Aspirin (acetylsalicylic acid) is a simple molecule first synthesized in Germany 150 years ago. Its pain-relieving properties were recognized and exploited commercially 100 years ago. In the last 50 years, aspirin has been shown to have remarkable antithrombotic benefits.
Aspirin's antithrombotic effect is mediated by inhibition of blood platelets. The drug blocks a platelet enzyme, cyclo-oxygenase, by acetylating the enzyme's active site. Inhibition of the enzyme blocks production of an important prothrombotic agent known as thromboxane A2. Thromboxane A2 causes activation and aggregation of platelets, which is an early step in thrombosis. Aspirin is more effective in preventing arterial thrombosis (myocardial infarction, stroke) than venous thrombosis (deep venous thrombosis, pulmonary embolism). The explanation for this difference seems to be that platelets play a larger role in causing arterial thrombosis.
Today, more potent platelet inhibitors than aspirin are available, but aspirin remains the most commonly used drug in this category and is still our most cost-effective antithrombotic drug. Aspirin (either 81 mg or 325 mg daily) is indicated in the following conditions:
- Unstable angina (acute coronary syndrome)
- Acute myocardial infarction
- Secondary prevention of myocardial infarction
- Secondary prevention of stroke (carotid or primary cerebrovascular disease)
- Prevention of peripheral arterial thrombosis
Heparin acts immediately to inhibit thrombin (factor IIa), and factors Xa and IXa. The drug can be given either subcutaneously or intravenously but must achieve a plasma level > 0.2U/ml to have its optimum effect in treating active thrombosis. Lower doses of heparin are used to prevent thrombosis. Heparin is used to treat unstable angina and to prevent and treat venous thromboembolism (VTE).
Body Weight-Based Dosing Of Intravenous Heparin In VTEInitial Dosing
Loading: 80 U/kg
Maintenance infusion*:18 U/kg/hr(APTT in 6 hrs.)
Subsequent Dose Adjustments
|APTT (sec)||Dose Change||Additional Action||Next APTT|
|<35 (<1.2 x mean normal)||+4 U/kg/hr||Rebolus with 80 U/kg||6 hrs|
|35-45 (1.2-1.5 x mean normal)||+2 U/kg/hr||Rebolus with 40 U/kg||6 hrs
|46-70** (1.5-2.3 x mean normal)||0||0||6 hrs***|
|71-90 (2.3-3.0 x mean normal)||-2 U/kg/hr||0||6 hrs|
|>90 (>3 x mean normal)||-3 U/kg/hr||Stop infusion 1 hr||6 hrs|
* Heparin 25,000 u in 250 mL D5W. Infuse at rate dictated by body weight through an infusion apparatus calibrated for low flow rates.
** The therapeutic range in seconds should correspond to a plasma heparin level of 0.2- 0.4 U/ml by protamine sulfate titration. When APTT is checked at 6 hrs or longer, steady state kinetics can be assumed.
*** During the first 24 hrs, repeat APTT every 6 hrs. Thereafter, obtain APTT once every a.m. unless it is outside the therapeutic range.
Overlapping Heparin And Warfarin During Acute Anticoagulation
- Give heparin bolus IV
- Obtain diagnostic study
- Heparin 80 u/kg IV bolus followed by 18u/kg/hr IV infusion
- Obtain APTT at 4-6 hrs and keep APTT in a range that corresponds to a plasma heparin level of 0.2-0.4 u/ml.
- Start warfarin on day one at 5 mg and dose daily with the estimated daily maintenance dose or start the estimated daily maintenance dose (2-5 mg.)
- Obtain platelet count every 3-5 days of heparin therapy up to 21 days.
- Give heparin and warfarin jointly for 5-7 days. Stop heparin thereafter when PT gives an INR of 2.0-3.0.
- Continue warfarin at an INR of 2.0-3.0
Managing Bleeding In Patients Receiving Heparin
- Discontinue heparin.
- Monitor vital signs, APTT, Hgb, Hct, platelet count.
- Discontinue heparin.
- Monitor vital signs, APTT, Hgb, Hct, platelet count.
- Give blood transfusions as necessary.
- Consider protamine reversal of heparin.
