2024 VTE Handout (Final) PDF

Maureen Smythe, Pharm.D, FCCP (maureen.smythe\@corewellhealth.org) **Objectives** 1. Provide an overview of the traditional coagulation cascade 2. Explain the initiation, amplification & propagation phase of the coagulation cascade 3. Cite the definitions of DVT and PE 4. Review compone...

Maureen Smythe, Pharm.D, FCCP (maureen.smythe\@corewellhealth.org) **Objectives** 1. Provide an overview of the traditional coagulation cascade 2. Explain the initiation, amplification & propagation phase of the coagulation cascade 3. Cite the definitions of DVT and PE 4. Review components of Virchow's Triad and their relationship to DVT 5. Outline disease progression for DVT and PE 6. Define the different classifications of PE 16\. Cite recommend dosing regimens for all agents October 30^th^: Objectives 1-13 (except warfarin), Pages 1-19 November 4th: Objectives 13-23, Review pages 19-27 before class References for Rotations: Michigan Anticoagulation Quality Initiative (MAQI) toolkit; https://anticoagulationtoolkit.org/sites/default/files/toolkit\_pdfs/desktop\_reference\_2.8.pdf I. **Hemostasis and the Clotting Cascade** A. Serves to limit blood loss by precisely regulated interactions between components vessel wall, circulating blood platelets, and plasma proteins. Cover **Inhibitors of Fibrinolysis** i. **Inhibitors of plasminogen activators** a. **Plasminogen activator inhibitor-1 released by platelets, inhibits active site of tpa (tissue plasminogen activator)** b. **alpha-2 antiplasmin: inactivates plasmin** B. Primary hemostasis -- platelet plug - Platelet activation occurs through exposure of blood to sub-endothelial collagen through vascular injury or by thrombin C. Secondary hemostasis -- Coagulation cascade 1. Biologic amplification system, few initiation substances sequentially activate a cascade of circulating precursor proteins which are the coagulation factor enzymes with end result being thrombin generation. Requires calcium and platelets; platelets provide phospholipid binding surface 2\. Classic Coagulation Cascade - Initiation: - The initial major trigger for coagulation is TF released from subendothelium which binds & forms complex with VIIa (extrinsic tenase). This complex activates FIX (FIXa) and Factor X (FXa) which converts prothrombin (FII) to thrombin (FIIa) in small amounts - Amplification: - FIIa binds to platelets and activates them - FIIa activates V (Va), VIII (VIIIa) and XI (XIa) - As activated platelets accumulate at site of injury, their phospholipid layer becomes the site of all enzymatic processes - Propagation: - Accumulated enzyme complexes (tenase and prothrombinase) catalyze thrombin generation - This is thrombin burst phase **II. Definitions / Pathophysiology** A. Thrombus - an aggregation of blood factors frequently causing vascular obstruction at the point of its formation. B. Embolus - part of a thrombus which breaks off and travels ( above the knee= proximal) below=distal) (venous clot that breaks off and travels to the lung= PE)  C. Virchow's triad -- an abnormality in any one of these 3 things can cause clotting 1. **Vascular/Endothelial injury:** - damage to blood vessels (surgery, trauma) 2. **Hypercoagulability: - can be inherited or acquired** (acquired:pregnancy,cancer, venous stasis) 3. **Venous Stasis: s**peed of blood flow -- slow blood flow reduces clearance of clotting factors **III. Link between venous thrombosis and atherosclerosis** A. Traditionally thought of separately; shared risk factors & common pathophysiologic principles including inflammation, hypercoagulability and endothelial injury. B. Emerging concept: VTE is part of pan-vascular syndrome including coronary artery disease, peripheral arterial disease and cerebral vascular disease. CV risk reduction should be promoted for those with VTE as well. C. VTE is increasing recognized as a chronic disease, \~ 30% reoccurrence at 10 years There is a relation between venous and arterial disease **IV. Progression of disease** A. DVT (deep vein thrombosis) 1. remain asymptomatic 2. spontaneously lyse 3. obstruct circulation causing post-thrombotic syndrome (PTS)= complication of DVT 4. propagate to more proximal veins 5. embolize B. Pulmonary Embolus (PE) -- Classification and Risk Stratification a\. Alveolar dead space; ventilation without perfusion b\. Hypoxemia c\. Increased pulmonary vascular resistance from clot d\. Increased right ventricular afterload, altered blood flow from right side of heart to the left - figure