitutes a threat to life. In people who are hospitalized for a long time, for example, clots sometimes form in the large veins of the legs .If these clots, or thrombi , travel to the lungs, they can cause death Such venous thrombi are dissolved in many cases with a combination of drugs that prevent coagulation and break down clots. Anticoagulants include the natural compound heparin , prepared from the lungs and livers of animals, and the synthetic chemicals dicumarol and warfarin . Clot-dissolving drugs, called thrombolytics , include two enzymes, urokinase and streptokinase , approved for medical use in 1979, and tissue plasminogen activator (TPA), a product of genetic engineering.
Interaction of thrombocytes with the fatty deposits found in atherosclerotic heart disease is thought to contribute to heart attacks. Compounds such as aspirin and sulfinpyrazone, which inhibit platelet activity, may decrease heart attacks in persons with atherosclerotic disease .
Definition of Anticoagulants: It is a drug to prevent and treat abnormal blood clotting. Anticoagulants are sometimes called “blood thinners”, but this name is misleading. These drugs do not “thin the blood”-they make your blood less likely to clot.

Some Pathological definitions related to anticoagulants:
q Embolism: obstruction of a blood vessel by an embolus, or foreign substance, that has been transported by the CIRCULATORY SYSTEM . The embolus may be a blood clot.
q Thrombosis: differs from embolism in that a thrombus consisting of a blood clot, or clump of blood cells, forms inside the affected blood vessel; a fragment of a thrombus becomes an embolus if it is dislodged and moves through the bloodstream to create an obstruction, or embolism.
q Stroke : damage of the brain due to a blockage in blood flow, or to a hemorrhage of blood vessels in the brain. Without blood, sections of brain tissue quickly deteriorate or die , resulting in paralysis of limbs or organs controlled by the affected brain area. The majority of stroke cases are due to arterial blockage caused by either thrombosis or embolism.

About anticoagulants
Indications: Among the the main indications for anticoagulant therapy comes Atrial fibrillation (AF) which is a recognized risk factor for thromboembolic events. This is due to the disturbance of blood flow in the left atrium of the heart. Recently, trials have shown the benefit of anticoagulation in patients with AF. A reduction in the incidence of strokes, systemic embolism and mortality have been strated. There is also an increased risk of thromboembolism in patients with prosthetic heart valves, because the valve acts as a focus for thrombi formation. The risk is also affected by the type of valve, its location and other patient factors. In brief words , Anticoagulants are used for atrial fibrillation because irregularly beating heart chambers cause pooling of blood. Pooled blood is more likely to develop blood clots, which can travel from the heart to the brain and cause a stroke. Anticoagulants help prevent the blood clots from forming and reduce the risk of stroke caused by atrial fibrillation.
Mode of action

The two most commonly used anticoagulant agents are heparin and the coumarin warfarin . Both of these agents exert their effect by acting on the clotting cascade.
  • Warfarin and other coumarins Warfarin and other coumarins inhibit the formation of factors II, VII, IX, and X which are all dependent on Vitamin K. The coumarins are chemically related to Vitamin K and so competitively inhibit the synthesis of the above clotting factors.
    Heparin Heparin exerts its main action by binding to antithrombin III. Antithrombin III is an inhibitor of thrombin, and heparin potentiates this effect. Antithrombin III also inhibits the activated factors XIIa, XIa and Xa, which results in less fibrin formation, so there is a reduced incidence of thrombus. Heparin also has a slight inhibitory effect on platelet function. It should be remembered that anticoagulants do not dissolve any existing clots. The body's own hermostatic mechanisms do this. Anticoagulants prevent any new clot formation while this process is taking place.
    Heparin

