Hemostasis and Thrombosis - part 8 pps

Risk stratification and therapy of mechanical valve patients High Risk Treat to INR 2.5 - 3.5 + ASA 80-100mg/day.. Patients with symptoms less than three hours old are candidates for thr

147Antithrombotic Therapy for Cardiac Disease

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in Table 20.6 It is relatively safe for short periods of time to stop anticoagulation.One should avoid large doses of vitamin K (greater than 1-2 mg) for reversal ofwarfarin anticoagulation The higher doses of vitamin K are no more effective thanlower doses, and when the patient needs to be restarted on warfarin it will take amuch longer time to reach a therapeutic prothrombin time when high doses ofvitamin K have been used

Bioprosthetic Heart Valves

Although the risk is lower, bioprosthetic hearts valves still have a definite risk ofassociated embolization This is highest immediately after surgery and in patientswith bioprosthetic valves who have other risk factors such as atrial fibrillation There-fore patients with a new bioprosthetic valve should be anticoagulated for 3 monthsafter surgery with warfarin to an INR of 2.0-3.0 Furthermore, patients with atrialfibrillation, history of embolism or those with left atrial thrombi should be antico-agulated indefinitely with warfarin

Chronic Heart Failure

Patients with left ventricular ejection fractions under 30% associated with globaldysfunction have rates of stroke of 3-4%/year In addition, these patients are also atrisk for venous thrombosis with as many as 20% of these patients dying of venous

Table 20.5 Risk stratification and therapy of mechanical valve patients

High Risk

Treat to INR 2.5 - 3.5 + ASA 80-100mg/day.

Valve implanted before 1980

Bileaflet valve in aortic position

Treatment and Risk Stratification of Bioprosthetic Valves

AVR or MVR: INR 2.5 - 3.5 for 3 months then ASA

+ a fib: INR 2-3

+ hx embolism, vascular disease or LA thrombus:

INR 2.5-3.5 + ASA 80 - 100 mg/day

Table 20.6 Risk(%) for embolic events when off anticoagulation (Pauker, JAMA)

Aortic Position One Day Two Weeks One Year

thrombotic disease Unfortunately this group of patients has not been well-studied,but patients with global cardiac dysfunction should be considered candidates foranticoagulation, especially if they have had previous emboli

3 Bloomfield P Choice of heart valve prosthesis Heart 2002; 87(6):583-9

4 Braunwald E, Antman EM, Beasley JW et al ACC/AHA 2002 guideline updatefor the management of patients with unstable angina and non-ST-segment eleva-tion myocardial infarction—summary article: J Am Coll Cardiol 2002;40(7):1366-74

5 Brogan GX Jr Bench to bedside: pathophysiology of acute coronary syndromesand implications for therapy Acad Emerg Med 2002; 9(10):1029-44

6 Chan AW, Moliterno DJ Defining the role of abciximab for acute coronary dromes: lessons from CADILLAC, ADMIRAL, GUSTO IV, GUSTO V, andTARGET Curr Opin Cardiol 2001; 16(6):375-83

syn-7 Choo JK, Young JJ, Kereiakes DJ A guide to drug use during percutaneous nary intervention Drugs 2002; 62(18):2589-601

coro-8 Fuster V, Ryden LE, Asinger RW et al ACC/AHA/ESC guidelines for the agement of patients with atrial fibrillation Eur Heart J 2001; 22(20):1852-923

man-9 Hart RG, Palacio S, Pearce LA Atrial fibrillation, stroke, and acute antithrombotictherapy: analysis of randomized clinical trials Stroke 2002; 33(11):2722-7

10 Kereiakes DJ, Montalescot G, Antman EM et al Low-molecular-weight heparintherapy for non-ST-elevation acute coronary syndromes and during percutaneouscoronary intervention: an expert consensus Am Heart J 2002; 144(4):615-24

