Antithrombotic Therapy in Critically Ill Patients

Kevin E. Anger

Bonnie C. Greenwood

Christopher D. Adams

John Fanikos

I. ANTIPLATELET AGENTS

A. Acetylsalicylic acid (aspirin) (Table 90-1).

1. General principles.

a. Gastrointestinal (GI) bioavailability 100%; rectal absorption is erratic (60% to 76%).

b. Aspirin is contained in many over-the-counter (OTC) products. Monitor total aspirin exposure.

c. Antiplatelet effect lasts for life span of platelet (7 to 10 days).

2. Mechanism of action.

a. Inhibits prostaglandin synthesis.

B. P2Y₁₂ inhibitors (Table 90-2).

1. General principles.

a. Prodrugs requiring hepatic activation.

b. Antiplatelet effect can last for life span of platelet (7 to 10 days).

2. Mechanism of action.

a. Inhibits activation of adenosine diphosphate (ADP)-mediated glycoprotein IIb/IIIa (GP IIb/IIIa) complex.

C. GP IIb/IIIa inhibitors (Table 90-3).

1. General principles.

a. Abciximab (a monoclonal antibody), eptifibatide (a heptapeptide), and tirofiban (a nonpeptide) cause competitive GP IIb/IIIa receptor blockade.

b. Duration of effect is agent specific and is influenced by its binding (i.e., abciximab irreversible up to 10 days) and renal function/elimination (i.e., for tirofiban and eptifibatide, 2 to 4 hours).

2. Mechanism of action.

a. Platelet function is inhibited by blocking the GP IIb/IIIa receptor, the major surface receptor involved in platelet aggregation.

D. Phosphodiesterase inhibitors (Table 90-4).

1. General principles.

a. Dipyridamole inhibits platelet activation and aggregation by increasing adenosine, a coronary vasodilator, and cyclic adenosine monophosphate (cAMP).

TABLE 90-1 Aspirin and Aspirin-Containing Products

Drug	Indications	Dosing, timing, duration	Monitoring	Precautions and contraindications
Acetylsalicylic acid (Aspirin)	Treatment of ACS +/− PCI	Loading dose: 325 mg orally 81 mg if on prior antiplatelet therapy Maintenance: 81-325 mg/d orally	CBC Signs of bleeding Blood pressure LFTs Renal function	*Precautions* Thrombocytopenia Bleeding disorders Alcohol use (three or more drinks per day) Pregnancy (third trimester) GI disorders Renal failure Severe hepatic insufficiency Concomitant antithrombotic medication use Alcohol consumption *Contraindications* Hypersensitivity to salicylates Children and teenagers with chickenpox or flu symptoms (risk of Reye syndrome)
	Primary and secondary prevention of MI in patients with chronic stable angina, previous MI, or UA	81-325 mg/d orally
	Secondary prevention in stroke and TIA patients	75-325 mg/d orally
	Acute thrombotic stroke	160-325 mg/d, initiated within 48 h (in patients who are not candidates for thrombolytics and are not receiving systemic anticoagulation)
	Secondary prevention in CABG, carotid endarterectomy patients	75-325 mg/d starting 6 h following procedure; if bleeding prevents administration at 6 h after CABG, initiate as soon as possible
ACS, acute coronary syndromes; PCI, percutaneous coronary intervention; CBC, complete blood count; LFT, liver function tests; MI, myocardial infarction; UA, unstable angina; TIA, transient ischemic attack; CABG, coronary artery bypass graft.

