Venous Thromboembolism VTE Deep Vein Thrombosis DVT Pulmonary

Venous Thromboembolism (VTE) Deep Vein Thrombosis (DVT) & Pulmonary Embolism (PE) Evaldas Giedrimas, MD Duane Pinto, MD The PVD. org

Overview • Etiology and Risk Factors of VTE • Symptoms of DVT and PE • Evaluation and Pretest Probability • Diagnostic Modalities • Treatment and Prevention Overview • FDA Approved Therapies • Length of Treatment • Unusual Site DVTs The PVD. org

Etiology of VTE • Virchow’s Triad: – – – Vascular injury Stasis Hypercoagulable state • 1/1000 or 400, 000 per year • increased incidence after age 60 • 30 day mortality is 30% (20% due to PE) • Subsequent risk of recurrent DVT – 30 % within 10 years The PVD. org

Etiology of VTE: PE • 4 th leading cause of death • 3 rd cardiovascular cause of death behind MI and CVA • 30 -50% from ileo-femoral DVTs and 10 -20% from upper extremity DVTs The PVD. org

Risk Factors of VTE • Majority of VTEs occur in non-surgical patients • Initial VTE event contributes to recurrence • Non-surgical – hospital or nursing home confinement, malignancy, central venous catheter or pacemaker, superficial venous thrombosis, and neurological disease with extremity paresis • IBD • Nephrotic syndrome – – Renal vein – involved in 35% of VTEs with nephrotic syndrome Urinary excretion of anti-thrombin III, platelet hyperactivity, elevated plasma viscosity • Travel – Increased risk when travel exceeds 10 hours • Malignancy – Incidence of VTE ~ 11%, after resection can increase to 40% • • The PVD. org Pancreas, GI tumors, ovary, prostate, lung are thombogenic Trousseau's syndrome – migratory thrombophlebitis

Risk Factors of VTE in Hospitalized Patients • Usually have more than one risk factor – – – – The PVD. org NYHA Class III/IV Heart Failure COPD exacerbation Sepsis Advanced age History of prior VTE Cancer Stroke with limb paresis Bed rest

Risk Factors of VTE in Surgical Patients • Orthopedic surgery, hip/knee replacement, hip fracture surgery, trauma surgeries with spinal cord injuries • Cancer, congenital thrombophilia, prior history of VTE, obesity, increasing age >60 years The PVD. org

Estrogen Associated Risk Factors for VTE During Pregnancy • Increases risk by 3 -6 x especially with increasing age • Incidence is even across 3 trimesters • Especially high during 6 weeks after delivery – – – Immobility and Obesity Prior VTE High estrogen Venous stasis Pelvic trauma with delivery Acquired hypercoagulability: elevated fibrinogen, von Wilebrand factor, and factor VIII, and decreased natural anticoagulants (Protein S) • Left leg > Right leg ( left iliac compression by the right iliac artery) The PVD. org

Estrogen Associated Risk Factors for VTE: OCP Use • Among women in 20 -30 s – 3 -6 x greater risk • Higher in Factor V Leiden or prothrombin mutation carriers • Greatest risk 6 -12 month after onset • Proportional to the estrogen dose • Trans-dermal preparation carry less risk The PVD. org

Symptoms of VTE • Deep Vein Thrombosis (DVT) – Sudden onset of pain, swelling, in one limb – Pain usually in the calf, crampy, bursting, worse with ambulation, precedes swelling – Bilateral presentation usually due to underlying malignancy or hypercoagulable disorder • Pulmonary Embolism (PE) – Abrupt onset of dyspnea, cough, syncope – Pleuritic chest pain The PVD. org

DVT Evaluation and Pretest Probability • Active cancer - 1 pt • Paralysis or recent limb casting – 1 pt • Recent immobility > 3 days – 1 pt • Local vein tenderness – 1 pt • Limb swelling – 1 pt • Unilateral calf swelling > 3 days – 1 pt • Collateral superficial vein – 1 point • Alternative diagnosis likely – subtract 2 points • High probability = 3+ • Moderate = 1 -2 • Low = <1 The PVD. org (Wells, Lancet 1997 & 2000)0

