Pharmacotherapy of Venous Thromboembolism Prevention & Treatment

Marie Meyer, PharmD Candidate 2007

Epidemiology / Incidence: 50,000-200,000 pulmonary embolism (PE) fatalities yearly
250,000-600,000 symptomatic VTE cases yearly
Causes:
Abnormal blood flow: atrial fibrillation, left ventricular dysfunction, hemostasis, vessel obstruction, hyperviscosity, sickle cell anemia
Abnormal surfaces in contact with blood: vessel injury, atherosclerosis, heart valve disease, heart valve replacement, indwelling catheters
Abnormal coagulation proteins: protein C deficiency, protein S deficiency, antithrombin deficiency, activated protein C resistance, prothrombin mutation, elevated factor VIII and X, antiphospholipid antibodies, hyperhomocysteinemia, tumor cell procoagulants, high dose estrogen therapy/pregnancy
Disease State Definition / Venous Thromboembolism (VTE) = thrombus (blood clot) formation in veins; clot may embolize (break off and travel through the circulation, usually through the heart and into the lungs)
Deep Venous Thrombosis (DVT) = blood clot in a deep vein (vein that accompanies an artery)
Pulmonary Embolism (PE) = blockage of an artery in the lung, usually by a blood clot
(rare: emboli may also be formed from fat cells, tumor cells, air bubbles, parasites, amniotic fluid)
Thromboembolic stroke
Ischemic stroke (85%) [symptoms last >24 hours (TIA if <24h)]; Hemorrhagic stroke (15%)
Cardiogenic stroke – thrombus from within heart chambers embolizes – usually to the brain
Patho-physiology
Patho-physiology
(continued) / Thrombosis
Atherosclerotic plaque forms on vessel endothelial wall
Lipid core of plaque contains thrombogenic material
Plaque fissures/ruptures (spontaneously or from mechanical trauma)
Thrombogenic core is exposed to blood and thrombus forms at area of rupture
Non-occlusive thrombus may embolize, or may decrease blood flow and increase shear force
Increase in shear results in increased platelet and fibrin aggregation and eventual vessel occlusion
Atrial fibrillation can lead to thrombus in the left atrium
White thrombus (arterial thrombosis)
High-flow arterial circulation, platelet rich thrombus
Occurs when atherosclerotic plaque ruptures
Consequences – MI, stroke, gangrene
Red thrombus (venous thrombosis)
Low-flow venous circulation, erythrocyte and fibrin rich thrombus
Occurs when natural protective mechanisms are overcome by procoagulant stimuli
Usually begin in muscular calf veins or valve cusp pockets of deep calf veins
Consequences – pulmonary embolism, chronic venous insufficiency
Other thrombosis consequences:
vessel obstruction, tissue inflammation, ischemia, propagation, atherosclerosis
Embolism
Blood clot travels through the circulation from one part of the body to another and causes blood vessel occlusion at a site distant from the clot origin.
If a thrombus in a systemic vein embolizes, the embolus will pass through the right side of the heart and end in the lungs; i.e. pulmonary embolism
If a thrombus in the left atrium embolizes, the embolus can land anywhere in the circulatory system
End circulation = areas of the body that have no redundant blood supply (heart, brain, lungs)
Coronary artery thrombosis à acute MI/unstable angina
Carotid artery disease à thromboembolic stroke
Peripheral vascular disease à arterial thrombosis
Clinical Presentation / Symptoms: non-specific, often no symptoms – objective test confirmation required for diagnosis
Deep vein thrombosis symptoms
Unilateral calf/leg swelling
Calf/leg pain or tenderness, erythema, warmth
Dilated superficial arteries
Palpable cord
Homan’s sign = pain in upper calf behind knee when foot is flexed up
Pulmonary embolism symptoms
Dypsnea, tachypnea
Chest pain
Tachycardia
Hypotension
Cyanosis
Hemoptysis
TIA/stroke symptoms
Focal neurological deficit
Muscle weakness/paralysis
Speech/language difficulty