TABLE 90-2 P2Y₁₂ Inhibitors

Drug	Indications	Dosing, timing, duration	Monitoring	Precautions and contraindications
Clopidogrel (Plavix)	Treatment of ACS +/- PCI	ACS LD: 300 mg X1 PCI LD: 300-600 mg X1 Maintenance: 75 mg orally once daily	Signs of bleeding CBC with differential Bleeding time LFTs Lipid panel (ticlopidine) Platelet function testing may be warranted in select patients (platelet aggregometry and/or vasodilator-stimulated phosphoprotein [VASP] phosphorylation) CYP2C19 genotyping if suspicion of poor metabolizer (clopidogrel)	*Precautions* Interruption of clopidogrel may cause in-stent thrombosis with subsequent fatal and nonfatal myocardial infarction Indwelling epidural catheter Combination of aspirin and clopidogrel in patients with recent TIA or stroke Liver disease Thrombotic thrombocytopenic purpura may occur (rare) Recent trauma, surgery/biopsy, or other pathologic condition Concomitant use with potent CYP3A inducers and inhibitors (ticagrelor) Use of daily maintenance doses of aspirin above 100 mg not recommended (ticagrelor) Underlying hematologic disorders Discontinue if ANC < 1,200/mm³ or platelet count < 80,000/mm³ (ticlopidine) Elevated triglycerides (ticlopidine) Clopidogrel concentrations may be reduced in poor metabolizers of CYP2C19 *Contraindications* Hypersensitivity to agent or any component of their product Recent stroke or TIA (prasugrel) Severe active bleeding (such as peptic ulcer or intracranial hemorrhage) Neutropenia/thrombocytopenia Severe liver impairment
	Primary and secondary prevention of MI in patients with chronic stable angina, previous MI, or UA	75 mg orally once daily
	Cerebrovascular accident
	Peripheral arterial occlusive disease
Prasugrel (Effient)	Treatment of ACS +/− PCI	LD 60 mg X1 Maintenance: 10 mg/d orally, consider 5 mg orally once daily in patients weighing <60 kg
Ticagrelor (Brilinta)	Treatment of ACS +/− PCI	LD 180 mg X1 Maintenance: 90 mg twice daily
Ticlopidine (Ticlid)	Placement of a stent in the coronary artery Secondary prevention in thromboembolic stroke	250 mg orally twice daily
ACS, acute coronary syndromes; LD, loading dose; PCI, percutaneous coronary intervention; CBC, complete blood count; LFT, liver function tests; MI, myocardial infarction; UA, unstable angina; TIA, transient ischemic attack; ANC, absolute neutrophil count.

TABLE 90-3 Glycoprotein IIB/IIIA Inhibitors

Drug	Indications	Dosing, timing, duration	Monitoring	Precautions and contraindications
Abciximab (Reopro)	Treatment of ACS +/− PCI	LD: 0.25 mg/kg IV bolus (over 5 min), followed by 0.125 µg/kg/min (maximum 10 µg/min) IV infusion for 12 h in combination with fibrinolytic treatment or after PCI, unless complications	Signs of bleeding CBC aPTT while on heparin ACT during PCI and prior to sheath removal Serum creatinine	*Precautions* Indwelling epidural catheter Do not remove arterial sheath unless aPTT is <45 s or ACT <150 s and heparin discontinued for 3-4 h. Platelet count below 150,000/mm³ Renal insufficiency (eptifibatide and tirofiban) Readministration of abciximab may result in hypersensitivity, thrombocytopenia, or diminished benefit due to formation of human antichimeric antibodies. Hemorrhagic retinopathy *Contraindications* Active internal bleeding Abnormal bleeding within the previous 30 d or a history of bleeding diathesis Concomitant or planned administration of other parenteral glycoprotein IIb/IIIa inhibitors Hypersensitivity to active ingredient or any other product component Hypersensitivity to murine proteins (abciximab) Major surgery (within the previous 6 wk) Stroke (within previous 30 d) Severe hypertension (systolic pressure over 180-200 mm Hg or diastolic pressure above 110 mm Hg) History or clinical suspicion of intracranial bleeding, tumor, arteriovenous malformation, or aneurysm Pericarditis Aortic dissection Thrombocytopenia following prior tirofiban administration
Eptifibatide (Integrilin)	Treatment of ACS +/− PCI	LD: 180 µg/kg IV bolus based on ABW (maximum 22.6 mg) as soon as possible, followed by 2 µg/kg ABW/min (maximum 15 mg/h) infusion until discharge or CABG surgery, up to 72 h If undergoing PCI, administer a second 180 µg/kg IV bolus 10 min after the first and continue the infusion up to discharge, or for up to 18-24 h after procedure, whichever comes first, allowing for up to 96 h of therapy Renal impairment: CrCl <50 mL/minute, 180 µg/kg actual body weight (maximum 22.6 mg) IV bolus as soon as possible, followed by 1 µg/kg/min (maximum 7.5 mg/h) infusion
Tirofiban (Aggrastat)	ACS treatment	LD: 0.4 µg/kg/min IV bolus for 30 min then 0.1 µg/kg/min for 12-24 h after PCI Renal impairment: CrCl < 30 mL/minute: Load 0.2 µg/kg/min IV for 30 min then 0.05 µg/kg/min
LD, loading dose; IV, intravenous; CBC, complete blood count; ACS, acute coronary syndromes; PCI, percutaneous coronary intervention; aPPT, activated partial thromboplastin time; ACT, activated clotting time; ABW, actual body weight; CABG, coronary artery bypass graft; CrCl, creatinine clearance.

