Keep catheter. Anticoagulate. Yes. Symptoms resolved? Yes. No Catheter needed? Other access sites available? Yes. Anticoagulate. Place new catheter

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1 Chief Anticoagulation and Thrombosis Service UCSF, SF VA MED CTR Thromboembolism Q&A Management of the Hospitalized Patient, SF, CA October 2012 CASES & ANSWERS 1. A 55 year old woman being treated for osteomyelitis of the spine develops right upper extremity swelling. U/S reveals a DVT in the subclavian and axillary vein. She has a PICC line in that arm. How do you manage this? a. Does she need anticoagulation? b. She will need another 3 weeks of IV antibiotics. Do you remove the PICC Line? Venous thrombosis Septic thrombophlebitis? No Yes Keep catheter Anticoagulate Yes Yes Severely symptomatic? No Catheter needed? Symptoms resolved? Yes Removal after fibrinolysis Antibiotics Anticoagulation if no contraindication Elevate involved extremity Remove catheter Anticoagulate If SVC syndrome or severe symptoms & low bleeding risk No No Other access sites available? Keep catheter Anticoagulate No Consider thrombolysis Consider thrombolysis Remove catheter Anticoagulate Yes Remove catheter Place new catheter Anticoagulate Management of catheter related venous thrombosis Anticoagulation generally recommended for 3 months one catheter is removed ACCP 2012 UE DVT (Stephan Moll MD, CLOTCONNECT.ORG) If DVT that involves the axillary or more proximal veins, anticoagulation therapy alone is suggested, rather than thrombolytic therapy. Length of anticoagulation: at least 3 months. In upper extremity DVT not associated with a central venous catheter: 3 months of anticoagulation is recommended. In upper extremity DVT associated with a central venous catheter: o Suggestion is to not remove the catheter if it is functional and there is an ongoing need for the catheter. Anticoagulation should be given as long as the catheter is in place. o If the catheter is removed, anticoagulation should continue for 3 months thereafter.

2 2. A 45 year old man presents with complaints of moderate but persistent calf pain and swelling. He was kicked playing soccer a five days ago and symptoms have developed since then. Ultrasound shows DVT in the posterior tibeal vein. What do you recommend? ACCP 2012 Distal leg DVT (Stephan Moll MD, CLOTCONNECT.ORG) a) Severe symptoms: Treat with anticoagulants. Length of treatment: 3 months (no matter whether DVT was associated with a transient risk factor (surgery, hospitalization, estrogen therapy, etc.) or was unprovoked (= idiopathic). b) No, mild or moderate symptoms (and no risk factors for clot extension see below): o o o No anticoagulation needed. Physician to obtain several ( serial ) Doppler ultrasound leg examinations over the next 2 weeks to make sure the DVT has not extended (which it does in about 15 % of patients). If DVT has extended: treat with anticoagulants for 3 months. If extension of clot has not occurred within the first 2 weeks, it is unlikely to occur subsequently. Risk factors for extension: positive D-dimer, DVT that is extensive or close to the proximal veins, no reversible provoking factor for DVT present, active cancer, previous history of blood clots, and inpatient status 3. A 55 year-old man presents with pleuritic chest pain. His BP is 120/70, HR 105, RR is 18, and his O2 sat is 97%. His physical exam is unremarkable. A chest CT shows multiple pulmonary emboli. ECG is normal. a. What is this patient's risk of early mortality related to PE? b. What anticoagulant regiman will you start and when? c. Will he be admitted and if so for how long? 2

3 PE-related early Hypotension ECHO/CTa/Biomarkers PESI score Management mortality High >15% YES Admit to ICU Thrombolysis and anticoagulation Intermediate 3-15% NO ECHO-RV dysfunction CTa- RV/LV ratio > 1.0 Low <3% NO ECHO-no RV dysfunction CTa-RV/LV ratio<1.0 No BNP or troponin elevation >II or HIGH I-II or LOW Inpatient treatment Consider thrombolysis on case by case basis Expedited discharge; OR consider outpatient treatment** Aujesky et al July Outpatient vs Inpatient tx PE Lancet 2011 **all PESI 1 or II. NOTE-they excluded O2 sat < 90% or p02 60, BP< 100, high bleed risk (stroke in 10 day s gi bleed in 14, <75K platelets, CrCl<30,on warfarin already, homeless, substance use, BMI> 150 Risk scoring system (Class I-II are low, class II-V are high) Risk Factor Points Age Points=age Male 10 Cancer 30 Heart failure 10 Chronic lung disease 10 HR > SBP < 100 mmhg 20 RR >30 20 Temp < Δ mental status 60 O2 sat <90% 20 Severity class Points 30 day mortality I 0-65 <1.7% II <3.5% III <7.1% IV % V > % Aujesky et al Eur Heart Journal 2006 Risk Factor points Age 1 if > 80 Cancer 1 Heart failure lung 1 disease SBP < 100 mmhg 1 O2 sat <90% 1 Severity class Points 30 day mortality LOW 0 1% HIGH 1 or more 10% Jimenez, D. et al. Arch Intern Med