below starts here e\. Decreased left ventricular preload f\. Decreased CO, hypotension, obstructive shock, death (cause of death is right ventricular failure) Summary of PE Risk Stratification **V. Venous Thromboembolism (VTE) Frequency, Risk Factors and Risk Assessment** **A. Annual frequency of DVT & PE in US** B. VTE risk factors: additive; previous VTE major risk factor; age is a risk factor with risk increasing beyond age 40. VTE risk factors by category +-----------------+-----------------+-----------------+-----------------+ | Venous Stasis | Vascular Injury | Hypercoagulable | Medications | | | | States | | +=================+=================+=================+=================+ | major acute | major | cancer | estrogen | | medical illness | orthopedic | | containing OC | | CHF or MI | surgery (TKA, | activated | | | | THA) | protein C | estrogen | | major surgery | | resistance, | replacement | | | Trauma | factor V Leiden | therapy | | paralysis | (fracture of | | (depends on | | | pelvis, hip) | Protein C | formulation) | | polycythemia | | deficiency | | | vera | indwelling | | selective | | | catheters | Protein S | estrogen | | obesity | | deficiency | receptor | | | | | modifiers | | varicose veins | | Antithrombin | | | | | deficiency | heparin | | immobility | | | | | | | **↑** factor | erythropoiesis | | air travel \> 8 | | VIII or IX | stimulating | | hrs | | levels | agents | | | | | | | | | pregnancy | | | | | | | | | | inflammatory | | | | | bowel disease | | +-----------------+-----------------+-----------------+-----------------+ C. DVT Risk Assessment: c\. Non- Validated models for medicine patients: Modified Caprini ( can be used to predict for surgical patients but it is not validated) 2\. Surgical patients: Modified Caprini DVT Risk Assessment Scoring Tool is most commonly use approach. Patients receive points for certain factors and total score determines risk and need for prophylaxis Example Caprini Risk Assessment **VI. VTE Consequences and Clinical Presentation** A. DVT consequences 2\. Acute & chronic: Increased risk of recurrent thrombosis 3\. Chronic: Post thrombotic syndrome (PTS): a. 1\. Acute mortality: 60-300,000 deaths in US annually 2\. Chronic: death from fatal PE recurrence over the next year 3\. Chronic: Chronic thromboembolic pulmonary hypertension (CTEPH)= CHRONIC Complication of PE a. Residual thrombus that did not reabsorb gets remodeled into tissue raising pulmonary artery pressures b. Syndrome of progressive dyspnea, fatigue exercise intolerance c. mean PAP \> 25 mm Hg which persists for 6 months PTS is a chronic complication of DVT C. Clinical Presentation of VTE 1. **DVT** clinical presentation a. ≥ 50% may be asymptomatic b. symptoms: pain, tenderness, and unilateral swelling, erythema & warmth c. Homan's sign: calf pain at dorsiflexion of foot; poor sensitivity 2. **PE** clinical presentation (risk factors identified \~ 40% of time) a. highly variable as patients can be low risk to massive PE with hypotension b. classic: abrupt onset of dyspnea at rest & pleuritic chest pain (caused by pleural irritation due to distal emboli causing pulmonary infarction) c. others: apprehension, cough, fever, tachycardia, hemoptysis due to pulmonary infarction and is not a contraindication to anticoagulation d. can be fatal on presentation 3. Wells Clinical Probability Scoring System: clinical probability of having DVT or PE \*DVT: score of 0 unlikely, 1-2 moderate/intermediate & \>2 likely Know how to interpret Wells DVT and PE Scores 4. Simplified Pulmonary Embolism Severity Index (sPESI) a. Tool to stratify patients into low and high risk of mortality simplified PESI score; add points total Patient characteristic Points -------------------------------------------------- -------- Age \> 80 years 1 History of cancer 1 History of heart failure or chronic lung disease 1 Heart rate 100 beats/minute or more 1 O~2~ saturation \< 90 % 1 **VII. Diagnostic Workup for VTE** A. Assess clinical probability using Wells score, score determines next step B. DVT Diagnostic Approach is CUS (compression ultrasound) \- those with unlikely probability of DVT should have D-dimer test as first step \- surveillance ultrasound for those with distal DVT would be in 7-14 days \- distal veins: tibial, peroneal, gastrocnemius, soleal \- proximal veins: popliteal, femoral or iliac  Routine work up for PE but not diagnostic: 1. 2. 3. 