PE Evaluation and Pretest Probability • Clinical symptoms of DVT – 3 pts • Alternate explanation less likely than PE – 3 pts • Heart Rate > 100 – 1. 5 pts • Immobilization or surgery within 4 weeks – 1. 5 • Prior VTE – 1. 5 pts • Hemoptysis – 1 pt • Malignancy – 1 pt • High probability >6 • Moderate = 2 -6 • Low <2 The PVD. org

Diagnostic Modalities • Ultrasound – uses compression – Sensitivity (SN) of 85 -90% and specificity (SP) of 86100% for diagnosis of DVT – Studies done on popliteal femoral, and iliac veins – Anatomical inability to compress completely makes the test less accurate • CT • V/Q scan – IOPED study – 72% had intermediate interpretations and required further testing – Useful when definite results: normal or high probability The PVD. org

Diagnostic Modalities (cont. ) • Pulmonary angiography – Gold standard • D-Dimer – Soluble degradation fibrin product also present in bleeding, trauma, surgery, pregnancy, AAA, malignancy – Sensitive for ongoing fibrinolysis, not specific for thrombosis – NPV 95% and helpful in exclusion of DVT/PE – PPV of <50% The PVD. org

Treatment and Prevention • Prevention of primary event and subsequent postphlebitic syndrome • Primary DVT prophylaxis – – – – Low-dose unfractionated heparin Warfarin Low Molecular Weight Heparin Fondaparinux Inferior Vena Cava Filters Lyrics Compression stockings, intermittent pneumatic compression devices • no change in mortality or PE, less effective • ASA, other platelet agents not effective The PVD. org

Treatment and Prevention (cont. ) Postphlebitic syndrome • Chronic sequela of acute DVT • 30 % of patients within 10 years • Chronic pain and swelling of the effected limp • 10% ulcer complications • Treatment – Compression stockings (30 -40 mm Hg) – Randomized Control Trial (RCT) evidence of 50% reduction if worn x 2 years The PVD. org

Treatment – FDA approved therapy Heparin/Unfractionated Heparin • Heterogeneous 5, 000 - 80, 000 unit chains • Facilitates/catalyzes ATIII mediated thrombin inhibition • Reduces mortality, morbidity, and recurrence of VTE • Monitoring – Overlap with warfarin for 5 days or INR 2 -3 and 48 hours – 5% risk of major hemorrhage during the overlap period The PVD. org

Treatment – FDA approved therapy Heparin/Unfractionated Heparin (cont. ) • Resistance – 25% of individuals who require > 35, 000 units per day – Non-specific binding, high factor VIII and fibrinogen levels, antithrombin III deficiency, increased heparin clearance, aprotinin and NTG use • Heparin Induced Thrombocytopenia (HIT) – 50% drop in platelets or < 100, 000 platelet count – 5 -7% of patients, 5 -10 days after initiation – 50% pro-thrombotic event rate lasting 30 days after discontinuation The PVD. org

Treatment – FDA approved therapy Warfarin • Inhibits vitamin K dependent pro-coagulation factors (II, VII, IX and X) • Also inhibits protein C and S synthesis which is associated with pro-coagulability and reason for overlap with heparin therapy • 24 hour decrease in Factor VIII, Protein C • Followed by Factor IX on day 2, Factor X on day 3. 5, Factor II on day 5 The PVD. org

Treatment – FDA approved therapy LMWH • Small heparin fragments (4000 -6000 k. D) still causes conformational change • Higher affinity for factor Xa than thrombin by anti-thrombin enzyme • Safe in a daily or BID dose based on weight • Similar and/or improved mortality, morbidity, recurrence and side effect profile • Effective for PE treatment but needs initial inpatient monitoring The PVD. org

Treatment – FDA approved therapy LMWH (cont. ) • HIT – less than 1% • Monitoring – Suggested in obese, pregnant patients, prolonged therapy, especially with renal insufficiency – Anti-factor Xa level - 4 hours after last LMW heparin dose (goal 0. 5 -1. 0 IU/ml BID & 1. 0 -2. 0 for QD dose) The PVD. org