11 McKay RG, Boden WE Small peptide GP IIb/IIIa receptor inhibitors as upstreamtherapy in non-ST-segment elevation acute coronary syndromes: results of thePURSUIT, PRISM, PRISM-PLUS, TACTICS, and PARAGON trials Curr OpinCardiol 2001; 16(6):364-9

12 Mukherjee D, Topol EJ The role of low-molecular-weight heparin in lar diseases Prog Cardiovasc Dis 2002; 45(2):139-56

cardiovascu-13 Ohman EM, Harrington RA, Cannon CP et al Intravenous thrombolysis in acutemyocardial infarction Chest 2001; 119(1 Suppl):253-277

14 Osula S, Bell GM, Hornung RS Acute myocardial infarction in young adults:causes and management Postgrad Med J 2002; 78(915):27-30

15 Stein PD, Alpert JS, Bussey HI et al Antithrombotic therapy in patients withmechanical and biological prosthetic heart valves Chest 2001; 119(1Suppl):220-227

16 Crowther MA, Ginsberg JS, Julian J et al A comparison of two intensities of farin for the prevention of recurrent thrombosis in patients with the antiphos-pholipid antibody syndrome N Engl J Med 2003; 349(12):1133-8

war-17 Hanly JG Antiphospholipid syndrome: an overview CMAJ 2003; 16(13):1675-82

18 Kearon C, Ginsberg JS, Kovacs MJ et al Extended low-intensity anticoagulationfor thrombo-embolism investigators Comparison of low-intensity warfarin therapywith conventional-intensity warfarin therapy for long-term prevention of recur-rent venous thromboembolism N Engl J Med 2003; 349(7):631-9

to more unusual causes of stroke in selected cases.

Acute Stroke

The patient with acute neurological defects demands a rapid decision as to whetherthe defect is ischemic in nature and, if so, what therapy should be instituted (Table21.1) Patients with symptoms less than three hours old are candidates for throm-bolytic therapy Evaluation of these patients should be rapid Patients should un-dergo a CT scan to rule out hemorrhage or mass lesion Evaluation for an underlyingsystemic process should also be undertaken

Patients who meet rigorous NINDS trial criteria should be considered for bolytic therapy (Table 21.2) Thrombolytic therapy is believed to be associated with

throm-an improvement in clinical outcome but the rate of intracrthrom-anial hemorrhage is highand patient selection is crucial The rate of bleeding complications is increased inpatients who did not meet the NINDS criteria but still received thrombolytic therapy.Absolute contraindications to thrombolytic therapy include CT evidence of intrac-ranial hemorrhage, systolic blood pressure greater than 185 mmHg or diastolic greaterthan 110 mm Hg, or a seizure with or before stroke onset Patients who undergothrombolytic therapy should receive tPA 0.9 mg/kg (maximum 90 mg) with tenpercent of the dose given in one minute The rest should be given over one hour.Patients who receive thrombolytic therapy should not receive any other form ofanticoagulation including aspirin for 24 hours These patients should be carefullymonitored for signs of bleeding

Table 21.1 Antithrombotic therapy of cerebrovascular disease

Transient Ischemic Attack

Ipsilateral carotid stenosis > 69%: endarterectomy

Others: aspirin 75-160 mg/day or clopidogrel in aspirin-intolerant patients

Patients who do not undergo thrombolytic therapy and do not have an obvious

embolic source for their stroke should be started on aspirin Two large trials haveshown a small but real benefit of aspirin in preventing death or disability Sincepatients with stroke also have risk factors for ischemic heart disease the aspirin will

be of benefit for this as well Clopidogrel can be substituted in the aspirin-intolerantpatient Currently the combination of aspirin and clopidogrel is being examined in

a large trial to see if it has any advantage over single drug therapy

Recently a trial using a novel sustained-release form of dipyridamole and aspirinshowed greater benefit in secondary stroke prevention than with aspirin alone How-ever, the results of this isolated trial have been controversial and in this trial thecombination pill had no effect on cardiovascular events Until further data is avail-able from an ongoing trial, the role of dipyridamole in stroke prevention remainsunknown

Patients who clearly have an embolic source for their stroke require life-long

anti-coagulation The timing of the initiation of heparin therapy is controversial, butpatients with small strokes without significant hemorrhage should be started onheparin within 24 - 48 hours of the event and maintained on warfarin at an INR of2-3

It is not clear how long the patient who suffers an intracranial hemorrhage onwarfarin should remain off this drug Recent data suggest that one to two weeks offwarfarin may be appropriate if the patient has a very strong indication for antico-agulation such as a mechanical valve One should carefully investigate the circum-stances around the time of the bleed to see if there are any reversible factors such as

a very high INR Given the lack of data, treatment should be tailored to the vidual patient’s circumstances

indi-Table 21.2 NINDS trial criteria for tPA

Patients Must Have All the Following

An ischemic stroke with a clearly defined time of onset,

A deficit measurable on the NIHSS (National Institutes of Health Stroke Scale), and Baseline computed tomographic (CT) scan of the brain showing no evidence of intracranial hemorrhage.

Exclusions (Any of the following)

Stroke or serious head trauma within the preceding 3 months;

Major surgery within the prior 14 days;

History of intracranial hemorrhage;

Systolic blood pressure above 185 mm Hg or diastolic blood pressure above

110 mm Hg;

Rapidly improving or minor symptoms;

Symptoms suggestive of subarachnoid hemorrhage;

Gastrointestinal hemorrhage or urinary tract hemorrhage within the previous 21 days; Arterial puncture at a noncompressible site within the previous 7 days;

Seizure at the onset of stroke;

Patient on oral anticoagulants with INR >1.7;

Patients on heparin within the previous 48 hours and still with an elevated aPTT; Platelet count below 100,000;

Prothrombin time higher than 15 seconds;

Glucose concentration below 50 mg/dl or above 400 mg/dl.

N Engl J Med 1995; 333(24):1581-7

151Stroke and Peripheral Vascular Disease

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A frequent cause of morbidity and mortality in the stroke patient is deep venousthrombosis and pulmonary embolism Stroke patients should receive prophylaxiswith low molecular weight heparin which has been shown to be safe and effective inthese patients and does not increase the risk of bleeding

Transient Ischemic Attacks

Patients with a transient neurological syndrome should be evaluated for the ence of carotid stenosis Patients with ipsilateral carotid stenosis of over 70% shouldreceive endarterectomy if they are surgical candidates All patients with TIA should

pres-be started on aspirin Clinical trials have shown that 30-75 mg of aspirin is lent to higher doses in secondary prevention For patients who are intolerant ofaspirin or who are aspirin failures clopidogrel is of benefit Patients with atheroscle-rosis should also receive aggressive treatment of risk factors such as adverse lipidprofiles and smoking

equiva-Patients with Recurrent Strokes

Except for a small effect of aspirin, there is no good strategy for secondary vention of nonembolic stroke Patients who fail antiplatelet therapy are often placed

pre-on warfarin Warfarin at high INRs (3-4.5) is associated with a high rate of nial bleeding and should not be used A trial looking at lower INRs (1.4- 2.8) alsodemonstrated that warfarin fails to offers any benefit over aspirin in the secondaryprevention of non-embolic strokes Currently a clinical trial is underway to see ifwarfarin at an INR 2-3 is effective for stroke prevention As noted above, trials areongoing to study novel approaches to antiplatelet therapy

intracra-Patent Foramen Ovale and Stroke

Patent foramen ovale (PFO) exists in 20% of normal individuals and the dence in young stroke patients, especially those with idiopathic stroke, may be ashigh as 60% Much controversy exists over the value of diagnosing PFO and ap-proach to management In general the PFO is more likely to be a source of embo-lism if:

inci-• There is no evidence of atherosclerosis;

• There is a source of venous thrombosis;

• MRI shows areas of multiple infarcts;

• The PFO shows significant shunting;

• There is the presence of atrial septal aneurysm

Management options for PFO are to 1) close the PFO either surgically or withcatheter devices, 2) use aspirin, or 3) use warfarin Presently there is much interest intranscatheter closure devices However, studies demonstrate a residual risk of throm-bosis and if the patient has an underlying hypercoagulable state, closure alone is notadequate therapy Although data is conflicting, a meta-analysis has demonstratedwarfarin still should be considered for patients with presumed embolic stroke andPFO

Stroke in Young Patients

Patients under age 50 with a stroke should receive aggressive evaluation (Table21.3) In younger patients, premature atherosclerosis and embolism are still the twomost common causes of stroke Patients should undergo a transesophagealechocardiogram to investigate for any underlying cardiac source of stroke

Management of patients who have an embolic source of stroke and ties on echocardiography is still controversial The rate of recurrent stroke in pa-tients with patent foreman ovale is approximately 1-2% per year Therapeutic optionsinclude surgical correction or life-long anticoagulation Patients with large defects,more than one event, or posterior circulation events appear to be at higher risk ofrecurrence

abnormali-Patients with premature strokes should receive a limited evaluation for agulable states There is no convincing evidence that deficiency of protein S, protein

hyperco-C, antithrombin or the presence of the factor V Leiden mutation increases risk ofstroke Patients should be evaluated for the presence of antiphospholipid antibod-ies, obtain a full lipid profile and have a homocysteine level determined Given theassociation with premature atherosclerosis, levels of lipoprotein(a) should also bedetermined

Peripheral Vascular Disease

Acute Ischemia

Patients who present with an acute occlusion of the arterial blood supply of alimb require rapid intervention to save the limb The time window is only four to sixhours from onset of ischemia for limb salvage Patient may suffer either an embo-lism or sudden thrombosis of a pre-existent atherosclerotic area Patients with em-bolic disease often just require removal of the thrombus Patients with thrombosisover atherosclerosis often require re-vascularization; therefore, differentiating be-tween these two entities is important in order to formulate therapy Patients whohave embolic occlusion have sudden onset of symptoms and rarely have pre-existingsymptoms Often there will an obvious source of the embolism such as atrial fibril-lation Patients with underlying atherosclerosis will have previous symptoms of pe-ripheral vascular disease

The presentation of acute ischemia is the classic “Five P’s”: Pain, Pallor, Paralysis Paresthesia, and Pulselessness The affected limb should undergo evaluation to de-

termine the degree of ischemia Patients with mild weakness and sensory loss butwithout profound paralysis of the limb need emergent therapy to salvage the limb.The patient should undergo rapid evaluation for systemic disease Although embo-lic occlusion can often be diagnosed on clinical grounds, angiography is indicated inmany cases to determine the underlying cause by either demonstrating diffuse ath-erosclerotic disease or a discrete embolism

Patients with acute ischemia require rapid anticoagulation with heparin Patientswith embolic disease and salvageable limbs require embolectomy via a Fogarty cath-eter Catheter- based thrombolytic therapy is required for thrombi that cannot beremoved with the catheter or for multiple small vessel thrombi Patients with embolic

Table 21.3 Evaluation of the young patient with stroke

Patients who have thrombosed their bypass grafts are often treated with warfarinanticoagulation with or without aspirin Patients whose grafts fail due to thrombosisand not due to technical reasons or fibrous hyperplasia should be given a trial ofwarfarin combined with low-dose aspirin

Table 21.4 Blue toe syndrome (after O’Keefe)

Deep venous thrombosis

Vasculitis

Microscopic polyarteritis Classic polyarteritis nodosa Lupus vasculitis

For acute venous thrombosis the approved doses are either enoxaparin 1 mg/kgevery 12 hours or tinzaparin 175 µ/kg every day (see Table 22.2 for all LMWHdoses) For low-risk patients (calf vein thrombosis, upper extremity thrombosis),once-a-day therapy with 1.5 mg/kg of enoxaparin can be used, but this may not beadequate for higher-risk patients and twice a day therapy should be used One trialdid demonstrate that once daily dalteparin was inferior to twice a day therapy forvenous disease and this dosing should not be used For short courses of therapy,most patients do not need to have LMW heparin levels drawn Patients who are veryobese (>two times ideal body weight), who have severe liver or heart failure, who arepregnant, or on long-term LMWH therapy should have levels performed.LMWH are renally cleared and the dose needs to be adjusted for renal function.For patients with creatinine clearance between 10-30 cc/hr the dose of enoxaparin is0.65 mg/kg q12 hours In patients on dialysis or with creatinine clearances less that

30 cc, the dose of enoxaparin should be 1 mg/kg/day The pharmacokinetics ofLMWH are not affected by weight and there should be no capping or adjusting ofdoses for overweight patients Levels are drawn four hours after injection and thetherapeutic range for enoxaparin is 0.7-1.2 anti-Xa units Therapeutic ranges forother low molecular heparins have not been as well established

The LMW heparins can be used in either inpatient or outpatient settings though LMW heparin is more expensive, inpatient savings can be realized sincemultiple aPTT’s, daily platelet counts, and continuous intravenous therapy are notneeded In addition, it was in the general inpatient population that clinical trialsdemonstrated LMW heparin’s effectiveness and safety over that of standard heparin

Al-Table 22.2 Agents and dosing

Heparin

Route of administration: Subcutaneous or intravenous

Prophylactic: 5,000 units tid

Therapeutic: Bolus 5-10,000 units followed by 1-2,000 units/hour to achieve heparin levels of 0.35-0.7 anti-Xa units

Low Molecular Weight Heparin

Prophylactic: 2850 units every 24 hours (38 units/kg in high risk patients)

Therapy: 86 units/kg every 12 hours or 171 units/kg every 24 hours

Tinzaparin

Prophylactic: 3500 units every 24 hours (4500 units in high risk patients)

Therapy: 175 units every 24 hours

Pentasaccharide

Fondaparinux

Prophylaxis: 2.5 mg every 24 hours

Therapy: 7.5 mg every 24 hours (consider 5.0 mg in patients under 50kg and 10 mg

in patients over 100 kg)

157Heparin and Heparin-Like Drugs

22

The ability to give LMW heparin subcutaneously has opened the door to tient therapy Careful patient selection is crucial Patients should be considered foroutpatient therapy if the only reason for admission was giving intravenous heparintherapy The first dose of LMW heparin is given as soon as possible after diagnosis,and warfarin is started the first evening after diagnosis The second dose of LMWHshould be a “transition” to get the patient on an 8am & 8pm schedule This isderived by multiplying the patient’s usual dose of 1 mg/kg by the time of the firstdose until the second subtracted from 12 For example, if a 60 kg patient receivedhis first dose at midnight, at 8am the patient would get 40 mg and from then on60mg every 12 hours Patients should be followed every day with a visit or phonecheck One still needs to overlap LMW heparin and warfarin by 24 hours once theINR is therapeutic

outpa-Antithrombotic Use of Standard Heparin

Standard heparin is fading from use due to its unfavorable and unpredictablepharmacokinetics If standard heparin is used, it is critical to give enough The stron-gest predictor of repeat thrombosis is failure to achieve adequate anticoagulation at

24 HOURS The bolus should be 5,000 units (10,000 for larger thrombi or

pulmo-nary embolism) The initial drip should be 1400 units/hr The traditional regimen

of starting with 1000 units/hour resulted in woefully inadequate anticoagulation inthe vast majority of patients The aPTT is checked 6 hours after the bolus and thedrip is adjusted accordingly if the aPTT is subtherapeutic Since a supratherapeuticaPTT may just reflect the bolus, one should never turn down the drip until twoconsecutive aPTT’s are supratherapeutic 6 hours apart Therapeutic range varieswith different aPTT reagents and must be standardized at each laboratory withheparin levels A national survey showed that therapeutic heparin levels can varyfrom aPTT ratios of 1.8-2.5 to 2.5-4.8! Some patients may require as much as2,000 to 2,400 units/hour

Fig 22.1 Mechanism of actions of heparin and heparin like anticoagulants.