4. **VIII. Contraindications to Anticoagulation, Assessing Bleed risk and Type of Bleeding** A. Contraindications (CI) +-----------------------------------+-----------------------------------+ | Absolute CI | Relative CI | +===================================+===================================+ | active internal bleeding | hemophilia or other bleeding | | | tendency | | severe thrombocytopenia(\ 200 mmHg or | | neurosurgery, ocular surgery or | DBP \> 120mm Hg | | intracranial bleeding last 10 | | | days | brain metastases | | | | | lumbar puncture, epidural or | recent major trauma | | spinal anesthesia within last 4 | | | hours or next 12 hours | GI or GU(genitourinary) bleeding | | | in past 14 days | | | | | | acute ischemic stroke in past 24 | | | hours | | | | | | infective endocarditis | +-----------------------------------+-----------------------------------+ B. Ri**sk factors for bleeding with anticoagulant therapy** C. Anticoagulant bleeding classification **IX. VTE Prevention in the hospitalized patient (important)** A. Goals: Primary goal is prevent fatal PE. Overall prevent thrombus extension and embolization (PE) and complications of DVT which is PTS and complications of PE which is CTPH. Effective VTE prevention strategies in the hospital can prevent \~ 70% of events related to surgery or hospitalization. Perform VTE risk assessment to determine if prophylaxis is indicated and which form may be most appropriate. Do not provide prophylaxis to low- risk patients. In low- risk patients early ambulation is sufficient. Ambulation is encouraged in all hospitalized patients as early in the stay as possible. B. Non- pharmacologic therapy options are the approach of choice in any patient who has an active bleed or is very high bleed risk. This mode can be added on to pharmacologic therapy in those at the highest risk of DVT. Orthopedic surgery often uses non-pharmacologic modes. Options include: C. Pharmacologic Therapy Overview 1\. SQ heparin dosing and monitoring b\. Patient monitoring for signs & symptoms of VTE 4\. hypersensitivity reactions +-------------+-------------+-------------+-------------+-------------+ | **Agent** | **Indicatio | **Dosing** | **Dose | **Timing of | | | n** | | Adjustments | 1^st^ | | | | | ** | Dose** | +=============+=============+=============+=============+=============+ | Enoxaparin | Knee | 30mg SQ q | 30mg daily | 12 -- 24 | | | replacement | 12 | if Clcr \< | hrs post | | | | | 30 ml/min | --op | +-------------+-------------+-------------+-------------+-------------+ | Enoxaparin | Hip | 30mg SQ q | 30mg daily | 12 -- 24 | | | replacement | 12 or 40mg | if Clcr \< | hrs post-op | | | | QD | 30 ml/min | | | | HFS(hip | | | | | | fracture | 40mg QD | | | | | surgery) | | | | +-------------+-------------+-------------+-------------+-------------+ | Enoxaparin | Medically | 40mg daily | 30mg daily | Medical: | | | ill | SQ | if Clcr \< | when at | | | | | 30 ml/min | risk | | | Abdominal | | | | | | surgery | | | Surgical: | | | | | | pre-op | +-------------+-------------+-------------+-------------+-------------+ | Dalteparin | Medically | 5000 units | None | When at | | | ill (just | SQ daily | | risk | | | know this | | | | | | one for the | | | | | | dose) | | | | +-------------+-------------+-------------+-------------+-------------+ | Dalteparin | Hip | 2500 units | None | 4-8 hrs | | | replacement | SQ x1 day | | post-op | | (Ignore) | --post op | then 5000 | | | | | dosing | units daily | | | +-------------+-------------+-------------+-------------+-------------+ | Dalteparin | Abdominal | 2500 units | ↑ dose to | No | | | surgery- | SQ pre-op | 5000units | specified | | (ignore) | | x1 day then | pre & post | | | | | 2500 units | op if | | | | | daily | malignancy | | | | | | or high | | | | | | risk for TE | | | | | | complicatio | | | | | | ns | | +-------------+-------------+-------------+-------------+-------------+ **e. no laboratory coagulation monitoring; does not typically prolong aPTT** **g. adverse events** 1\. bleeding: rare with prophylaxis unless higher dosing is used ***PARTIAL*** *reversal with protamine discussed in VTE treatment* 2\. HIT 3\. Fondaparinux (Arixtra) +-----------------+-----------------+-----------------+-----------------+ | ***Fondaparinux | **Dosing** | **Dosing in | **When to give | | *** | | severe renal | initial dose** | | | | impairment** | | | VTE prevention | | | | | | | **(\ | P-gp & | | | | | 2.5mg/dl | strong CYP | | | | | not studied | 3A4 | | | | | | inhibitors | | | | | reduce dose | (ketoconazo | | | | | by 50%with | le, | | | | | combined | itraconazol | | | | | P-gp & | e | | | | | strong CYP | &, | | | | | 3A4 | ritonavir ) | | | | | inhibitors | | | | | | (ketoconazo | | | | | | le, | | | | | | itraconazol | | | | | | e | | | | | | & | | | | | | ritonavir) | | +-------------+-------------+-------------+-------------+-------------+ | Edoxaban | Yes (at | 60mg once | 30mg once | NOT FDA | | | least 5 | daily; | daily with | approved | | | days | | any one of | | | | pre-treatme | | the | | | | nt | | following: | | | | ) | | weight | | | | | | [\ - swallow capsule whole, do not open or crush - dabigatran keep in original container - may cause dyspepsia 6\. Effect on Coagulation Tests a\. the PT and aPTT **cannot** quantitate level of anticoagulation 7\. Patient Monitoring a\. Prior to script: Assess age, weight, baseline labs (renal and liver function, CBC), history of bleed, concomitant drugs, comorbidities, overall bleed risk, patient preference, b\. Each visit: patient education, assess adherence, review signs and symptoms of thrombosis and bleeding, changes in drugs, inform patient the action to take if ADR, understanding of step down in dosing for acute VTE for apixaban and rivaroxaban, monitor renal function at least annually, frequency of monitoring of renal function = CrCl/10; with a CrCl of 60mL/min would monitor every 6 months 8\. DOAC Major Bleeding e\. Life Threatening Bleeding for Direct Xa Inhibitors Non-specific options: 1. Activated 4 Factor PCC: 25 -- 50 units/kg (HIT history) 1. Andexanet alfa , a recombinant modified decoy factor Xa that binds to Xa inhibitors -- FDA approved (very expensive) Advantages: FDA approved Disadvantages: may increase thrombotic risk, time intensive to prepare, costly **XII. VTE Treatment: Putting it All Together** A. B. DOACS are preferred in eligible patients who can afford, consider insurance and copay C. Duration of Anticoagulant Therapy ***VTE Event*** ***Initial Treatment (up to 3-6 months)*** ***Extended Treatment or Secondary Prevention*** --------------------------------------------------------------------- -------------------------------------------- -------------------------------------------------- Provoked DVT/PE by transient factor (example by estrogen treatment) 3-6 months Not needed Provoked DVT/PE by chronic factor (cancer, IBD) 3-6 months Indefinite unless bleed risk is high Unprovoked DVT/PE ( we do not why it happened) 3-6 months Indefinite unless bleed risk is high \*\*Extended defined as no scheduled stop date; annual re-evaluation of risk benefit. D. Outpatient Treatment of DVT and PE b. Recent bleeding c. Severe renal or hepatic disease d. Severe thrombocytopenia e. Nonadherence f. Doesn't feel well enough for home treatment g. Cardiac or respiratory insufficiency h. Poor home health care support environment (live alone) i. Right ventricle strain or increased cardiac biomarkers in PE i. Simplified Pulmonary Embolism Severity Index (sPESI) score [\]1 E. Aspirin has no role in initial VTE treatment. Only role is for secondary VTE prevention is for those who elect to stop anticoagulant therapy. F. Considerations for anticoagulant selection based upon patient characteristics 1. Non-adherence with medication ingestion: warfarin 2. Elderly, [\>] 65 years of age: Beers Criteria: potentially inappropriate medications - Avoid warfarin, avoid rivaroxaban (higher bleeding risk), dabigatran (higher bleed risk): use with caution - Apixaban not on Beers criteria 3. Severe liver dysfunction, Child Pugh Class C: warfarin 4. Moderate liver dysfunction, Child Pugh Class B: warfarin or apixaban or dabigatran 5. Pregnancy- warfarin is teratogenic during the first trimester, agent of choice is enoxaparin, continue during pregnancy and 6 weeks post partum 6. Cancer- see prothrombotic lecture 7. Dialysis- warfarin or apixaban 8. Pediatric VTE: rivaroxaban and dabigatran are approved for VTE treatment and secondary prevention after 5 days of initial parenteral pre-treatment, weight- based dosing G. Treatment considerations based upon Thrombosis/Bleeding 1\. Acute isolated distal DVT are less likely to embolize a. thrombolytic therapy for those not at high bleeding risk: - alteplase 100mg infused IV over 2 hours - Tenecteplase 30-50mg (depending on weight) IV bolus 5\. Isolated sub-segmental PE b\. rule out presence of proximal DVT c\. role of anticoagulation is controversial 6\. Recurrent VTE A filter placed in IVC to protect against embolization in those in whom anticoagulation is contraindicated or who failed anticoagulant therapy H. **Bridging Overview**