3. Anticoagulant: An anticoagulant is a substance that prevents coagulation; that is, which stops blood from clotting Anticoagulants reduce blood clotting. This prevents Deep vein thrombosis, Pulmonary embolism, Myocardial infarction Stroke.
4. PT and INR Prothrombin time (PT) evaluates the ability of blood to clot properly, it can be used to help diagnose bleeding. When used in this instance, it is often used in conjunction with the PTT to evaluate the function of all coagulation factors. the test may be used to screen patients for any previously undetected bleeding problems prior to surgical procedures.
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7. INR Equation ( ) Patient’s PT in Seconds Mean Normal PT in Seconds INR = ISI INR = International Normalized Ratio ISI = International Sensitivity Index
8. The International Normalized Ratio (INR) is used to monitor the effectiveness of blood thinning drugs such as warfarin (Coumadin). These anti-coagulant drugs help inhibit the formation of blood clots. They are prescribed on a long-term basis to patients who have experienced recurrent inappropriate blood clotting.
9. The test result for PT depends on the method used, with results measured in seconds and compared to the average value in healthy people. Most laboratories report PT results that have been adjusted to the International Normalized Ratio (INR) for patients on anti-coagulant drugs. These patients should have an INR of 2.0 to 3.0 for basic "blood-thinning" needs. For some patients who have a high risk of clot formation, the INR needs to be higher - about 2.5 to 3.5.
10. Prothrombin Time Blood Test-PT: This test is done to evaluate the blood for its ability to clot. It is often done before surgery to evaluate how likely the patient is to have a bleeding or clotting problem during or after surgery. Normal PT Values: 10-12 seconds
11. Partial Thromboplastin Time Blood Test-PTT This test is performed primarily to determine if heparin (blood thinning) therapy is effective. It can also be used to detect the presence of a clotting disorder. It does not show the effects of drugs called “low molecular weight heparin” Normal PTT Values: 30 to 45 seconds Extended PTT times can be a result of anticoagulation therapy, liver problems, lupus and other diseases that result in poor clotting.
12. International Normalized Ratio Blood Test-INR Normal INR Values: 1 to 2 The INR is used to make sure the results from a PT test is the same at one lab as it is at another lab.
13. Common drugs influencing INR values : INR / PT decreases INR /PT increases amoxicillin kinolons cephalosporins makrolid antibioti cs paracetamol salicylat e amiodaron allopurinol omeprasol heparin e NSAID & COX2 inh. tricycli c antidepressan t s rifampin antihistamin barbiturat carbamazepin digoxin diuretic s pills c offein pentoxiphyllin Vitamin K
19. THROMBOSIS Collagen XIa Tissue Factor IXa Platelet Clumping Thrombus Formation Thrombus Growth HEMOSTASIS Tissue Factor & Collagen Platelet Aggregation Platelet-rich Hemostatic Plug Xa Fluid Thrombin HEP HEP & HIR Heparin Inhibits Hemostasis
20. Only approximately one third of an administered dose of heparin binds to AT, and this fraction is responsible for most of its anticoagulant effect. The remaining two thirds has minimal anticoagulant activity at therapeutic concentrations, but at concentrations greater than those usually obtained clinically, both high- and low affinity heparin catalyze the AT effect of a second plasma protein, heparin cofactor II
21. The heparin-AT complex inactivates a number of coagulation enzymes, including thrombin factor (IIa) and factors Xa, IXa, XIa, and XIIa. Of these, thrombin and factor Xa are the most responsive to inhibition, and human thrombin is 10-fold more sensitive to inhibition by the heparin-AT complex than factor Xa
22. For inhibition of thrombin, heparin must bind to both the coagulation enzyme and AT, but binding to the enzyme is less important for inhibition of activated factor X (factor Xa ) Molecules of heparin with fewer than 18 saccharides do not bind simultaneously to thrombin and AT and therefore are unable to catalyze thrombin inhibition. In contrast, very small heparin fragments containing the high-affinity pentasaccharide sequence catalyze inhibition of factor Xa by AT. By inactivating thrombin, heparin not only prevents fibrin formation but also inhibits thrombin-induced activation of factor V and factor VIII
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25. AT HC II ++++ - - - - Interaction of Heparin Co-Factors with Thrombin Heparin has a higher affinity for AT than for HC II and there is more AT in plasma than HC II Thrombin H F S C Thrombin H F S C
26. AT Free Thrombin Antithrombin and Free Thrombin AT alone does not inactivate free-thrombin Thrombin H F S C
27. Heparin binds to antithrombin and increases the rate of thrombin inactivation AT Heparin Inactivation of Thrombin by Heparin-AT Complexes Thrombin H F S C
28. AT Fibrin-Bound Thrombin The rate at which AT inactivates fibrin-bound thrombin is reduced 50-fold Effect of Antithrombin on Fibrin-Bound Thrombin Thrombin H F S C
29. Inactivation of Thrombin by Heparin-AT Complexes When thrombin binds to fibrin, it becomes resistant to inactivation by heparin. Heparin Fibrin AT Thrombin H F S C
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32. AT Unfractionated Heparin Differential inhibitory activity against factor Xa and IIa activity AT LMWH By binding to AT, most UH and LMWH can inhibit Xa activity. Fewer than half the chains of LMWH are of sufficient length to also bind factor IIa, therefore has decreased anti-IIa activity. Thrombin (IIa) H F S C Thrombin (IIa) H F S C
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34. 5/98 MedSlides.com METHOD OF ADMINISTRATION FREQUENCY RECOMMENDED DOSE (based on 150 lb [68 kg] patient) Deep Subcutaneous (Intrafat) Injection Initial Dose 5,000 units by IV injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously A different site should be used for each injection to prevent the development of massive hematoma Every 8 hours or 8,000 to 10,000 units of a concentrated solution Every 12 hours 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial Dose 10,000 units, either undiluted or in 50 to100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial Dose 5,000 units by IV injection Continuous 20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion
35. Each mL of the 1,000 Units per mL preparation contains: 1,000 USP Heparin Units (porcine); 9 mg sodium chloride; Water for Injection q.s. Made isotonic with sodium chloride. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0-7.5). Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, is available as follows: Each mL of the 5,000 Units per mL preparation contains: 5,000 USP Heparin Units (porcine); 6 mg sodium chloride; 15 mg benzyl alcohol (as a preservative); Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0-7.5).
36. Side Effects : Hemorrhage: Hemorrhage is the chief complication that may result from heparin therapy . An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug . Bleeding can occur at any site but certain specific hemorrhagic complications may be difficult to detect:
37. Adrenal hemorrhage , with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy. Therefore, such treatment should be discontinued in patients who develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of corrective therapy should not depend on laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient's Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. This complication, if unrecognized, may be fatal. Retroperitoneal hemorrhage. Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT
38. Hypersensitivity Generalized hypersensitivity reactions have been reported , with chills, fever and urticaria as the most usual manifestations, and asthma, rhinitis lacrimation ,headache , nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar side of the feet, may occur painful, ischemic and cyanosed limbs have in the past been attributed to allergic vasospastic reactions. Whether these are in fact identical to the thrombocytopenia-associated complications, remains to be determined.
39. Local Irritation Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous injection of heparin sodium. These complications are much more common after intramuscular use, and such use is not recommended. Miscellaneous Osteoporosis following long-term administration of high doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported. Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin.
40. Platelet Inhibitors Drugs such as acetylsalicylic aci d, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet- aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium.
41. Other Interactions Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium. Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are recommended during coadministration of heparin and intravenous nitroglycerin.
59. Target INRs for Various Indications Indication Target INR Target INR Range Acute MI (high risk) 2.5 2-3 Atrial fibrillation 2.5 2-3 Prosthetic valve* -- 2-3.5 Mechanical valve + risk factors 3 2.5-3.5 Mechanical valve with systemic embolism despite adequate anticoagulation 3 2.5-3.5 Venous thromboembolism 2.5 2-3
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63. Dosage Adjustment Algorithm Current Daily Dose (mg) 2.0 5.0 7.5 10.0 12.5 Warfarin INR Dose Adjustment* Adjusted Daily Dose (mg) 1.0-2.0 Increase x 2 days 5.0 7.5 10.0 12.5 15.0 2.0-3.0 No change — — — — — 3.0-6.0 Decrease x 2 days 1.25 2.5 5.0 7.5 10.0 6.0-10.0 † Decrease x 2 days 0 1.25 2.5 5.0 7.5 10.0-18.0 § Decrease x 2 days 0 0 0 0 2.5 >18.0 § Discontinue warfarin and consider hospitalization/reversal of anticoagulation † Consider oral vitamin K, 2.5–5 mg § Oral vitamin K, 2.5–5 mg * Allow 2 days after dosage change for clotting factor equilibration. Repeat prothrombin time 2 days after increasing or decreasing warfarin dosage and use new guide to management (INR = International Normalized Ratio). After increase or decrease of dose for two days, go to new higher (or lower) dosage level (e.g., if 5.0 qd, alternate 5.0/7.5; if alternate 2.5/5.0, increase to 5.0 qd).
64. Drug Interactions with Warfarin: Potentiation Level of Evidence Potentiation Alcohol (if concomitant liver disease) amiodarone (anabolic steroids, cimetidine, † clofibrate, cotrimoxazole, erythromycin, fluconazole, isoniazid [600 mg daily] metronidazole), miconazole, omeprazole, phenylbutazone, piroxicam, propafenone, propranolol, † sulfinpyrazone (biphasic with later inhibition) Acetaminophen , chloral hydrate , ciprofloxacin, dextropropoxyphene, disulfiram, itraconazole, quinidine, phenytoin (biphasic with later inhibition), tamoxifen, tetracycline, flu vaccine Acetylsalicylic acid, disopyramide, fluorouracil, ifosflhamide, ketoprofen, iovastatin, metozalone, moricizine, nalidixic acid, norfloxacin, ofloxacin, propoxyphene, sulindac, tolmetin, topical salicylates Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole I II III IV
65. Drug Interactions with Warfarin: Inhibition Level of Evidence Inhibition Barbiturates, carbamazepine, chlordiazepoxide, cholestyramine, griseofulvin, nafcillin, rifampin, sucralfate Dicloxacillin Azathioprine, cyclosporine, etretinate, trazodone I II III IV
66. Drug Interactions with Warfarin: No Effect Level of Evidence No Effect Alcohol, antacids, atenolol, bumetadine, enoxacin, famotidine, fluoxetine, ketorolac metoprolol, naproxen, nizatidine, psyllium, ranitidine ‡ Ibuprofen, ketoconazole Diltiazem, tobacco, vancomycin I II III IV
The blood coagulation process can be activated by one of two pathways, the tissue Factor pathway (formerly known as the extrinsic pathway) and the contact activation pathway (known as the intrinsic pathway). Tissue Factor binds to and activates Factor VII and the Tissue Factor/VIIa complex then activates Factor X and Factor IX to Xa and Ixa respectively. Factor X can also be converted to Xa by Ixa (in the presence of Factor VIII). The intrinsic pathway is activated when Factor XII comes in contact with a foreign surface. The resulting Factor XIIa then activates Factor XI, which in turn activates Factor IX. Factor Ixa then activates Factor X. Thus Factor Xa can be generated by activation of the tissue factor or contact activation pathways. Factor Xa then cleves prothrombin and the resulting thrombin converts fibrinogen to fibrin. Four of these clotting factors (Factors IX, VII, X and prothrombin) are Vitamin K dependent and therefore their activity is decreased by the Vitamin K antagonist, warfarin. The half-lives of these four Vitamin K dependent clotting factors are shown on this slide. Factor VII has the shortest half life of the Vitamin K dependent coagulation factors. However, for adequate anticoagulation one needs to reduce the other coagulation factors appropriately, including Factor II (prothrombin) which has a 60 hour half life. It takes several days after initiation of warfarin therapy to reduce Factor II and thus warfarin and heparin need to overlap for approximately 4–5 days when starting therapy.
The prothrombin time (PT) is the test most commonly used to monitor warfarin dosing. The reliability of the result of the PT is influenced adversely by the variability in the sensitivity of thromboplastin reagents used by different laboratories. This problem has been markedly reduced by reporting the PT ratio as an International Normalized Ratio (INR).
The INR is a mathematical correction that normalizes the PT ratio by adjusting for the variability in the sensitivity of the different thromboplastins.
The INR is calculated by the formula shown on this slide. The ISI is the International Sensitivity Index. Each thromboplastin is assigned an ISI which reflects the sensitivity of the thromboplastin to Warfarin-mediated reduction of the Vitamin K dependent clotting factors. By convention, the ISI of the reference thromboplastin is 1.0. The higher the ISI, the less sensitive the thromboplastin is to Warfarin-mediated reduction of the Vitamin K dependent clotting factors. The next two slides provide an example of how the ISI (sensitivity) of the thromboplastin influences the PT ratio (PTR) and how the resulting variability is corrected by expressing the results as an INR.
The four Vitamin K dependent clotting factors are synthesized in the liver.
The details of stopping warfarin and introducing heparin are listed on this slide. Full dose heparin should be discontinued approximately 4 hours preoperatively to allow the APTT to fall to normal during the invasive procedure. Thereafter, heparin can be restarted when considered safe to do so depending on the procedure. Adjusted dose subcutaneous heparin or low dose subcutaneous heparin should be discontinued approximately 12 hours pre-procedure.
This shows a dosage adjustment algorithm which has been used successfully in an anticoagulation clinic.
This slide lists the various drugs that have been reported to interact with and potentate warfarin The strength of the evidence is shown in the left hand column with level I being strongest and level IV the weakest based on the study design of the report.
This slide lists the various drugs and foods that have been reported to interact with and inhibit warfarin. The strength of the evidence is shown in the left hand column.
This slide lists the venous drugs and foods that have been reported to have no effect on warfarin The strength of the evidence is shown in the left hand column. With excessive consumption, alcohol potentiates the effect (Slide 33), but when limited to two glasses of wine /day, it has been reported not to influence the ant/coagulant effect of warfarin.