TABLE 90-4 Phosphodiesterase Inhibitors

Drug	Indications	Dosing, timing, duration	Monitoring	Precautions and contraindications
Cilostazol (Pletal)	Intermittent claudication	100 mg orally twice daily	Signs of bleeding CBC Coagulation panel Blood pressure Heart rate LFTs Signs of congestive heart failure (Cilostazol)	*Precautions* Hypotension Severe coronary artery disease, abnormal cardiac rhythm Avoid in patients with severe hepatic insufficiency (Aggrenox). Avoid in patients with severe renal failure (Aggrenox and cilostazol). Coagulation abnormalities *Contraindications* Hypersensitivity to agent or any components of the product CHF of any severity (cilostazol) Hemostatic disorders or active pathologic bleeding (bleeding peptic ulcer or intracranial bleeding)
Dipyridamole (Persantine)	Thromboembolic prophylaxis after heart valve replacement	With concomitant warfarin therapy: 75-100 mg orally four times daily
Dipyridamole extended release/aspirin (Aggrenox)	Secondary prevention in stroke and TIA patients	200 mg dipyridamole, 25 mg aspirin (one capsule) orally twice daily Patients with intolerable headache 200 mg dipyridamole, 25 mg aspirin orally daily at bedtime, with 81 mg of aspirin in the morning. Return to usual dose as soon as tolerance to headache develops (usually within a week)
CBC, complete blood count; LFT, liver function tests; TIA, transient ischemic attack; CHF, congestive heart failure.

b. Cilostazol produces nonhomogenous vasodilation, with greater dilation in femoral beds than in vertebral, carotid, or superior mesenteric arteries, but without effect in renal arteries.

2. Mechanism of action.

a. Phosphodiesterase inhibition and suppression of cAMP degradation increase cAMP in platelets and blood vessels. This causes reversible inhibition of platelet aggregation induced by various stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress.

II. ANTICOAGULANTS

A. Unfractionated heparin (UFH) (Table 90-5).

1. General principles.

a. Glycosaminoglycan extracted from porcine intestinal mucosa.

b. Intravenous (IV) administration results in immediate onset with a t_1/2 of 60 to 90 minutes. Liver and renal disease prolonged t_1/2.

c. Subcutaneous (SC) administration delays onset of action (20 to 60 minutes).

d. Heparin resistance occurs in patients who require unusually high heparin doses (>35,000 units/day), to achieve a therapeutic-activated partial thromboplastin time (aPTT), and is attributable to antithrombin deficiency, increased heparin clearance, excess heparinbinding proteins, factor VIII, and fibrinogen (Table 90-6).

e. Heparin dosing protocols are more effective in achieving goal anticoagulation than an ad hoc approach.