Treatment – FDA approved therapy Fondaparinux • Ultra-low molecular weight heparin • Synthetic pentasaccharide analog for ATIII activation • Given SQ, renal excretion (not for pts with Cr. Cl <30) • Evidence for Use – Superior DVT prophylaxis after hip fracture surgery & hip and knee replacement surgeries – MATISSE-DVT trial showed enoxaparin or fondaparinux + warfarin to be equally effective with similar bleeding profiles – MATISSE-PE trial showed the two low weight heparin to be as effective The PVD. org

Treatment – FDA approved therapy Fondaparinux (cont. ) • HIT – negligible due to very small size, unable to bind PF-4 (platelet factor) • Monitoring – Protamine is not effective in reversal due to neutral charge – Bleeding: 2 -3% compared to 0. 2 -2% with enoxaparin – Factor Xa can provide therapy measurement (similar to LMW) The PVD. org

Treatment – FDA approved therapy Inferior Vena Cava Filters • Indications – Contraindication to anticoagulation – Anticoagulation failure • Effectiveness – 2 -3 % PE rate with fatal complication of 0. 1% • Complications – 2 fold increased risk for lower extremity DVTs within 2 years of placement – 5% filter dislodgement – 16% filter thrombosis The PVD. org

Treatment – FDA approved therapy Fibrinolytics • Use in VTE patients AND hemodynamic instability • Use in right ventricular dilation/dysfunction remains controversial • Directed Lytic therapy for DVTs has not be proven in RCT The PVD. org

Length of Treatment • Idiopathic Thrombosis – 6 -12 months treatment – Use of low dose warfarin • PREVENT - low-dose warfarin (INR 1. 5 -2. 0) to placebo - reduced risk of VTE recurrence by 3 -10 fold compared to placebo • ELATE - low-dose warfarin (INR 1. 5 -2. 0) to conventional INR 2. 0 -3. 0 - similar bleeding rates, no advantage for low dose warfarin beyond 6 months • Provoked or identified etiology Thrombosis – 3 months The PVD. org

Length of Treatment • Management of INR (goal 2 -3) – PCP – regardless of specialty • 5 -8% rates of thrombosis or major bleeding – Specialized coumadin clinic • 2 -5% annual event rates • Complications of treatment – Skin necrosis – rare but serious (more common with protein C deficiency) • Due to procoagulable thrombosis in post-capillary venules, with resultant dermal necrosis in breast, abdomen, buttocks and thighs, due to rapid falls in protein C levels The PVD. org

Unusual Site DVT Upper Extremity Thrombosis • Often due to catheters, cardiac device implantation • Can approach 50% in hospitalized patients with central lines • Etiology – Consider thoracic outlet syndrome in out-patients – Malignancy, congenital, acquired thrombophilic disorders • Complications – PE - 10 -20% (vs 30 -50% in ileo-femoral DVTs) – Smaller thrombi with lower mortality rates – Postphlebitic syndrome is rare due to robust venous collateral potential The PVD. org

Unusual Site DVT Upper Extremity Thrombosis (cont. ) • Diagnosis – duplex ultrasound, CT, MRI • Treatment – Thoracic Outlet Syndrome • catheter directed thrombolysis & anticoagulation, and surgical decompression – Removal of offending catheter, followed by anticoagulation The PVD. org

Unusual Site DVT Mesenteric Venous Thrombosis • Rare, diverse, mean age 50 • Etiology – malignancy, underlying liver disease, pancreatitis, recent surgery, abdominal surgery, intra-abdominal sepsis, hormonal, thrombophilic states, pregnancy • Presentation – Variceal bleeding or ascites, portal hypertension, bowel infarction, acute abdomen, jaundiced, asterixis, weight loss The PVD. org

Unusual Site DVT Mesenteric Venous Thrombosis (cont. ) • Diagnosis: – Duplex ultrasound, CT or MRI • Treatment: – Surgery with bowel resection, anticoagulation with heparin + warfarin The PVD. org

