1 Hypercoagulable States Daniel A. Forman, DO April 26, 2014 Risk Factors for Venous Thromboembolism (VTE) Hereditary thrombophilias How long to treat Newer agents
2 The hypercoagulable states Ann Intern Med Jun;102(6): Patients are considered to have hypercoagulable states if they have laboratory abnormalities or clinical conditions that are associated with an increased risk of thrombosis (prethrombotic states) or if they have recurrent thrombosis without recognizable predisposing factors (thrombosis-prone). These disorders are generally inherited.. Secondary hypercoagulable states are generally acquired disorders in patients with underlying systemic diseases or clinical conditions known to be associated with an increased risk of thrombosis: for example, malignancy, pregnancy, use of oral contraceptives, myeloproliferative disorders
3 Venous Thrombo-Embolism (VTE) Incidence 1 to 2 per 1,000 general population 1 per 100 over 80 year olds Deaths 60, ,000/year
4 Acquired Thrombophilia Major Risk Factors Acute Respiratory Failure Extensive trauma, LE fractures Metastatic Cancer ± Chemotherapy Age > 70 Acute CVA, Paralysis CHF, Class III or IV ICU Admission Septicemia Pregnancy, PP PHx of VTE Major Surgery (Especially THR & TKR) Others
5 Acquired Thrombophilia Minor Risk Factors Obesity (BMI >28 or 30) Acute Infection Central catheter Estrogen, OC CHF, Class I or II Chronic Respiratory Disease Nephrotic Syndrome Smoking ( 1 pack/day) Varicose Veins (Factor V Leiden) FHx of VTE Long Travel Acute Rheumatic Diseases Age >40 Inflammatory Bowel Diseases Others.
6 Which of the following is not a hereditary thrombophilia? A. Protein C deficiency B. Prothrombin gene mutation C. Elevated factor VIII level D. Antiphospholipid Antibody Syndrome
7 Inherited Thrombophilia Factor V Leiden mutation Prothrombin gene mutation Protein S deficiency Protein C deficiency Antithrombin (AT) deficiency Elevated Factor VIII level Rare disorders
8 APC Resistance = Factor V Leiden Factor Va propagates clot by helping to form thrombin Activate Protein C inhibits this step (anticoagulant) Hereditary mutation in Factor V that causes a resistance to inactivation by protein C Can be heterozygous or homozygous
9 Factor V Leiden (FVL) Heterozygous State (50% of thrombophilias): Caucasians 5.3 percent Hispanic Americans 2.2 percent Native Americans 1.2 percent African Americans 1.2 percent Asian Americans 0.45 percent Condition Relative Risk Incidence % / year Oral contraceptives (O.C.) FVL (heterozygous) OC plus FVL (heterozygous) 35 (16?) 0.29 FVL (homozygous) to 1.0
10 Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: A rational approach to contraception. Blood 2011 Aug 25; 118:2055. Risk VTE: OC =.19 FVL =.35 OC +FVL =.49 FVL+Preg = 1.97 Hypothetical analysis by authors: If we withhold BCP to 100,000 woman we will see 336 VTE in condom users but on 6 in OC users. Conclusion: Okay to use BCP in FVL and Prothrombin Gene Mutation
11 Prothrombin (Factor II) Gene Mutation-G20210A 1-4% whites Increased Prothrombin production Less risk of VTE (vs FVL)
12 Protein C, Protein S, and Antithrombin Deficiency Autosomal Dominant Screen using activity assay Type Antigen Activity I Low Low II Normal Low Falsely low activity in acute clot, warfarin use High clinical penetrance Acquired deficiencies occur (ex. Liver Dz, NS)
13 Protein S Deficiency Unlikely to be a risk factor of DVT Pintao MC et al. Protein S levels and the risk of venous thrombosis: Results from the MEGA case-control study. Blood 2013 Oct 31; 122:3210.
14 Homocysteine and the MTHFR Gene Elevated homocysteine levels are associated with increase risk of venous thrombosis ( X) and arterial vascular disease RCTs of Vitamin supplementation to lower homocysteine has not proven to decrease risk of recurrent arterial or venous events ( 8 negative RCTs) Do not screen for elevated homocysteine levels or MTHFR
15 Thrombophilia, Clinical Factors, and Recurrent Venous Thrombotic Events Leiden University Medical Center Christiansen et al JAMA. 2005;293: patients followed prospectively for 3 years Clinical factors more important than laboratory Risk of clot higher idiopathic clots, men, and women using OC s Combined abnormalities not predictive
16 Work up for idiopathic DVT Don t miss a malignancy (5-10%) Think about venous obstruction Hospitalized Consider Heparin Induced Thrombocytopenia (HIT) Arterial clots too. Check CBC to exclude Polycythemia Vera and Essential Thrombocythemia Arterial clots too. Consider Paroxysmal Nocturnal Hemoglobinuria (PNH) if unusual location (hepatic, portal, or mesenteric vein)
17 Testing for Hypercoagulability: Consider only for unprovoked VTE in patients under 40 (50?). Testing for Antithrombin, Protein C, and Protein S deficiency reasonable if young and family history. Minimal value for testing for FVL & Prothrombin Mutation. Testing Family doesn t make sense (financial implications) These test don t identify increased risk for recurrent clot Order testing for Anti-Phospholipid Antibody Syndrome (arterial clots too) Cardiolipin IgG or IgM B2- Glycoprotein 1 AB (IgG, IgM) Lupus Anticoagulant
18 Thrombotic Risk Factors are additive BLOOD CLOT Surgery Hospitalization Infection/Inflammation Increasing Age Smoking Obesity Factor V Leiden
19 Phases of treatment of VTE Initial phase (5-7 days) Long term phase (7 days to 3 months) Therapeutic anticoagulation reduces recurrence and complications. Extended phase (> 3 months) prolonged prophylaxis Reserved for high risk Not meant to be life long No bridging if on warfarin
20 How Long to Treat? Idiopathic VTE may have a 50% risk of recurrence Patient counseling Provoked 10% risk 5 years Unprovoked 30-40% 5 years Prandoni et al Haematologica 2007; 92:
21 Risk Stratification for recurrence Women Lower Risk High Risk Age (HR 1.17) Younger age Male Sex (HR 1.56) Distal DVT (HR 0.49) PE (HR 1.19) Estrogen-related VTE Increased D-dimer (OR 2.36) Better for men
22 Predicting Risk of Recurrence- Risk Assessment Model Prospective Cohort Study Followed 929 patients for 43 months Risk Recurrence = 25% Higher Risk- Male, Prox. Thrombosis, PE, and elevated D-dimer Hereditary Thrombophilias not predictive Develop Nomogram 5 year risk 5-30% depending on clinical parameters Circulation 2010; 121:
23 Current CHEST Guidelines suggest more extended phase therapy In patients with an unprovoked DVT of the leg (isolated distal or proximal), we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B). After 3 months of treatment, patients with unprovoked DVT of the leg should be evaluated for the risk-benefit ratio of extended therapy. In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk, we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B).
24 Clarification: If a patient has a unprovoked PE, even if FVL is determined upon a hypercoagulable workup, the chart notation should read: Unprovoked VTE (location, date) We should avoid the inaccurate notation: Hypercoaulable due to FVL
25 Extended therapy: What to do? Repeat the Ultrasound. Check D-dimer? Does the patient have lymphedema or PTS? Does the patient have another indication for anticoagulation? Did he present with a PE? Discuss risks : benefits and ask what patient prefers. If not bleeding, and no problems, why not take it a few months at a time. (indefinite duration)
26 Options for Extended Treatment BMJ 2013;347:5133 (Icon Array) 13 study meta analysis
27 Next patient is a 42 year old female with multiple dvt s, a second trimester miscarriage, and laboratory confirmed Anti-phospholipid Antibody Syndrome (APAS). She has to leave work early for INR testing and it is causing conflict with her employer. Her INR s have been therapeutic for 6 months on 3 mg alternating with 4mg warfarin every other day. Which of the following is the best approach for this patient? A. Change to dabigatran 150mg po bid. B. Change to aspirin 81mg daily. C. Change to enoxaparin 1.5 mg/kg/day. D. Check the INR every 3 months.
28 Give your patient a break! PRINT Study- Randomized Controlled Trial, Concluded: Stable patients can have INR s performed every 12 weeks. Less dose change (2% vs. 18%) no increased bleeding. Accepted by CHEST guidelines (2B). Not for Everyone (CHF, New Disease Development, etc). Schulman et al Ann Intern Med 2011; 155:653-9
29 You are treating a 55 y.o. black male presenting with an acute L. lower extremity DVT with IV Heparin, and warfarin that was started on his first hospital day. His dose of warfarin is 5 mg daily. His day 3 INR was 1.0. What is the next best action? A. Stop IV Heparin, start LMWH at therapeutic dosing. Continue warfarin 5 mg daily. B. Change to LMWH as above; but increase warfarin 10 mg daily. C. Continue IV Heparin. Continue warfarin 5 mg daily. D. Continue IV Heparin. Increase warfarin 10 mg daily.
30 Newly diagnosed VTE disease case: If the INR = 1.0 on Day 3 then double starting dose. LMWH is better than UFH for VTE Disease! No lab testing, Less risk HIT, more clot regression, lower recurrence, lower bleeding, less deaths One study reported 60% patient on UFH failed to achieve adequate aptt response in 24 hours. ACCP 2B recommendation. Arch Intern Med 1988; 148:1321 Chest 2012; 141: e495s
31 Ideal anticoagulant Safe and effective Rapid acting Available p.o. and parenteral Rapid elimination Free of drug interactions Predictable effect and wide therapeutic window No need for monitoring Minimal toxicity and side effects Reversible with an antidote
32 Warfarin VS. Newer Rxs Features Warfarin Newer Agents Onset Slow (days) Rapid Dosing Variable Fixed Half life Long Short Food effects Yes No Drug Interactions Many Few Monitoring Yes No Antidote Yes No (but short ½ life) Cost Low High
33 Your patient is a 50 y.o. male who presented 6 months ago with syncope due to an idiopathic PE. He is afraid of dying and does not want to stop warfarin, but he is an international traveler and is concerned about work related travel due to his INR testing. His INR s have not been stable. He takes no other medications. What is the best option for this patient? A. Stop warfarin and recommend aspirin. B. Check INR every 3 months. C. Change to LMWH. D. Change to Rivaroxaban 20 mg daily.