Protamine reversal for patients receiving constant intravenous heparin:
- Give protamine sulfate (1% solution) at 25 mg by slow IV infusion over 15 min.
- Repeat APTT in 20 min. and 1 hr.
- In patients receiving subcutaneous heparin, it may be necessary to repeat the protamine sulfate infusion after 1 hr. because of variable heparin absorption.
Protamine sulfate can cause severe, anaphylactoid reactions. Use this agent only when severe bleeding warrants it. Have resuscitation equipment nearby.
Heparin Induced Thrombocytopenia, Lepirudin & Argatroban
Standard unfractionated heparin can cause an antibody-mediated (Type II) thrombocytopenia in 2-3% of individuals who receive this drug for longer than 7 days. When the platelet count falls precipitously, STOP heparin. Do not start low-molecular-weight heparin because it will cross-react with the antibody 90% of the time. If a rapidly acting drug is needed, substitute a direct thrombin inhibitor, either lepirudin (Refludan®) or agatroban.
Dosing Lepirudin in Acute Heparin-Induced Thrombocytopenia
- Stop unfractionated heparin
- Do not substitute LMW-heparin
- Hold warfarin
IV infusion (for rapid therapeutic anticoagulation).
- Loading dose: 0.4 mg/kg bolus i.v..
- Maintenance: 0.15 mg/kg/hr i.v. (up to 110 kg body weight
- Adjust maintenance dose to maintain activated partial thromboplastin time (APTT) at 1.5 to 2.5 times the laboratory's mean normal value.
Dosing Argatroban in Acute Heparin-Induced Thrombocytopenia
- Stop unfractionated heparin
- Do not substitute LMW-heparin
- Hold warfarin
IV infusion (for rapid therapeutic anticoagulation)
- Loading dose: no loading dose
- Maintenance: 2 ug/kg/min
- Adjust mainenance dose to maintain APTT at 1.5 to 2.5 times laboratory's mean normal value
Give lepirudin or argatrobn for at least 3 days while holding warfarin. When the platelet count has recovered above 100,000/uL, give warfarin at 5 mg/day and adjust dose by INR.
Clearance of these drugs can be reduced in patients with hepatic or renal insufficiency. Contact the manufacturer of lepirudin (Aventis) or argatroban (SmithKline Beecham) for details of usage in HIT.
* This outline is intended only for initiating therapy in an emergent situation. Contact the manufacturer of danaparoid (Organon) for details of usage in HIT.
Low Molecular Weight Heparins
Low molecular weight heparins are smaller pieces of the heparin molecule that inhibit clotting factor Xa more than factor IIa (thrombin). These drugs are given subcutaneously and can usually be administered in a weight-based dose without subsequent monitoring or dose-adjustment. At a higher dose these drugs are used to treat active thrombotic disease and at lower dose to prevent thrombosis. Three LMW-heparins are widely used in the United States and Canada. They are dalteparin, enoxaparin, and tinzaparin.
Use Of Low Molecular Weight Heparin To Prevent Thrombotic Disease
||2500 anti-Xa U q 24 h|
|Higher-risk Abdominal Surgery, Hip Replacement||5000 anti-Xa U q 24 h|
|Enoxaparin(Lovenox®)||Hip, Knee Replacement||30 mg* q 12 h|
|Abdominal Surgery, Higher-risk Medical Patients||40 mg q 24 h|
|Tinzaparin(Innohep®)||No prophylactic approval in U.S.||75 anti-Xa U/kg q24h|
For enoxaparin 1 mg = 100 antiXa units. Enoxaparin also is used at 40 mg q 24h for longer term outpatient proplylaxis in outpatients after hip or knee replacement.
Use Of Low Molecular Weight Heparin To Treat Unstable Angina
LMW-heparins have proven to be at least as effective as intravenous unfractionated heparin in the treatment of unstable angina. Cost-analysis of LMW-heparin treatment of unstable angina indicate that when total costs are considered, LMW-heparin incurs no more expense than unfractionated-heparin. Dalteparin and enoxaparin are both approved for treatment of unstable angina. Enoxaparin or dalteparin can be given safely to any patient who is a candidate for unfractionated heparin. The major contraindications are active internal bleeding and heparin-induced thrombocytopenia (HIT).