Unusual Site DVT Renal Vein Thrombosis (RVT) • Associated with nephrotic syndrome and membranous glomerulonephritis • Incidence in nephrotic syndrome: 1. 9 – 42% • Etiology – Idiopathic, malignancy (Renal Cell Carcinoma), nephrotic syndrome, infection, post-operative, dehydration, IBS, hormone therapy, thrombophilia – Renal Cell Ca – associated with thrombus in 4 -25% of cases • Presentation – Asymptomatic often until renal failure, abdominal pain, hematuria The PVD. org

Unusual Site DVT Renal Vein Thrombosis (RVT) (cont. ) • Diagnosis: – Duplex ultrasound, visualization of thrombi or dilation, atrophy – CT, MRI are useful as well • Therapy: – – – The PVD. org Conserve renal parenchyma and renal function Nephrectomy is usually not recommended Anticoagulation – no RCT data, but observed Cr. Cl improvement

Unusual Site DVT Ovarian Vein Thrombosis • Rare, but often post-partum • Etiology – – R>L, due to tortuosity and multiple valves Suppurative pelvic thrombophlebitis • Presentation and Complications – – The PVD. org Fever unresponsive to antibiotics PE, thrombus extension into L renal vein or IVC Ureteral obstruction Low rate of recurrent thrombosis and thromboembolism

Unusual Site DVT Ovarian Vein Thrombosis (cont. ) • Diagnosis – often incidental – Clinical diagnosis during postpartum period or laparotomy – CT is preferred, with MRI, Ultrasound also used • Therapy – 7 -10 day course of heparin and antibiotics for postpartum OVT – Excellent long-term survival The PVD. org

Unusual Site DVT Budd-Chiari Syndrome • Rare • Etiology – of hepatic venous drainage most commonly due to hepatic vein thrombosis – Tumor (hepatocellular Ca, renal cell Ca, Wilms tumor), primary veno-occlusive disease, congenital obstruction, myeloproliferative disease, paroxysmal nocturnal hemoglobinuria, pregnancy, OCP • Presentation – Can be slow insidious to rampant progression of acute hepatic failure – Type 1 – IVC is occluded +/- hepatic veno-obstruction – Type 2 – occlusion of major hepatic veins – Type 3 –fibrous obliteration of small centrilobular intra-hepatic venules often during BMT The PVD. org

Unusual Site DVT Budd-Chiari Syndrome (cont. ) • Symptoms – Sinusoidal congestion, venous HTN, stasis, hypoxia, hepatocyte necrosis, hemorrhage, parenchymal damage. • Diagnosis – Doppler ultrasound, MRI, CT • Therapy – Decompression, functional restoration, prevention of thrombus propagation and recurrence – Fibrinolytics: • hemodynamic instability after PE, catheter-directed lytic therapy has not been proven in RCT – Anticoagulation is controversial – Surgical shunts can be helpful The PVD. org

Unusual Site DVT Cerebral Venous Sinus Thrombosis • Young-to-middle aged women • Etiology – Heterogeneous age group with heterogeneous risk factors – 70% - Occur in superior sagittal and lateral sinuses – Idiopathic, hormone therapy, malignancy, venous malformation, post-operative, infectious, dehydration, pregnancy, IBS, thrombophilia • Presentation – Headache, focal neurological deficits, seizures, or altered consciousness The PVD. org

Unusual Site DVT Cerebral Venous Sinus Thrombosis (cont. ) • Diagnosis – CT- ~ 80% sensitivity and specificity ; MRI – more accurate yet still often incorrect – Cerebral angiography – definitive diagnosis • Therapy – Heparin use but little evidence for support of use, duration and dose The PVD. org

Unusual Site DVT Retinal Venous Thrombosis • Atherosclerosis risk factors rather than VTE • Etiology – Associated with HTN, DM, CAD, connective tissue disease, malignancy, OCP use, IBS • Presentation – Retinal arterial HTN, atherosclerosis, causing retinal venous compression and stasis – Visual loss 2 nd to diabetic retinopathy – Retinal hypertension, macular edema, vitreous hemorrhage and glaucoma • Therapy – surgery, topical steroids, cyclocryotherapy, photocoagulation The PVD. org