34 Newer Anticoagulants FDA Approval Drug Dabigatran (Pradaxa) Prophylaxis (ortho) A. Fib ACUTE DVT Prolonged treatment DVT/PE x x x Rivaroxaban (Xarelto) x x x x Apixaban (Eliquis) x x Edoxaban
36 Drug CYP 3A4 P-gp Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Yes Yes Yes Yes
37 Dabigatran (Pradaxa) Direct thrombin inhibitor Renal excretion VTE approval (bridging) Not for use with mechanical heart valves (increase CVA and bleeding) NEJM 2013; 369:1206 Slight increase for CAD (0.2%) Circulation 2012; 125:669 Dyspepsia
38 Patient is a 57 y.o. male school teacher recently diagnosed with AIDS while admitted for an acute PE. Which of the following is correct? A. HIV/AIDS is not a risk factor for VTE disease. B. Intravenous unfractionated heparin is preferred in HIV patients with acute VTE disease. C. Rivaroxaban is contraindicated in patient on protease inhibitor therapy due to CYP3A inhibition.
39 Rivaroxaban (Xarelto) Once daily with food (BID for acute VTE x 3wk) Avoid with medications that affect both the P-gp and Cytochrome P450 3A4. Cyp3A4 inhibitors: (HIV protease inhibitors, ketoconazole, voriconazole) CYP3A4 inducers: (Rifampin, carbamazepine, or phenytoin) No need for overlapping parenteral Tx (ex. LMWH)
40 Rivaroxaban (Xarelto) vs. Warfarin for acute PE Symptomatic PE +/- DVT Excluded: Cr clearance < 30, Liver disease, SBP <110 or >180, drugs that affect CYP 3A4 Average age 57 10% treated outpatient 12% ICU Conclusion: Rivaroxaban is non-inferior with similar bleeding risk (less major bleeding) N Engl J Med 2012; 366:
41 Apixaban (Eliquis) Twice daily Less bleeding? AMPLIFY Major bleeding or clinically relevant for acute DVT/PE 4.3% vs. 9.7% (warfarin) AMPLIFY EXT for continued therapy after 6-12 months no higher bleeding then placebo. Risk of DVT 12 mo. 1.7% 2.5mg, 1.7% 5mg, and 8% placebo Risk of Death 12mo 3.8%, 4.2%, 11.6% N Engl J Med 2013; 368:699-70
42 Edoxaban Once daily (60mg) 30mg/d. Cr.Cl or weight less than 60kg. Approx. 10% < 60 kg Approx. 10% > 75 y.o. More effective than warfarin in patients with high risk PE. (RV enlargement, elevated BNP). N Engl J Med 2013; 369:
43 Bleeding Patients Supportive measures Last dose? Renal or hepatic dysfunction? Other anticoagulants? If PT normal, unlikely any effect of rivaroxaban. If PTT is normal, unlikely any effect of dabigatran. Oral Anticoagulants: The old and the new. 2012; American Society of Hematology Webinar King et al Chest 2013; 143;:1362
44 Control of bleeding Modality Dabigatran Rivaroxaban Apixaban Charcoal X X X Hemodialysis X Prothrombin Complex Concentrates Kcentra x x avii??? King et al Chest 2013; 143: 1362 Gonsalves et al Mayo Clin Proc. 2013; 88: 495
45 Future is here: 59 y.o. female with breast cancer. Oct 24 th, 2013 Hi Dr. Dan, I bet you thought I died or something. Just got back from the Italy trip on Monday night - had a wonderful time. Didn't think that I was going to be able to go. About a month ago, I had such bad chest pain that I thought I was having a heart attack - turned out to be a blood clot on my lung. Was in the hospital for a week until they got my INR levels correct. Now I am on Warfarin. Oct 25 th, 2013 Dr. Dan, Just had a chemo. treatment today and they checked my pro-time levels must have been all that wine I drank in Italy. Dr. Latif told me not to take my warfarin tonight and also tomorrow night, but I am to resume on Sunday, but only 5 mg. not the 7.5 mg s- present Future One week in the hospital Numerous tests Exposure to sick patients Discharged on therapeutic warfarin Outpatient labs, risk of over and under dosing. Missed work, bills, etc. Start rivoroxaban BID for three weeks then daily. Discharge from the ED or hospital the next day. Or dabigitran
46 Conclusions: 1. Age is an important cause of hypercoagulability. 2. FVL and PG mutation are wimpy risk factors for first VTE, and are not predictive of subsequent clotting. 3. O.C.s are reasonable in known FVL. 4. Homocysteine and MTHFR: Just say No. 5. Having an unprovoked VTE is a major risk factor for subsequent VTE. 6. Prolonged anticogulation can be carried out with warfarin, aspirin, or newer agents.