Guidelines for Enoxaparin Treatment of Unstable Angina
- Obtain baseline ECG, cardiac enzymes, troponin, APTT, PT, and CBC
- Determine need for thrombolytic therapy
- Start aspirin, ß-adrenergic blocker and nitrates
- Check for contraindications to LMW-heparin
- Start enoxaparin* or dalteparin* subcutaneously q 12 hr without monitoring or dose-adjustment
- Determine need for long-term anticoagulants (warfarin)
*Dalteparin: 120 anti-Xa U/kg subcutaneously q 12 hr. Enoxaparin 1 mg/kg subcutaneously q 12 hr
Thrombolytic Therapy and LMW-Heparins
LMW-heparin is used in place of unfractionated heparin in unstable angina (UA). If a patient with unstable angina requires thrombolytic therapy because of ST-segment elevation or new LBBB, follow these recommendations:
- TPA (Activase®, Retavase® or TNKase ): If the last LMW-heparin injection occurred within 6 hrs, the patient can be assumed to be anticoagulated and no concurrent heparin is necessary. If the last LMW-heparin injection occurred more than 6-8 hrs. previously, give concurrent IV unfractionated heparin with the TPA.
- Streptokinase- Hold the LMW-heparin during the SK infusion and give the next injection as scheduled after the APTT or TT has returned to less than 1½ times mean normal.
- Invasive Procedures and LMW-Heparins- If cardiac catheterization or coronary artery bypass surgery is to occur within 6 hrs. of a LMW-heparin dose, the patient can be assumed to be fully anticoagulated. If the procedure is to be done more than 6 hrs. after a LMW-heparin dose, IV unfractionated heparin can be given and followed with an activated clotting time (ACT). LMW-heparins have very little effect on the ACT.
- Reversing the effect of LMW-heparin- Although it is rarely necessary, LMW-heparin can be partially neutralized with protamine sulfate. This is rarely necessary. Please see the package insert or PDR for details.
Dalteparin has been studied in the treatment of deep venous thrombosis (DVT) and unstable angina (UA).
Treatment of DVT
Dalteparin Dose: 120 anti-Xa U/kg q 12 h
- A Collaborative European Multicentre Study. Thromb Haemostasis 1991; 65:251-56
Dalteparin Dose: 200 anti-Xa U/kg q 24 h
- Lindmarker P, Holmstrom M, Granqvist S, et al. Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost 1994; 72:186-90
- Fiessinger JN, Lopez-Fernandez M, Gatterer E, et al. Once-daily subcutaneous dalteparin, a low molecular weight heparin, for the initial treatment of acute deep vein thrombosis. Thromb Haemost 1996; 76:195-9
- Luomanmaki K, Granqvist S, Hallert C, et al. A multicentre comparison of once-daily subcutaneous dalteparin (low molecular weight heparin) and continuous intravenous heparin in the treatment of deep vein thrombosis. J Int Med 1996; 240:85-92
Treatment of UA
Dose: 120 anti-Xa U/kg q 12 h
- Fragmin during Instability in Coronary Artery Disease (FRISC) Study Group. Lancet 1996;347:561-8
Tinzaparin has been studied in both DVT and PE. The drug is approved for treatment of DVT with or without PE. The effective treatment dose is 175 anti-Xa U/kg q24h.
1. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heaprin compared with continuous intravenous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992;326:975-82
2. Simonneau G, Sors B, Charbonnier Y, et al. A comparison of low-molecular-weight heparin with unfractionalted heparin for acute pulmonary embolism. N Engl J Med 1997;337:663-9
Algorithm For DVT Care Path
|Initial Assessment of Patient|
|Evidence of DVT. Stool guaiac and
weight in office
||F.U. Telephone call from office|
|Call Case Manager. Send for duplex sonography||NEG
|Evaluate inpatient vs. outpatient criteria-||In-Pt. Crit.||Admit; initiate inpatient Care Path|
|Eligible for outpt. Rx.|
|Day 1 >>>||1. Pt. to lab in Wc from Ultrasound.
2. Call Case Mgr. with orders.
3. Patient Education.
4. Administer 1st doses of LMWH & Warfarin after normal lab results back.
|Day 2 >>>||RN Telephone Assessment
|Day 3 >>>||PT/INR/Plt Ct.