    Initial therapy
    Choice of therapy is primarily determined by the indication for treatment. If it is for the treatment of AF, immediate anticoagulation is not necessary. But, in the treatment of a thromboembolic event, anticoagulation is required immediately to prevent further life-threatening embolism.
    For immediate initiation, heparin is the drug of choice ­ it has a rapid onset of action and a short half-life (0.5-2hr).
    Initially, a loading dose of between 5,000 and 100,000u (or 50-75u/kg) is given intravenously over five minutes to neutralise the high level of clotting factors in the blood. This is then followed by a maintenance dose which may be given as an IV infusion of 20,000-40,000u over 24 hrs (or 25u/kg/hr).
    Alternatively, heparin can be given subcutaneously every 12 hrs. The dose needs to be slightly higher at around 15,000-20,000u every 12 hrs. The injection acts as a depot, with the heparin being released over the next 12 hrs.
    Subcutaneous heparin is available as both the sodium and calcium salt. There seems to be little difference between the two as regards efficacy or adverse effects. IV heparin is always given as the sodium salt.
    N.B: The anticoagulant drug heparin has proved valuable in vascular surgery and cerebral thrombosis.
    Monitoring of heparin
    The clotting status of the patient is measured by the Activated Partial Thromboplastin Time (APTT). An equivalent measure sometimes used is the Kaolin Cephalin Clotting Time (KCCT). The normal (control) value for APTT is between 24 and 36 seconds. If possible, this should be measured for the patient before any anticoagulation is started, to ensure the patient's coagulation status is normal. The APTT is then measured six hours after the infusion has started and the rate adjusted to maintain the APTT at 1.5-2.5 ­ the normal value. If the result is <1.5, the patient is still at risk of further thrombi forming. If it is >2.5 the patient may be at risk of haemorrhage. The APTT should be checked at least daily while the heparin infusion continues.
    Low molecular weight heparins
    These include enoxaparin, tinzaparin, dalteparin and certoparin . Evidence suggests they are as effective as unfractionated heparin in the treatment of thromboembolic events and are now being used for initial treatment. They have a longer duration of action than unfractionated heparin and do not need any monitoring. This means patients could be discharged from hospital earlier.

    Warfarin

    Once the diagnosis has been confirmed, oral anticoagulation is initiated. Heparin treatment is maintained until the activity of the oral coagulant is therapeutic. This may take up to 5 days to allow any existing clotting factors to be cleared from the blood.
    Warfarin is usually used for oral anticoagulation. Other agents include nicoumalone and phenindione but these are seldom used.
    There are several ways of initiating warfarin. Commonly, patients are loaded using 10mg on day one, 10mg on day two and 5mg on day three. In many cases, though, subsequent measurement of the clotting status shows these doses to be excessive.
    An alternative method is shown in Table 2. No single method will be accurate for all patients and daily monitoring is essential to establish a safe and effective dose.
    Monitoring of warfarin
    The clotting status of a patient on warfarin is established by measuring their Prothrombin Time (PT), expressed as a ratio of a normal control sample ­ the International Normalised Ratio (INR). The normal control PT is roughly 12-16 seconds.
    The INR range aimed for depends on the indication for treatment. Different centres may use slightly differing ranges, but the common ones are illustrated in Table 3. However, an individual patient's circumstances must always be taken into consideration when deciding on a suitable INR range.
    As a patient stabilises, and successive INR measurements remain within the therapeutic range, the patient's clotting status can be monitored less frequently. This should be a gradual process and most clinics see even their most stable patients at least every three months. If a stable patient presents with an INR outside their range, they should then be seen more regularly until they stabilise again.
    Several computer programmes are now available to assist in dosing alterations in response to a change in INR. These may also suggest appropriate appointment intervals depending on a patient's previous results and history.
    Duration of treatment
    This will vary according to indication. Patients being treated for AF will require lifelong therapy, as will those with prosthetic valves. Those receiving warfarin for recurrent deep vein thrombosis or pulmonary embolism will also need long-term therapy.
    Treatment of first thromboembolic event is more complicated as recommendations vary depending on whether a specific cause is identified.
    Three months is the standard treatment length, although some references now suggest six weeks.
    Adverse effects