4 3a.His PESI score is 65, placing him in Class I, very low risk of PE related mortality. You decide to discharge him to home. He weighs 100 kg. He has CKD with CrCl of 39 ml/min. What dose of enoxaparin do you recommend? Suggested anticoagulation regimens for the initial treatment of VTE. Event DVT or nonmassive PE Deep venous thrombosis, upper extremity Submassive PE Massive PE VTE in severe renal insufficiency VTE in Cancer Treatment (choose one) LMWH Enoxaparin 1 mg/kg subcutaneously twice daily Tinzaparin 175units/kg subcutaneously daily Dalteparin 200units/kg subcutaneously daily Subcutaneous UFH: apttmonitoring 17,5000 every 12 hours (initial dose) with aptt monitoring Subcutaneous UFH: no aptt monitoring 330units/kg x 1 then 250units/kg every 12 hours Fondiparinux 7.5mg-10mg subcutaneously daily, depending on weight IV unfractionated heparin bolus of 5,000 units followed by a continuous infusion of at least 30,000 units for the 1st 24 hours weight-based regimen of 80 units/kg bolus followed by a continuous infusion of 18u/kg/hr. Note: begin warfarin with initial dose of parenteral anticoagulant as selected above See DVT, lower extremity Consider thrombolysis in appropriate candidates See DVT, lower extremity Risk stratification suggested to guide triage and possibly therapy. IV Unfractionated heparin Thrombolytic therapy (choose one) tpa-100mg infusion over 2 hours, followed by IV unfractionated heparin Bolus tpa if actual cardiac arrest Urokinase, 4,400 IU/kg loading dose followed by 2,2000IU/kg for 12 hours. Note: for urokinase, heparin infusion should be administered concurrently Unfractionated heparin (See Deep venous thrombosis, lower extremity) Dalteparin (See Deep venous thrombosis, lower extremity) Continue LMWH therapy for 3-6 months, no transition to warfarin Use UFH preferentially in the following scenarios: Immediate risk of bleeding o T1/2 of UFH 1-2 hours, LMWH ranges from 2-8 hours o UFH 100% reversible with protamine, LMWH only 60% 4

5 Renal Failure o Dosing less reliable with CrCl < 30 ml/min Extremes of weight o Dose effect of LMWH may be less predictable in patients <50kg and BMI>30 kg/m2 Massive PE and submassive PE when considering thrombolysis Enoxaparin has been shown to accumulate in low weight individuals with antixa levels 50 % higher in this population. (Female patients weighing 45 kg or less and male patients weighing 57 kg or less). Heparin levels should be monitored in patients nearing lower weight limit. Enoxaparin in renal insufficiency Consider use of unfractionated heparin in low weight patients. Enoxaparin has also been shown to accumulate in patients with moderate renal insufficieny (CrCl ml/min). While prescribing information does not offer guidance on dosage adjustment in this population there is literature supporting use of lower dosing. Consider anti-xa level monitoring in patients with renal insufficiency, particulary those who may be on therapy > 10days. Overall Recommendations for renal insufficiency (based on studies): Treatment Doses Enoxaparin 1 st 48hrs: 1mg/kg q12hrs* Maintenance: dose adjust based on renal function*: Est CrCl (ml/min) Fraction of usual daily dose ^Accumulation for use > 10 days is unknown, consider monitoring of anti Xa levels, and adjust * from Barras 2008 &2010 (adapted from Green et al 2005) Barras (2008) 14 : Individualized Compared with Conventional Dosing of Enoxaparin 122 patients were randomized into standardized dosing vs. individualized dosing Usual dose of 1mg/kg q12hrs is used for the first 2 days because PK analysis show subtherapeutic concentration of factor Xa is more likely in the first 48hrs Endpoints Individualized arm Conventional arm P value N=46 N= 54 Any bleeding 1 (2%) 9 (15%) 0.03 Composite bleeding and bruising 6 (12%) 21 (40%)