2. Mechanism of action.

a. Combines with antithrombin to block activated factors II, IX, X, XI, and XII.

B. Low molecular weight heparin (LMWH) (Table 90-7).

1. General principles.

a. Produced from UFH, with more predictable dose response.

b. SC administration results in onset of action of 20 to 60 minutes with a t_1/2 of 3 to 6 hours.

c. Eliminated via the kidneys.

d. Dosing for obese patients is based upon adjusted body weight (AjBW).

AjBW = LBW + CF × (TBW − LBW)

CF = correction factor = 0.4

LBW = (height − 150 cm) × 0.9 + 45 kg (female) or LBW = (height − 150 cm) × 0.9 + 50 kg (male)

where LBW = lean body weight; TBW = total body weight; cm = centimeters.

e. Discontinuation should be considered 12 to 24 hours before procedure or surgery.

TABLE 90-5 Unfractionated Heparin

Drug	Indications	Dosing, timing, duration	Monitoring	Precautions and contraindications
Unfractionated heparin	VTE treatment	LD: 80 units/kg bolus 18 units/kg/h infusion adjusted per local heparin nomogram	Signs of bleeding CBC aPTT: at least 4 h after initiation, then at least once daily Anti-Xa levels (alternative if available, consider in patients with heparin resistance or antiphospholipid antibody syndromes) HIT antibody testing (not warranted in the absence of thrombocytopenia, thrombosis, heparin-induced skin lesions, or other signs pointing to a potential diagnosis of immune-mediated HIT	*Precautions* Allergic or hypersensitivity-type reactions Congenital or acquired bleeding disorders Indwelling epidural catheter GI ulceration and ongoing tube drainage of the small intestine or stomach Hepatic disease with impaired hemostasis Hereditary antithrombin III deficiency and concurrent use of antithrombin Neonates and infants weighing <10 kg Premature infants weighing <1 kg Risk of delayed onset of HIT and HITT *Contraindications* Uncontrollable active bleeding, except when due to disseminated intravascular coagulation Instances in which blood coagulation tests cannot be performed at necessary intervals Severe thrombocytopenia Positive test for immune-mediated HIT Patients within a remote history of HIT (>100 days) could be considered for a rechallenge with heparin provided a negative antibody test
	ACS treatment	LD: 60 units/kg (max 4,000 units) 12 units/kg/h (max initial dosing 1,000 units/h) +/- fibrin specific adjusted to maintain aPTT 1.5 to 2 times control or per local heparin nomogram
	Bridge therapy for atrial fibrillation, cardioversion	IV infusion: 60-80 units/kg bolus Target aPTT, 60s (range 50-70 s)
	Prophylaxis of VTE in the medically ill or surgical population	5,000 units SC q8 h
	Prophylaxis of VTE in pregnancy (with prior VTE)	7,500-15,000 units SC q12 h
VTE, venous thromboembolism; LD, loading dose; CBC, complete blood count; aPPT, activated partial thromboplastin time; ACS, acute coronary syndromes; HIT, heparin-induced thrombocytopenia; HITT, heparin-induced thrombocytopenia with thrombosis.

TABLE 90-6 Heparin Dose Adjustment Nomogram

Variables	Adjustment
Initial dose	80 units/kg bolus, then 18 units/kg/h
aPTT < 35 s	80 units/kg bolus, then increase 4 units/kg/h
aPTT 35-45 s	40 units/kg bolus, then increase 2 units/kg/h
aPTT 46-70 s	No change
aPTT 71-90 s	Decrease infusion rate by 2 units/kg/h
aPTT > 90 s	Hold infusion 1 h, then decrease infusion rate by 3 units/kg/h
aPTT, activated partial thromboplastin time.
Adapted from Raschke R, Gollihare B, Peirce J. The effectiveness of implementing the weight-based heparin nomogram as a practice guideline. Arch Intern Med 1996;156:1645-1649.