Visual changes
Risk Factors / Risk factors are cumulative – multiple risk factors à increased VTE risk severity
VTE risk factors
surgery: very high risk = knee or hip replacement, major abdominal surgery, neurosurgery
major trauma, lower extremity trauma, immobility
previous VTE
age >40
pregnancy & postpartum, contraceptive or hormone replacement estrogen therapy
selective estrogen receptor modulators
malignancy, cancer therapy
acute illness
heart failure, respiratory failure
obesity, smoking
inflammatory bowel disease, nephrotic syndrome, myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria, varicose veins, central venous catheterization, thrombophilia
Thromboembolic stroke risk factors
Valvular heart disease, prosthetic valve replacement
Atrial fibrillation
Dilated left atrium or left ventricle
Hypertension
Diabetes Mellitus
Left ventricular dysfunction
Anterior myocardial infarction
History of previous stroke, TIA, VTE
Diagnosis / VTE laboratory tests
D-dimer test – negative rules out VTE, positive requires confirmation by appropriate diagnostic test
Hypercoaguable assessment
protein C deficiency, protein S deficiency, anti-thrombin III deficiency, activated protein C resistance, antiphosphorlipid antibodies, anticardiolipin antibodies, lupus anticoagulant
DVT diagnostic tests
Venography/phlebography
Ultrasound, Doppler, Duplex Doppler
Impedance plethysmography
I125 fibrinogen leg scan
PE diagnostic tests
Pulmonary angiography
Lung scan – V/Q scan, ventilation/perfusion scan
TIA/stroke diagnostic test
Echocardiography
Desired Therapeutic Outcomes* / Prophylaxis
Prevent VTE in hospitalized or surgical patients
Treatment
Prevent thrombus extension
Prevent early and late VTE recurrences
Prevent VTE mortality
*The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126
Treatment Options**
(Non-drug and Drug Therapy – include all therapeutic classes/agents available and preferences per treatment guidelines)
**See Treatment Options Table / Non-phamacologic
Compression – elastic compression stockings, intermittent pneumatic compression
Thrombectomy, pulmonary embolectomy
Vena-cava filter
Catheter extraction or fragmentation
Ambulation
Pharmacologic
Heparins
Unfractionated heparin (UFH)
Low-molecular weigh heparins (LMWH)
enoxaparin (Lovenox)
dalteparin (Fragmin)
tinzaparin (Innohep)
Vitamin K antagonists (VKAs)
Warfarin (Coumadin)
Platelet inhibitors
Aspirin
Ticlopidine (Ticlid)
Clopidogrel (Plavix)
Note: Glycoprotein IIb/IIIa receptor antagonists are indicated for percutaneous coronary intervention, coronary stents, unstable angina, acute coronary syndrome (beyond the scope of this topic)
Direct Thrombin Inhibitors
Lepirudin (Refludan)
Bivalirudin (Angiomax)
argatroban
Selective Anti-Xa Inhibitor
Fondaparinux (Atrixa)
Thrombolytics
There is no evidence that supports the use of thrombolytic agents for the initial treatment of
DVT in the large majority of patients. Furthermore, in patients with DVT, mortality from PE is very uncommon (approximately 1%) once anticoagulant therapy has been initiated*.
For most patients with PE, we recommend clinicians not use systemic thrombolytic therapy*
*The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126
Monitoring
(Efficacy and Toxicity Parameters) / Platelets, hemoglobin, hematocrit, signs of bleeding,
Activated partial thromboplastin time (aPTT)
Prothrombin time (PT)
International normalized ratio (INR) = calculation
INR = patient prothrombin time/mean normal prothrombin time
ISI = international sensitivity index
INR should be increased by 2-31/2 times depending upon indication.
See treatment options table for complete monitoring per drug/class

Marie Meyer, PharmD Candidate 2007 Pharmacotherapy Presentation – Pharmaceutical Care Rotation

University of Maryland School of Pharmacy Happy Harry’s Pharmacy Patient Care Center, Perryville, MD