6 Barras (2010) 16 : Individualized dosing of enoxaparin for subjects with renal impairment is superior to conventional dosing at achieving therapeutic concentrations Endpoints Therapeutic Xa levels (0.5 1) Supratherapeutic Xa (> 1) Subthreapeutic Xa levels (<0.5) Individualized arm N=46 Conventional arm N= 54 Pvalue 69.9% 42.6% % 37.1% % 15.7% 0.97 Barras MA, Duffull SB, Atherton JJ, Green B. Individualized compared with conventional dosing of enoxaparin. Clin Pharmacol Ther Jun;83(6): Green B, Greenwood M, Saltissi D et al. Dosing strategy for enoxaparin in patients with renal impairment presenting with acute coronary syndromes. Br J Clin Phmarcol. 2005; 59: Barras MA, Duffull SB, Atherton JJ, Green B. Individualized dosing of enoxaparin for subjects with renal impairment is superior to conventional dosing at achieving therapeutic concentrations. Ther Drug Monit Aug;32(4): A 68 year old woman falls and fractures her hip. She is in CHF on admission so OR time is delayed. On HD #3 she becomes acutely short of breath and is found to have PE and DVT. How do you manage her anticoagulation perioperatively? ACCP 2012 Vena cava filter (Stephan Moll MD, CLOTCONNECT.ORG) Should only be placed in the patient with an acute DVT who cannot tolerate blood thinners because of active bleeding or a high risk for bleeding. We do not consider that a permanent IVC filter, of itself, is an indication for extended anticoagulation. 6

7 Indication for IVC Filter Placement Acute VTE and contraindication to anticoagulation VTE despite anticoagulation Preoperatively in patients who have had recent VTE (within one month) and must have anticoagulation interrupted for surgery Proximal DVT in patient with poor cardiopulmonary reserve ACCP( 1) AHA (2) British Committee for Standards in Hematology (3) Thrombosis Interest Group of Canada (4) YES YES YES YES If proximal DVT present NO YES MAYBE High intensity oral anticoagulation or LMWH should be considered prior to placement of filter YES (VTE within 4 weeks prior to surgery) NO Anticoagulation should be intensified or alternative agent started. IVC filter will not prevent progression YES (VTE within 2 weeks prior to major surgery) YES There is no agreement on definition of poor reserve Free-floating thrombus NO NO Thrombolysis with NO NO proximal DVT Primary prophylaxis in selected high risk patients (surgical, trauma etc) NO NO 7

8 5. How long will you recommend the 55 yo man with unprovoked PE this patient stay on anticoagulation? a. 3 months b. 6 months c. 12 months d. Indefinitely 5a How long will you recommend the 68 yo woman with provoked PE stay on anticoagulation? e. 3 months f. 6 months g. 12 months h. Indefinitely THROMBOTICS T Trauma, travel H heme- P. Vera, ET, PNH, DIC, MM, MGUS, sickle cell R nephrotic syndrome O oral contraceptives/hrt/pregnancy/tamoxifen M malignancy B bedbound/immobilization O obesity T thrombophilia, thrombosis history I inflammatory states: IBD/Behcets syndrome/lupus C catheters S surgery 8

9 When evaluating a patient with thrombosis always consider the systemic diseases that can accompany VTE Systemic disease Clinical Features Diagnostic Data Inflammatory bowel disease Nephrotic syndrome Bloody diarrhea, aphthous ulcers, arthritis, rash Periorbital edema, peripheral edema, HTN, hypercholesterolemia Histologic analysis of intestinal biopsy specimens Urine protein analysis Behcets Myeloproliferative disorders (P. Vera, Essential thrombocytosis) Oral ulcers, genital ulcers, ophthalmologic issues Pruritis, plethora -- CBC, JAK-2 mutation Sickle cell disease Anemia, sickle crises Evaluation of the blood smear, hemoglobin electrophoresis Antiphospholipid antibody syndrome Livedo, arthritis, rash Lupus anticoagulant, ELISA for anticardiolipin antibody IgG and IgM (assess 3 months after acute event) Cancer Weight loss, night sweats CBC, LFTS, PSA, pap smear, routine cancer screening Paroxysmal nocturnal hemoglobinuria Hemolytic anemia CBC, Flow cytometry for CD55, CD59 Pregnancy Amenorrhea Urine pregnancy test (all women of childbearing age) 9

