Venous Thromboembolism PDF

Venous Thromboembolism Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Objectives 1. Identify risk factors and signs and symptoms of deep vein thrombosis (DVT) and pulmonary embolism (PE) 2. Describe the processes of hemostasi...

Venous Thromboembolism Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Objectives 1. Identify risk factors and signs and symptoms of deep vein thrombosis (DVT) and pulmonary embolism (PE) 2. Describe the processes of hemostasis and thrombosis, including the role of the vascular endothelium, platelets, coagulation cascade, and thrombolytic proteins 3. Determine a patient’s relative risk of developing venous thrombosis Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Objectives 4. Formulate an appropriate prevention strategy for a patient at risk for DVT 5. State at least two potential advantages of the low-molecular weight heparins (LMWHs) and fondaparinux over unfractionated heparin (UFH) Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university INTRODUCTION Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Venous Circulation (Fig. 10-1) Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Venous Thromboembolism (VTE) VTE’s happen from thrombosis formation in the venous circulation. Manifested as: Deep vein thrombosis (DVT) Pulmonary embolism (PE) Often provoked by: Can also occur with little to no provocation in patients with an underlying hypercoagulable disorder Prolonged immobility Vascular injury Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university VTE Most frequently seen in: Hospitalized patients Trauma Major surgery Often has few or no symptoms First manifestation often sudden death Long-term sequelae Post-thrombotic syndrome (PTS): due to damage to the vein caused by a blood clot that leads to development of symptomatic venous insufficiency such as chronic lower extremity swelling, pain, tenderness, skin discoloration, and ulceration. Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university VTE Prevention of VTE: Improves outcomes Rapid and accurate diagnosis is critical Anticoagulation management services improve quality of care and reduce overall cost. Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university EPIDEMIOLOGY AND ETIOLOGY Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Epidemiology and Etiology True incidence is unknown >50% have no overt symptoms Incidence doubles every decade after 50 Incidence is slightly higher in men Estimated 2 million VTE’s in US/year 600,000 hospitalized 60,000 die Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university VTE Risk Factors (see Table 10-1) Age: Risk doubles each decade after 50 Prior history of VTE: Strongest known risk factor Major surgery i.e. Orthopedic procedures of leg(s)/hip(s) Trauma Malignancy Pregnancy or estrogen use Hypercoagulable states Drug Therapy: Estrogen-containing medications, Chemotherapy Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Virchow’s Triad Three major elements leading to VTE Consists of: Stasis in blood flow: Venous stasis: Reduced rate of flow reduces the clearance of activated clotting factors leading to thrombogenesis Vascular endothelial injury Hypercoagulable state Activated Protein C resistance most common These risk factors are additive! Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university PATHOPHYSIOLOGY Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Pathophysiology Vessel injury Hemostatic plug seals the vessel wall Inappropriate response can lead to clot Endothelial cells inside blood vessels Create substances that: Inhibit platelet adherence Prevent activation of coagulation cascade Facilitate fibrinolysis Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Pathophysiology (Cont.) Injury exposes subendothelium Platelets adhere to subendothelium via: Use of glycoprotein (GP) 1b receptors Facilitation by von Willebrand’s factor (vWF) Platelets become activated Release a number of procoagulants Platelets expose GP IIb-IIIa receptors Allows platelets to adhere to one another Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Pathophysiology (Cont.) Damaged vascular tissue: Releases tissue factor This activates the extrinsic pathway of the coagulation cascade Clotting cascade Stepwise series of enzymatic reactions Results in formation of fibrin mesh Final steps are formation of thrombin and fibrin Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Summary of coagulation pathways Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university  Final Steps in Coagulation Cascade: 1. Converting prothrombin to thrombin. Thrombin responsible for fibrin production. Also converts factors V and VIII TO ACTIVE FORM Enhances platelet aggregation. 2. Conversion of fibrinogen to fibrin. plasmin is a fibrinolytic protein that degrades fibrin mesh into soluble products Thrombin creates a positive feedback loop that greatly accelerates the entire cascade. Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Coagulation Activators & Inhibitors Fig10-2; Page 188 Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Control of Coagulation Cascade Circulating proteins AT Inhibit thrombin and factor Xa Heparan sulfate Secreted by adjacent intact endothelium Accelerates AT and HCII activity Proteins C & S Vitamin K-dependent anticoagulants Made in the liver Inhibits factor Va and VIIIa activity Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university CLINICAL PRESENTATION AND DIAGNOSIS Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university VTE Majority of VTE’s begin in lower extremity Can either: Remain asymptomatic Spontaneously lyse Obstruct the venous circulation Propagate into proximal veins Embolize Slowly incorporate into the endothelium Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university VTE Symptoms Symptoms are very nonspecific Unilateral leg pain/warmth/swelling Shortness of breath and/or cough Tachypnea and/or tachycardia Hemoptysis Objective tests used to confirm VTE Radiographic studies (Gold standard) D-dimer test: Can distinguish between acute VTE and PTS; is a quantitative measure of fibrin breakdown in the serum (A level 150 kg: ABW calculated by IBW + (ABW-IBW) x 0.4 Adjust infusion based on response Requires extremely close monitoring aPTT most widely used aPTT of 1.5-2.5x control value (reference value) Should obtain aPTT at baseline, 6 hours after initiation, and 6 hours after each dose change Could also monitor with whole blood clotting time, activated clotting time (ACT), antifactor Xa activity, and plasma heparin concentration Should also monitor CBC and BP Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university UFH Dosing of SQ UFH: Can give 333 units/kg bolus followed by 250 units/kg given SQ every 12 hours in patients with DVT 5,000 unit IV bolus 17,500 units SQ every 12 hours Dose in children: 50 units/kg bolus followed by an infusion of 20000 units/m2 per 24 hours Dosing of IV UFH 80 units/kg loading dose Max of 10,000 units 18 units/kg/hour maintenance dose Max of 2,300 units/hour Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university  UFH Dose changed based on aPTT levels. aPTT 93: Hold for 1 hour Decrease infusion by 3 units/kg/hr Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university UFH Side effects: Bleeding Patient’s risk of major bleed is related to the intensity and stability of therapy, age (>65 years), concurrent drugs (thrombolytics, NSAIDs, and antiplatelet agents), history of GI bleed, risk of falls/trauma, heavy alcohol use, renal failure, cerebrovascular disease, malignancy, and recent surgery. Thrombocytopenia Hypersensitivity Hyperkalemia Alopecia Osteoporosis Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university UFH If major bleeding occurs, use protamine sulfate Give 1 mg protamine sulfate per 100 units of UFH Max dose of 50 mg Given as slow IV infusion over 10 minutes Neutralizes the effects of UFH in 5 minutes Effects persist for about 2 hours Can repeat dose if needed Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university UFH Heparin-induced Thrombocytopenia (HIT) Serious adverse effect seen with heparin Suspected if platelets drop by 50% ;. HIT also suspected if platelets drop below 120,000 or if thrombosis occurs while on therapeutic heparin Discontinue all heparin products Alternative anticoagulation is needed FDA pregnancy category C Very cautious in the peripartum period due to risk of maternal hemorrhage Is not secreted in breast milk Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university LMWHs When compared to UFH, have better: Pharmacokinetics Longer half-lives Improved SQ bioavailability Dose-independent renal clearance Pharmacodynamics Side effect profile Do not require monitoring of activity Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university  Are at least as safe and effective as UFH for treatment of VTE and are preferred in patients with adequate renal function.  Rate of mortality lower in patients treated with LMWH in clinical trials.  These are smaller heparin fragments obtained by chemical or enzymatic mixtures of glycosaminoglycans.  Each product has slightly different molecular weight distributions and pharmacologic properties.  Exhibit less protein binding which creates a more predictable response.  Have a lower incidence of HIT and osteopenia.  Dosed once or twice daily due to longer half-lives (usually 3-6 hours but is agent specific).  Prolonged in patients with renal impairment. Care must be taken as there is an increased risk of drug accumulation and bleeding with renal failure.  SQ bioavailability is >90%.  Peak effect is 3-5 hours after SQ dose.  Should get baseline prothrombin time (PT), INR, aPTT, CBC, and serum creatinine (SCr) with these meds.  Check platelet count every 2-3 days during first 2 weeks and every 2-4 weeks with extended use. Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university LMWHs Halt propagation & growth of thrombi Anticoagulant effect from AT binding Cannot bind AT & thrombin simultaneously Have greater activity against factor Xa Inhibit thrombin (IIa) to a lesser degree Xa:IIa ratio anywhere from 2:1 to 4:1 Agent specific Prepared by Dr. Munther Alnajjar; PhD in clinical Pharmacy / Al Ahliyya Amman university LMWHs Dosing is based on patient’s weight Dalteparin 200 units/kg SQ daily or 100 units/kg twice daily Enoxaparin 1.5 mg/kg SQ daily or 1 mg/kg twice daily CrCl