    The main adverse of all anticoagulants is haemorrhage. In severe cases, this may present as intracranial or gastro-intestinal bleeding which could be life-threatening. Less serious bleeding includes nose bleeds or haemorrhoid bleeding. All bleeding should be treated seriously. An immediate INR should be taken and if raised, intravenous vitamin K should be administered ­ 1mg is usually sufficient, although in life-threatening situations 5mg may be given along with fresh frozen plasma.
    Patients with a history of gastro-intestinal bleeding, or stroke prior to anticoagulant therapy, should be considered high risk, treated with caution and monitored closely. Patients with impaired liver function are particularly sensitive to the effects of oral anticoagulants and are at a high risk of bleeding. They should only be treated if absolutely necessary.
    Other adverse effects of warfarin include:
  • teratogenicity The greatest risk of congenital abnormalities due to warfarin is in the 6-9th week of gestation. Women requiring anticoagulation are transferred to heparin therapy during their first trimester
  • rash
  • alopecia
    skin necrosis thought to result from a paradoxical hypercoagulable state following initiation of warfarin and causing extensive capillary thrombosis. Other adverse effects of heparin include:
  • thrombocytopenia occurs usually after 6-12 days of treatment. The Committee on Safety of Medicines recommends platelet counts for patients receiving heparin for longer than five days
  • osteoporosis has been reported after long-term use.
  • hypersensitivity
    skin necrosis at the site of injection. Contraindications

    Warfarin
    Contraindications include pregnancy (but see notes above), active haemorrhage, recent CNS surgery, severe uncontrolled hypertension, alcoholism/severe liver disease.
    Heparin
    Contraindications to heparin include : haemophilia , active haemorrhage , thrombocytopenia , known hypersensitivity, severe liver disease , severe uncontrolled hypertension, recent major trauma or surgery .

    Interactions with warfarin
    These can be non-drug or drug interactions. The two main non-drug interactions are alcohol and vitamin K . Alcohol can potentiate the effect of warfarin resulting in an increase in INR . Vitamin K is found in many green vegetables and a radical change in diet could effect its dietary intake. This would affect the action of warfarin and subsequent INR results.
    mechanisms of interaction are possible including:
  • displacement of warfarin from serum albumin
  • induction/inhibition of the cytochrome P-450 system in the liver
  • effects on vitamin K synthesis
    unknown, idiosyncratic interactions.
    Patient counselling

    Because of the potential toxicity and narrow therapeutic index of oral anticoagulants it is of vital importance that patients understand the nature of their treatment. All new patients need counselling to ensure complete compliance with their treatment. The following points should always be covered at an initial counselling session.
  • Dose: the dose may be the same each day or may differ throughout the week. It is imperative that the patient understands the regime and diary cards/compliance charts should be supplied if needed. Patients should be encouraged to take the medication at the same time each day to maintain a stable INR.
  • Appearance of tablets : if possible, the patient should be shown the different strength tablets to differentiate between them.
  • Anticoagulant effects: the patient needs to know what an anticoagulant is, its effect on the blood, what the INR result means and why frequent blood tests are necessary. He or she also needs to be aware of the risks of non-compliance, ie the risk of thrombosis/haemorrhage.
  • Overcoagulation : symptoms include any bleeding/bruising problems which may suggest the INR is higher than desired.
  • Missed/extra doses: there will always be times when a dose is missed. The patient should either make a note of the discrepancy and continue as normal the following day, or contact the clinic/GP for advice if more than one dose is missed. If an extra dose is taken, the patient should come to the clinic for an INR check.
  • Drug interactions: these should include both OTC and pre ion medicines. The patient should be encouraged to inform all health care professionals that he or she is on warfarin therapy.
  • Alcohol: the importance of maintaining a moderate alcohol input should be expressed to the patient, along with the danger of marked changes in intake.
  • Diet: the patient should be encouraged to continue with their normal diet. The clinic should be told of any changes.
    Clinic arrangements: these should include location, clinic operation, appointment times, any transport arrangements and a contact telephone number. Anticoagulants & Pregnancy:
    q Heparin: does not cross the placenta and has no effect on the foetus.
    q Oral anticoagulants: cross the placenta and have been associated with an increase in abortion rate in the first trimester. There may also be an association with foetal cerebral hemorrhage when given within a few days of vaginal delivery.
    q NSAIDs & Salicylic acid salts: May prolonggestation and labour, and result in premature closure of the ductus arteriosus. Also , they may beassociated with neonatal hypertension and hemorrhage.
    Anticoagulants & Lactation
    Individual maternal and infant situations must be taken into account before any drug is prescribed for the mother.
  • In general, all drugs should be avoided in premature or low birth weight infants, or in those who have any underlying conditions.
  • If a drug is prescribed, it should be at the lowest practical dose and for the shortest time.
    The table (1) shows the effect of different anticoagulants on lactation depending on the results of several experiments. Drugs Suitability for use in lactation Comments Warfarin YesOral anticoagulant of choice during breast feeding. Very low levels in milk. No effects on infant. Phenindione NoSingle report of haematoma in breast-fed infant Heparin sodium/calcium Yes Low molecular weight heparins yesNot absorbed by infant but limited clinical experience Anticoagulants Interfere with Newborn Screening Results:

    (News from the Texas Department of Health)

    Invalid newborn screening results for Congenital Adrenal Hyperplasia (CAH) and Congenital Hypothyroidism (CH) will occur from improper collection techniques. Anticoagulants such as EDTA (purple top tube or purple-ringed capillary tube) and sodium citrate (blue top tube or blue-ringed capillary tube) used during the collection of blood from the infant's heel for newborn screen testing will cause the specimens to give false and misleading test results for CAH and CH.
    A false negative result from the T4 (thyroxine ) testing can be serious. The diagnosis for an infant with CH can be missed since the anticoagulants will cause invalid normal results. A falsely elevated 17- hydroxy-progesterone test result is interpreted as CAH and means extra expense and time for the infant's family, physician, Newborn Screening Follow-up nurses and the laboratory. In addition, the family suffers undue worry and the infant is put through unnecessary additional testing.
    Proper collection technique as described on the Newborn Screening Filter Paper Collection Form or in the Texas Newborn Screening Program - A Practitioner's Guide must be followed:

    After the collection site is properly prepared, the infant's heel is pricked with a sterile lancet.
    Blood from the infant's heel is applied directly to the filter paper collection card using a single application of blood per circle.
    Time is allowed for complete saturation and absorption of the blood onto the filter paper.
    Blood should not be collected into capillary tubes, test tubes (e.g. Vacutainer®) or syringes before applying to the filter paper card. Adhering to proper collection techniques for Newborn Screening specimens will help to ensure accurate and timely test results.
    Antiplatelet effect of NSAIDs: Aspirin in small doses inhibits the synthesis of TXA 2 in platelets by irreversible acetylation of the enzyme Cox 1. Because the platelet lacks a nucleus, it cannot synthesize new enzyme during its lifetime (7-10 days). Aspirin also affects PGI 2 synthesis in endothelium but since it possesses a nucleus it can synthesize new COX and PGI 2 . TXA 2 synthesis in platelets with little effect on endothelial PGI 2 production.] Aspirin is preferred over other NSAIDs as an antiplatelet since it is the only NSAID that inhibits Cox 1 in platelets irreversibly, while other NSAIDs have less pronounced antiplatelet effect.
    Examples for anticoagulant drug from the plant kingdom:
    (GARLIC)

    Botanical origin: Fresh dried bulbules of Allium sativum ,fam: Liliaceae.
    Geographical origin: All Mediterranean countries,and it was introduced as well to Northern European countries when the Turks invaded Europe.
    Brief historical background: Garlic has long been used in traditional medicine.The earliest indications that garlic served as medicinal plant come from the stone age ,a garlic recipe written cuneiform characters in about 3000 BC has been found.An ancient Egyptian papyrus dated 1600 BC described the importance of garlic daily use to keep the men working on the pyramids fit and strong.
    Constituents: Garlic bulb contains a number of active principles , which include :
    Volatile oil : (0.1-0.3 %),it contains more than 17 sulpher containing compounds,the major ones: 1] Alliin: highly sensitive and quite unstable ,changes rapidly into Allicin under the effect of allinase enzyme.
    2] Allylmethyl trisulphide ,diallyl disulphide , diallyl trisulphide methylcystein sulphoxide ,propylallyl disulphide ,diallyl sulphide ,and numerous other sulphide components .
    3] Ajoene: self conensation of allicin.

    Minerals: such as :Iodine,Selenium,Germanium,and Zinc.
    Vitamins: such as vitamins:A,C,B1,and B2 nicotinamide.
    Glutathione:
    Uses: In geriatrics having numerous cardiovascular disorders ,as it possesses antiplatelet aggregation and Fibrinolysis hypoglycemic hypotensine effects ,as well as it reduces LDL concentration of blood and hence,it reduces possibility of arteriosclerosis. Sources and references:

    Encarta encyclopedia 2001
    (Pharmacognosy for pharmacy students) –fifth edition.