10 Indication 8th ACCP guidelines 2008 BTS guidelines 2003 ASH recommendations 2008 First episode of VTE secondary to a transient risk factor First episode of idiopathic (unprovoked) VTE Other (recurrent, active cancer,...) 3 months (Grade 1A). At least 3 Months, prefer long-term treatment if risk/benefit ratio ok (Grade 1A). Long term (Grade 1A). 4 6 weeks (grade A). 3 months (Grade A). At least 6 months (Grade C). 3 months 6 months Long term if APLS, AT deficiency or recurrence Parletti, D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med Oct 26;355(17): Clinical Risk score Clinical predictors Leg red or swollen or hyperpigment 5-7 mos after event D-dimer >250 ug/l on AC BMI >30kg/m2 Age> 65 Female patients with 0-1 risk factor had recurrence risk of 1.6%: 2 = 14% Rodgers et al CMAJ August

11 VIENNE PREDICTION RULE DASH D-dimer (+2) Age > 50 (+1) Sex-male (+1) Hormones (-2) Score Annualized Risk 1 3.1% 2 6.4% % Tosetto A et al J Thromb Haemost EICHINGER CIRCULATION 2010 Recurrent VTE ASA 6.6% Placebo 11.2 % VTE 40% No difference in major bleeding 11 Becattini C et al. N Engl J Med 2012

12 5c. Do either of these patients need a work up for laboratory thrombophilia? In general, testing for thrombophilia should be avoided in patients in the acute setting of thrombosis. Acute thrombosis will affect antithrombin, protein C, protein S, factor VIII, lupus anticoagulant assays and antiphospholipid antibody assays. In addition, warfarin and heparin can interfere with protein C, S, antithrombin and lupus anticoagulant assays. Presence of common thrombophilia (ie., factor V Leiden, prothrombin gene mutation, hyperhomocysteinemia) does not strongly influence the risk of recurrent VTE and therefore will not likely influence recommendations for duration of therapy. Acutely, even presence of significant thrombophilia will not influence recommendations for anticoagulation in first idiopathic DVT/PE (with the rare exception of significant antithrombin deficiency, where patients may be less sensitive to heparin). test Acute VTE Heparin Warfarin Anticardiolipin antibodies elevated No effect No effect Lupus anticoagulant prolonged prolonged prolonged Protein C, S decreased No effect decreased Antithrombin level decreased No effect decreased Factor VIII level increased No effect No effect Consider Work up for Laboratory Thrombophilia (age < 50 years old) Women of childbearing years Patients with suspicion for APLS Strong family history of VTE Patients with recurrent VTE Results will influence therapy (duration) 12

13 6. A 33 year old woman diagnosed with left lower extremity DVT 3 months ago maintained on warfarin present with complaints of pleuritic chest and shortness of breath. A CT angio of the chest reveals new bilateral subsegmental pulmonary emboli. She reports compliance with her warfarin therapy and has an INR of 2.5 at the time of admission. She is admitted to your service for recurrent VTE. a. How do you manage this? VTE DESPITE ANTICOAGULATION Medication adherence Antiphospholipid antibody syndrome Cancer DIC/Trousseaus Heparin-induced thrombocytopenia Myeloproliferative disorder Antithrombin deficiency Structural defect Anticoagulant Therapy for Warfarin failure Transition to LMWH then transition to warfarin with higher target OR continue LMWH Anticoagulant therapy for LMWH failure Change to BID dosing Increase dosing by 25% Follow anti-xa levels year old man with history of AFIB, diabetes, hypertension is having total hip arthroplasty. He is on warfarin as an outpatient for stroke prophylaxis. How do you mange his anticoagulation in perioperative period? 13

14 For high bleed risk procedures wait a full hours before starting full dose anticoagulation. Recommend stepwise increase from prophylaxis to intermediate ro treatment dose of heparin/low molecular weight heparin Spyropoulus et al How I treat anticoagulated patients undergong an elective procedure or surgery. Blood 2012;120: