ANTICOAGULANTS Prevent clot formation and/or clot extension – Flashcards

induces its anticoagulant effect by binding and activating the endogenous anticoagulant Antithrombin III (AT III), which in turn neutralizes activated clotting factors II, IX, X XI and XII (Figure 1-A) and kallekrein. Heparin is not absorbed from the gastrointestinal tract and therefore is given parenterally via the intravenous (IV) or the subcutaneous (SC) rout.

Due to its rapid onset of action and short duration, it's given as a continuous IV infusion during the acute phase of a thromboembolic event. More recently, various products containing fragments of heparin commonly referred to as low molecular weight heparin (LMWH) derived from chemical modification of the natural product have been developed

are examples of low molecular weight heparin available in the U.S. The low molecular weight heparins are reported to cause thrombocytopenia less frequently in addition to requiring minimal monitoring of their anticoagulant effect.

involves the administration of a bolus or a loading dose of heparin ranging between 70-100 units/kg followed by a continuous IV infusion at15-25 units per kg per hour. The subcutaneous administration of heparin is considered less aggressive and is often intended for prophylaxis.

Performing routine measurements (every 6 hours during IV therapy) of activated partial thromboplastin time (aPTT) measured in seconds, monitors and guides the dosing of heparin therapy. The range for baseline (prior to start of anticoagulation therapy) aPTT is 24-36 seconds. Depending on the treatment (i.e., MI, DVT etc.) there is a predetermined target range for raising the aPTT time interval to 1.5-2.5 times a patient's base line, thereby reducing the risk of thromboembolism.

Coagulation homeostasis is maintained through a critical balance between coagulation or clot formation and clot dissolution.

is the process of halting excessive blood loss from damaged vessels due to injury. The interaction of platelets and the subendothelial regions exposed due to vascular injury leads to an initial platelet adhesion in an attempt to control bleeding. Tissue contact and the aggregated platelets stimulate the activation of plasma coagulation factors in a cascading fashion (Figure 1-A), ultimately resulting in the formation of fibrin. Fibrin clings to the aggregated platelets, further reinforcing the hemostaitc plug and controlling excessive bleeding.

After tissue injury is repaired, the fibrin-platelet clot is broken down by the fibrinolytic process (Figure next slide). Thromboembolism or pathological clot formation describes the abnormal formation of arterial or venous thrombi due to: Tissue injury Infections Neoplastic diseases stasis Oral contraceptives pregnancy

Clot breakdown: Thrombolysis Plasminogen Activator Plasminogen Plasmin Fibrin Clot Soluble Fibrin Fragments Profibrinolysin) (Fibrinolynsin) (Fibrin Degradation products Abnormal formation of clots in the legs (deep venous Thrombosis-DVT) or the lungs (pulmonary embolus-PE) results in blood flow obstruction and consequently affecting their normal function. Clots reaching the carotid arteries often result in central nervous system oxygen deprivation (stroke) leading to varied degrees of mental and physical disability. Clots forming secondary to plaque rupture in the coronary arteries often result in compromised oxygen delivery to heart tissue and subsequent myocardial infraction (MI).

Adverse effects: Predictably, the most common adverse effect of heparin therapy is hemorrhage, which is basically an extension of its pharmacological effect. Of greater concern, is the loss of platelets or thrombocytopenia. This necessitates routine monitoring of blood components count (Complete blood count-CBC) in addition to aPTT during heparin therapy. The patient vital signs including blood pressure and heart rate are monitored, as hypotension may be indicative of an internal hemorrhage. The patient is also observed for any signs of bleeding in the urine or stool. Patient receiving SC heparin or LMWH therapy do not require aPTT monitoring..

Indications: DVT, PE, MI, Prophylaxis of thrombosis. Contraindications: Hypersensitivity to heparin, Presence of active bleeding, Hemophilia, Thrombocytopenia, Intracranial hemorrhage, Bacterial endocarditis or Active tuberculosis, Ulceration of the GI tract, Severe hypertension, Threatened abortion And Visceral carcinoma Reduced interaction with platelets (lower incidence of thrombocytopenia

Enoxaparin (Orgaran), dalteparin (Fragmin), tinzaparin (Innohep). Dosed once or twice a day subcutaneously. Produced by depolymerizing standard heparin with MW ranging from 2000 to 9000. Longer half-life, high bioavailability. Less liver clearance and binding to macrophages. Less non-specific binding with tissues. Therefore, it requires Little monitoring Use: prevention of DVT following hip or knee replacement, but also used to treat established DVT, ischemic stroke, pulmonary embolism, and thomboembolism in cancer patients Side effects: Bleeding

Fondaparinux (Arixtra) is a synthetic pentasaccharide identical to the antithrombin binding region of heparin. Mechanism of Action: In conjunction with antithrombin it inhibits factor Xa, but not thrombin. Bleeding risk, can lower platelets but no heparin induced thrombocytopenia.