Thrombolytic agents are proteins that activate a plasma proenzyme, plasminogen, to the active enzyme plasmin. Plasmin then solubilizes fibrin and degrades a number of other plasma proteins, most notably fibrogen.
Agents Available And Indications
Streptokinase (SK)- Derived from group C, ß-hemolytic streptococci. Not fibrin specific. Activates adjacent plasminogen by forming a non-covalent SK-plasminogen activator complex. Plasma half-life 30 min. Stimulates antibody production making retreatment difficult.
Urokinase (UK)- Derived from cultured human cells. Not fibrin specific. Activates plasminogen directly by enzymatic action. Plasma half-life 20 min.
Tissue Plasminogen Activator- Derived by recombinant genetics from human DNA. Fibrin specific. Activates plasminogen associated with fibrin directly by enzymatic action. Short plasma half-life. Two preparations of tPA are available.
- Alteplase (tPA) is the glycosylated protein of 527 amino acids produced by recombinant DNA technology.
- Reteplase (sometimes called rPA) is the 39,571 molecular weight non-glycosylated deletion mutein of tPA. It contains 355 of the 527 amino acids of native tPA and includes the kringle 2 and the protease domains of the parent molecule.
- Tenecteplase is the 527 amino acid protein produced by recombinant DNA technology. It differs from alteplase by 6 amino acids
- Acute myocardial infarction- streptokinase, tPA (Alteplase, Reteplase & Tenecteplase)
- Acute ischemic stroke - tPA (Alteplase)
- Acute pulmonary embolism - SK, UK, tPA (Alteplase)
- Acute deep venous thrombosis - SK
- Clotted AV fistula and shunts - UK
- Bleeding is the major complication of thrombolytic therapy. Consequently, absolute contraindications include dissecting aortic aneurysm, pericarditis, stroke, or neurosurgical procedures within 6 months or known intracranial neoplasm. Relative contraindications include major surgery or bleeding within 6 weeks, known bleeding diathesis, and severe uncontrolled hypertension.
- Allergic reactions: SK and anistreplase are potentially allerogenic. Patients are usually pretreated with intravenous hydrocortisone 100 mg.
- Antibody production: SK and anistreplase induce antibody production, which makes retreatment with either of these agents less effective.
Thrombolytic Therapy In Myocardial Infarction
Intravenous Dosing Of Thrombolytic Agents In Acute MI
|(All patients with acute MI should receive one chewable aspirin 160-325 mg as soon as the diagnosis is suspected)|
|Drug||Loading Dose||Maintenance Dose||Duration Of Infusion||Concurrent Heparin|
|Streptokinase||No||1.5 million IU (45 mL NaCl)||1 hr||No|
|tPA (Alteplase)||15 mg||50 mg over 30 min** and 35 mg over next hr*** (100 mL sterile H2O)||90 min||Yes|
|tPA (Reteplase)||Given by 10 + 10 U double bolus, 10 U bolus over 2 min, wait 30 min and repeat 10 U over 2 min.||34 min||Yes|
|tPA (Tenecteplase)||30-50 mg by single bolus body weight
(see package insert for precise dosing)
|** 0.75 mg/Kg, not to exceed 50 mg over 30 min. *** 0.50 mg/Kg, not to exceed 35 mg over the next hour.|
Other Regimens For Thrombolytic Agents
Peripheral Intra-arterial Infusion
SK: 20,000 IU bolus followed by 2,000 IU/min for 60 min.
UK: 6,000 IU/min for 1-2 hrs. (Both SK and UK should be given with concurrent systemic heparin.)
Clotted IV Catheter Clearance with UK
Inject UK 5,000 IU in 1 mL into catheter. For central venous catheter inject 5,000 IU/mL in volume equal to volume of the catheter. Allow 30-60 min for thrombolysis.
Clotted AV Cannula Clearance with SK
Inject SK 250,000 in 2 mL in each end of cannula. Clamp ends and allow 30-60 min for thrombolysis.