Drugs which only inhibit thrombin, not through antithrombin, preventing blood coagulation. Originally derived from leeches (hirudin).

Used in place of heparin when heparin induces thrombocytopenia [HIT] (where the circulating platelets are reduced but thrombosis increases) Dosing by IV and is expensive. Lepirudin production has been permanently been discontinued as of April 2012. The discontinuation was not related to any safety concerns but due to a business decision by Bayer HealthCare

Synthetic Derivative Inhibits thrombin by blocking the catalytic site. Treats thrombosis in HIT, IV administration

Synthetic Derivative--20 amino acid peptide. Direct thrombin reversible inhibitor Given in combination with aspirin to prevent clot formation with unstable angina undergoing coronary angioplasty. IV administration Metabolized by the liver.

Intrinsic XII XIIa (H) XI XIa (H) (C) IX IXa (H) Ca++ F III VIII (C) X Xa (H) Ca++ PF III Extrinsic (C) VII VIIa V (C) (Prothrombin) II II (thrombin) (H) XIII Fibrinogen Fibrin(loose) Fibrin (tight)

Mechanism of action and administration Warfarin is the prototype oral anticoagulant. Warfarin inhibits the synthesis of vitamin K dependent factors (II, VII, IX & X, protein C and S). The diminished production of these clotting factors results in a decreased coagulation tendency of the blood. In contrast to heparin, warfarin onset of action is delayed (requires 5-7 days), while its duration is long making it ideal for chronic or long-term prevention in patients at risk for thromboembolism. In contrast to the acute use of heparin during thromboembolic events, warfarin therapy is strictly prophylactic anticoagulation

via the use of international normalized ratio (INR) for monitoring warfarin therapy. INR is more universal and permits comparing INR values from different laboratories.

food (vitamin K content) interactions in the anti-coagulated patient is relatively high. Strict compliance with warfarin use and dietary consistency is essential to successful anticoagulation therapy. To reduce the risk of bleeding in anti-coagulated patients the use alcohol and over the counter medications, particularly those containing non-steroidal anti-inflammatory drugs (NSAIDS) such as Ibuprofen, ketoprofen and numerous others in this class is restricted. Adverse effects: Generally well tolerated, excessive anticoagulation may increase bruising and bleeding tendency

Indications: For the treatment of and prevention of recurrence of thromboembolism in: Prosthetic heart valves, Chronic atrial fibrillation, Moderate/high risk surgical procedures Adjunct to treatment of coronary artery occlusion Contraindications: Same as above for heparin, in addition, warfarin is relatively contraindicated in any of the following: Severe hepatic or renal disease, Vitamin K deficiency, and Chronic alcoholism, Need for use of NSAIDS or Salicylates (Aspirin-like drugs) Inability to comply with the therapy.

Stop the Drug, first and foremost Fluid Replacement, if hypotensive due to excessive bleeding Fresh Frozen Plasma, if hypotensive due to excessive bleeding Vitamin K for Warfarin overdose, specific antagonist to Warfarin's effects. May be given orally, SC or IV depending on the urgency. Protamine Sulfate. Reverses the effects of heparin. Given IV as antidote for heparin overdose or to reverse heparin's effects used during surgery Aminocaproic acid. Prevents excessive bleeding.

Prevent platelet adhesion. Platelets provide the initial hemostatic plug at the site of vascular injury. They are also involved in the processes implicated in atherosclerosis and it's potentially catastrophic sequale such as MI and stroke. The use of drugs capable of diminishing the ability of platelets to aggregate (Platelet deaggregants) is rapidly growing due to the well-established efficacy of this class of drugs in treating and/or preventing life-threatening vascular events such as MI and stroke. Several, recently marketed anti-platelet drugs block platelet aggregation by specifically blocking certain receptors on the surface of platelets thereby inhibiting their ability to cross-link and adhere to each other.

The oldest and most readily identified anti-platelet agent is Aspirin. Along with a large class of drugs generally referred to as non-steroidal anti-inflammatory drugs (NSAIDs) aspirin inhibits cyclooxygenase, the enzyme responsible for the activation and subsequent adherence of platelets. Whereas aspirin and the NSAIDs are used to treat pain, inflammation and fever, only aspirin has demonstrated anti-thrombotic efficacy in treating vascular events.

Dose: 80-325mg daily, a dose should be chewed immediately if an acute event such as MI is perceived to be in progress. Side effects : Increased bleeding time, gastrointestinal (GI) upset, potential for drug/drug interactions particularly potentiating the anticoagulant effects of warfarin resulting in excessive bleeding

Generally dosed at 75 mg three times daily alone or in combination with aspirin. Inhibits phosphodiesterase thereby increasing levels of cyclic AMP in the platelet leading deaggregation. Much less frequently used due to the superior efficacy, and lower cost of aspirin. The side-effect profile is relatively low with rare case reports of bleeding and thrombocytopenia.

The side effects profile of plavix is similar to that of aspirin. In addition, although rare, potentially life-threatening bone marrow toxicities including agranulocytosis, leukopenia and neutropenia have been reported with Plavix. Dose: 75 mg daily, Ticlid, 250 twice daily. These agents cause selective, irreversible inhibition of adenosine diphosphate (ADP)-induced platelet aggregation. They are not effective immediately as aspirin, therefore should not be used for acute events such as MI. Plavix possesses similar efficacy to aspirin in preventing vascular events although it is significantly more expensive.

Drugs capable of dissolving formed clots are known as thrombolytics, often referred to as "clot busters" by the lay media. The use of thrombolytic therapy provides clot dissolution & restoration of blood flow to the occluded area. They are utilized if the patient does not adequately improve with anticoagulant therapy or if there is a life threatening clot resulting in continued deterioration and hemodynamic compromise. In PE, thrombolytic therapy may lead to quicker recovery from compromising emboli & restoration of hemodynamic disturbances, nonetheless, no improvement in mortality is observed.

In DVT, lysis of the clot may prevent the PE complication and its sequale. In general using thrombolytics results in more prompt resolution of symptoms than with heparin therapy alone. However the risk of bleeding is greater when they combined in the usual manner with heparin. Indications: PE, DVT, MI and stroke. Mechsnism of action: Activation of plasminogen to plasmin, which breaks down the clot (see Figure earlier) Products: Urokinase, Streptokinase (SK), tissue-Plasminogen Activator (t-PA). Administration: Thrombolytic therapy is most effective when used the earliest time possible following the event. For PE, effective if used within 7 days of event, may be effective up to 14 days after signs and symptoms of PE.

cause an allergic reaction than other thrombolytics particularly if the patient had recent strep infection. Urokinase is no longer available in the US as of 10/2012.

(Alteplase & Reteplase ) are recombinant DNA products and therefore identical to endogenous plasminogen. They are also colt specific and unlikely to precipitate allergic reactions.

Active internal bleeding, GI/Genitourinary Recent surgery, organ biopsy (7-10 days) Recent needle puncture of non-compressible vessels (jugular/subclavian, aorta, femoral vessels) CPR with rib fractures Uncontrolled hypertension Intracranial vascular disease (e.g., aneurysm, malignancy) Recent trauma with possibility of internal injury Pregnancy Age is not a contraindication to thrombolytic the elderly should be treated when indicated. Adverse effects: Bleeding, Hypotension, Thrombocytopenia, Allergic or hypersensitivity reactions (streptokinase)

Used when anticoagulation & thrombolytic therapy is contraindicated, cannot be safely administered or it has failed. Treatment of clotting deficiencies: Hemophilia type A is caused by factor VIII deficiency, while hemophilia type B due to factor IX deficiency. The only treatment for these diseases for these diseases is a life-long intermittent administration (replacement) of these factors. These replacement factors are isolated from human plasma, therefore carry the risk of transmitting hepatitis and HIV

increased half-life, and thus shorter infusions for MIs (only specific approved indications)

only approved for acute MI Derivative of tPA (Alteplase). reteplase (355 amino acids) vs t-PA (527 amino acids) activates plasminogen which is fibrin-bound (fibrin selective) activates plasminogen bound to platelets and endothelial cells not very antigenic half life: 13-16 minutes two separate two minute IV bolus separated by 30 minutes bleeding risk

Highest fibrin selectivity 20-24 minute half life (more resistant to tPA circulating inhibitors) 5 second IV bolus injection