Rapid Evaluation Of Patients With Suspected Acute Myocardial Infarction
|Chest pain or other symptoms suggestive of acute myocardial ischemia|
|ECG shows one of these:
|Give one chewable aspirin 160 mg - 325 mg|
|Confirm absence of contraindications to thrombolytic agents*|
|Symptoms present less than 6 hrs.||Symptoms present between 6 & 12 hrs.||Symptoms present more than 12 hrs.|
|Give thrombolytic agent, therapy most beneficial||Strongly consider thrombolytic agent, therapy moderately beneficial||Therapy less effective, but consider if pain continues or recurs|
* See section on indications. Thrombolytic agents seem to offer less benefits in patients over 75 although age is not a contraindication.
Thrombolytic Therapy In Ischemic Stroke
Dosing tPA (Alteplase) In Acute Ischemic Stroke
- Duration of symptoms and findings less than 3 hours
- CT scan of head shows no intracranial bleeding
- Blood pressure not higher than 185/100 mm Hg (BP must be kept below 185/110 mm Hg during and after therapy)
tPA (Alteplase) Dose
- 0.9 mg/kg IV over one hour (no concurrent heparin or aspirin)
Note: Patients must be carefully selected and treated within 3 hours. Other thrombolytic agents cannot be substituted for tPA. Please refer to the reference given below before using tPA in ischemic stroke.
Clinical debate: should thrombolytic therapy be the first-line treatment of acute ischemic stroke? New England Journal Of Medicine 1997; 337:1309-13
Thrombolytic Therapy In Pulmonary Embolism and Deep Venous Thrombosis
|Dosing Thrombolytic Agents In PE/DVT|
|Drug||Indication||Loading Dose||Maintenance Dose||Duration Of Infusion||Concurrent Heparin|
DVT or arterial thromboembolism
|250,000 IU over 30 min,
250,000 IU over 30 min
|tPA (Alteplase)||PE||None||100 mg||2hrs.||Optional|
|Urokinase||PE||2,000 IU/lb over 10 min||2,000 IU/lb/hr||12 hrs.||NO|
|Interfacing Heparin And Thrombolytic Agents|
|Drug||First Step||Second Step||Third Step||Last Step|
|SK, UK||Stop heparin Infusion||Infuse thrombolytic agent in prescribed fashion||Stop thrombolytic agent infusion||Restart heparin Infusion with or without a loading dose when APTT or thrombin time returns to less than twice normal (usually after 3-4 hours)|
|tPA||If it is elected to discontinue heparin during tPA Infusion for PE, follow directions for the other thrombolytic agents given above.|
Warfarin is taken by mouth to inhibit vitamin K. This vitamin is essential for effective production of clotting factors II, VII, IX, X, and anticoagulant proteins C&S. Warfarin is given once daily. It is monitored by the prothrombin time and the international normalized ratio (INR).
Warfarin is a narrow therapeutic index drug (NTI). When the INR falls below 2.0 thrombosis risk increases and when the INR rises above 4.0 serious bleeding risk increases.
Therapeutic Recommendations For Warfarin
|Mechanical Heart Valves||2.5-3.5|
Duration of Action
Warfarin takes 4-7 days to have its optimum effect. Large loading doses do not markedly shorten the time to achieve a full therapeutic effect but cause rapid falls in the level of protein C, which may precipitate paradoxical thrombosis in the first few days of warfarin therapy. The following general recommendations for warfarin use are made.
- Initiate therapy with the estimated daily maintenance dose (2-5 mg.).
- Elderly or debilitated patients often require low daily doses of warfarin (2-4 mg.).
- Patients are confused by alternating daily doses (e.g. 7.5 and 5.0 mg).
- Significant changes in INR can usually be achieved by small changes in dose (15% or less).
- 4-5 days are required after any dose change or any new diet or drug interaction to reach the new antithrombotic steady state.
Frequency of Dosing
Warfarin is monitored by the one stage prothrombin time. Prothrombin times are reported in seconds, as a ratio of the prothrombin time in seconds to the mean normal prothrombin time of the laboratory, and as the international normalized ratio (INR). The INR is the most reliable way to monitor the prothrombin time.
Some Drug Interactions With Warfarin
|Drugs That May Lengthen PT||Drugs That May Shorten PT|
|(higher INR; increased warfarin effect)||(lower INR; decreased warfarin effect)|
|Lovastatin||Vitamin E (large doses)|
Remember: Drug interactions with warfarin are not always known or predictable. Repeat an INR 5-7 days after adding, subtracting or changing the dose of any drug in a patient receiving warfarin.
Dietary And Other Interactions With Warfarin
Patients taking warfarin should eat a diet that is constant in vitamin K.
- Minimize changes in intake of green leafy vegetables (spinach, greens, and broccoli), green peas, and oriental green tea.
Conditions that interfere with vitamin K uptake or interfere with liver function will increase the warfarin effect.
- Expect a longer prothrombin time in patients with CHF, jaundice, hepatitis, liver failure, diarrhea, or extensive cancer or connective tissue disease.
- Expect a longer prothrombin time when patients receiving warfarin are hospitalized for any reason.
Metabolic alterations can affect the prothrombin time.
- Expect a longer prothrombin time in patients with hyperthyroidism or high fever.
- Expect a shorter prothrombin time in patients with hypothyroidism.
Initiating Warfarin Therapy
Are there any contra-indications?
- History of warfarin-induced purpura
- Active Bleeding
Has the patient been instructed on drug interactions and a diet of constant vitamin K intake?
Has a baseline PT, APTT, and platelet count been obtained?
|Day 1||Day 2||Day 3||Day 4 & after|
|In-patient Anticoagulation||Warfarin Dose||5 mg||5 mg||2-5 mg||2-5 mg|
|Out-patient Anticoagulation||Warfarin Dose||2-5 mg||2-5 mg||2-5 mg||2-5 mg|
** Starting on day 3, adjust subsequent doses as outlined below based on INR. Obtain INR 3-4 times in week 1; twice in 2nd week; then weekly until stable; then monthly. Elderly or debilitated patients often require low daily doses of warfarin (2-3 mg).
Initiating Therapy: Dose Adjustment
|5.0 - 10.0 mg
2.5 - 5.0mg
0.0 - 5.0 mg
5.0 - 7.5 mg
0.0 - 5.0 mg
7.5 - 10.0 mg
0.0 - 5.0mg
|7.5 - 12.5 mg
5.0 - 10.0 mg
0.0 - 7.5 mg
Stable Patients: Dosing Algorithm To Achieve INR Of 2.0 - 3.0
Warfarin Sodium¹: Monitoring and Dosage Adjustment in Stable Anticoagulated Patients (based on a starting dose of 4 mg/d)
|>10.0||Stop warfarin. Contact patient for examination.|
|7.0-10.0||Stop warfarin for 2 days; decrease weekly dosage by 25% or by 1 mg/d for next week (7 mg total); repeat PT³ in 1 week.|
|4.5-7.0||Decrease weekly dosage by 15% or by 1 mg/d for 5 days of next week (5 mg total); repeat PT in 1 week.
|3.0-4.5||Decrease weekly dosage by 10% or by 1 mg/d for 3 days of next week (3 mg total); repeat PT in 1 week.|
|1.5-2.0||Increase weekly dosage by 10% or by 1 mg/d for 3 days of next week (3 mg total); repeat PT in 1 week.|
|<1.50||Increase weekly dose by 15% or by 1 mg/d for 5 days of next week (5 mg total); repeat PT in 1 week.|
¹ - Coumadin®, 1mg tablet
² - INR: International Normalized Ratio = (x/y)z , where:
x = Prothrombin Time of sample (sec)
y = Mean Normal Prothrombin Time (sec)
z = [ ISI of Thromboplastin]
Evaluation Of Atrial Fibrillation
|Atrial fibrillation on ECG
(constant or intermittent)
|Obtain history and physical exam
(valvular, ischemic or hypertensive
heart disease present? Diabetes
or thyrotoxicosis present?)
|Obtain surface echocardiogram
(valvular heart disease, atrial or
appendegeal thrombus or
LV dysfunction present?)
|Valvular, ischemic, or hypertensive heart disease present; diabetes, previous stroke or TIA present; or patient 65 years or older.||Thrombosis?
|No heart, or systemic disease
detected and patient less than 65
INR of 2.0-3.0
("Lone atrial fibrillator")
If low intensity anticoagulation is contraindicated, aspirin at 325 mg daily may offer some benefit, but warfarin has performed better in most comparisons to aspirin.
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