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Introduction to thrombosis Assistant Professor of Medicine Hematology/Oncology2014.

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1 Introduction to thrombosis Assistant Professor of Medicine Hematology/Oncology2014

2 Objectives 1. Arterial Thrombosis: 1. Arterial Thrombosis: -Pathophysiology, Risk factors, Symptoms and Signs, treatment 2. Venous Thrombosis: 2. Venous Thrombosis: -Pathophysiology, Risk Factors, Symptoms and Signs 3. Common anticoagulants 3. Common anticoagulants 4. Hereditary and acquired Hypercoagulable Disorders 4. Hereditary and acquired Hypercoagulable Disorders

3 Summary of Hemostasis Platelet plug forms forms Stabilization by fibrin formation (clotting cascade) Extension of clot limited by: Natural anticoagulants Fibrinolysis

4 Arteries versus Veins Thick,muscular Thin, pliable High pressure High oxygen Low pressure Low oxygen Exception: pulmonary artery –O2 low

5 Blood Clotting Arterial Venous Platelets more important Blood clotting factors more important

6 Pathogenesis Atherosclerosis is a slow process that starts in childhood and results in occlusion of arterial blood vessels Atherosclerosis is a slow process that starts in childhood and results in occlusion of arterial blood vessels Interruption of blood flow leads to hypoxia which causes ischemic damage of tissue, in the worst case tissue death (infarct) Interruption of blood flow leads to hypoxia which causes ischemic damage of tissue, in the worst case tissue death (infarct) Ischemia causes pain and malfunction of tissue/organ ( angina/Myocardial infarct, arrhythmias in the heart) Ischemia causes pain and malfunction of tissue/organ ( angina/Myocardial infarct, arrhythmias in the heart)

7 Risk factors for arterial thrombosis Smoking Smoking HTN HTN cholesterol cholesterol diabetes diabetes Homocysteine ? Homocysteine ? obesity obesity sedentary life style sedentary life style Advanced age Advanced age Family History Family History Inflammation Inflammation Endothelial dysfunction Fatty streak Soft plaque Hard plaque Plaque rupture Thrombosis/Occlusion

8 Arterial Thrombosis-Clinical manifestations 1. Myocardial Infarction (Heart Attack) 1. Myocardial Infarction (Heart Attack) -chest/arm pain pain, SOB, collapse, stomach pain 2. Cerebrovascular accident CVA (Stroke) -dizziness, slurred speech, facial droop, one sided arm/leg weakness 3. Peripheral Vascular Disease (PVD), chronic versus acute 3. Peripheral Vascular Disease (PVD), chronic versus acute -sudden onset of severe pain, palor, cold skin ( No pulse palpable)

9 Treatment of arterial thrombosis Acute: Anticoagulation with heparin plus thrombolytic (tPA, urokinase, streptokinase)=“clot busters” Acute: Anticoagulation with heparin plus thrombolytic (tPA, urokinase, streptokinase)=“clot busters” Long-term for primary or secondary prevention: antiplatelet therapy with ASA( acetylic salicylic acid=aspirin) Long-term for primary or secondary prevention: antiplatelet therapy with ASA( acetylic salicylic acid=aspirin) After Stent placement: Clopidogrel (Plavix) and ASA After Stent placement: Clopidogrel (Plavix) and ASA No role for warfarin No role for warfarin Risk factor modification important Risk factor modification important

10 Objectives 1. Arterial Thrombosis: 1. Arterial Thrombosis: -Pathophysiology, Risk factors, Symptoms and Signs, treatment 2. Venous Thrombosis: 2. Venous Thrombosis: -Pathophysiology, Risk Factors, Symptoms and Signs 3. Common anticoagulants 3. Common anticoagulants 4. Hereditary and acquired Hypercoagulable Disorders 4. Hereditary and acquired Hypercoagulable Disorders

11 Case #1 24 y/o female AF cadet notices DOE over the course of 1 month 24 y/o female AF cadet notices DOE over the course of 1 month Can’t finish 2 hour hiking exercise, sent to local ED Can’t finish 2 hour hiking exercise, sent to local ED CT Chest with PE protocol shows: CT Chest with PE protocol shows:

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13 Case #2 A 63 y/o male develops new Right sided bulky Lymph adenopathy, night sweats and weight loss. A 63 y/o male develops new Right sided bulky Lymph adenopathy, night sweats and weight loss. He is diagnosed with Diffuse large B-cell lymphoma and will require Chemotherapy He is diagnosed with Diffuse large B-cell lymphoma and will require Chemotherapy He undergoes placement of a PICC line R arm He undergoes placement of a PICC line R arm 3 days later he returns with a swollen, painful Right arm that is warm and has a slightly dusky discoloration. 3 days later he returns with a swollen, painful Right arm that is warm and has a slightly dusky discoloration. US Doppler shows a thrombus in the axillary vein US Doppler shows a thrombus in the axillary vein

14 Case #3 A 76 y/o woman presents to the ER with a 2 day history of LE swelling. She also feels slightly SOB and has had hemoptysis on one occasion this morning. A 76 y/o woman presents to the ER with a 2 day history of LE swelling. She also feels slightly SOB and has had hemoptysis on one occasion this morning. 2 weeks ago, she underwent Right hip replacement. She finished a course of prophylactic heparin injections 4 days ago 2 weeks ago, she underwent Right hip replacement. She finished a course of prophylactic heparin injections 4 days ago US Doppler shows acute DVT extending from her popliteal vein into her femoral vein covering the entire thigh US Doppler shows acute DVT extending from her popliteal vein into her femoral vein covering the entire thigh CT Chest by PE protocol shows PE in the RLL with signs of early infarction. CT Chest by PE protocol shows PE in the RLL with signs of early infarction.

15 Venous Thromboembolism (VTE) Incidence and Impact in the United States Approximately 2 million VTEs occur every year 1 Each year 1 person in 1,000 will experience his/her first VTE in the US 2 One third manifest pulmonary embolism ([PE], with or without deep vein thrombosis [DVT]) Death within 1 month of diagnosis 2 : ~6% of DVT cases ~12% of PE cases Recurrent DVT: ~17% of DVT patients 2 years after initial treatment* 3 ~30% of DVT patients 8 to 10 years after initial treatment* †3,4 1. Hirsh J, Hoak J. Circulation. 1996;93: American Heart Association. Heart Disease and Stroke Statistics – 2004 Update. 3. Prandoni P et al. Haematologica. 1997;82: Pengo V et al. N Engl J Med. 2004;350: *High dose standard heparin or LMWH for at least 10 days; oral anticoagulant therapy was initiated during the first week and continued for at least 3 months; † Unfractionated heparin was given as an initial IV bolus followed by IV infusion; oral anticoagulant therapy was initiated after the first week and continued for at least 6 months.

16 NBC News Correspondent David Bloom. While covering the war in Iraq, Bloom was stricken with a fatal pulmonary embolism (PE), a complication of DVT. “ March 2, 2011 Serena Williams suffers pulmonary embolism Tennis star undergoes emergency treatment in L.A. for complications stemming from blood clot in lungs”

17 Venous thrombosis-Clinical Manifestations 1. Extremities, Deep venous thrombosis (DVT) 1. Extremities, Deep venous thrombosis (DVT) Swelling, Redness/dusky color, warmth Swelling, Redness/dusky color, warmth sudden onset vs. gradual sudden onset vs. gradual 2. Pulmonary embolism (PE) SOB, acute versus gradual Diminished exercise capacity chest pain syncope cardiac arrest/death Less common sites: Portal vein, renal vein,cerebral sinus vein

18 PE: Clinical Presentation Symptom or Sign Percent Dyspnea82 Respiratory Rate >20/min 60 Heart Rate >100 beats/min 40 Chest pain 49 Cough20 Syncope14 Hemoptysis7 Goldhaber SZ, et al. Lancet Most Common Sx/Si Among 2454 Pts in International Cooperative Pulmonary Embolism Registry Goldhaber SZ, et al. Lancet 1999.

19 Venous thrombosis-Limb Sudden or gradual occlusion of a vein leads to Sudden or gradual occlusion of a vein leads to -impaired venous return with blood flow “backing up”, edema develops due to increased hydrostatic pressure, pain present -impaired venous return with blood flow “backing up”, edema develops due to increased hydrostatic pressure, pain present -blood flow through alternative routes leads to dilated superficial veins -blood flow through alternative routes leads to dilated superficial veins -thrombus leads to inflammatory response with redness and warmth of the affected area -thrombus leads to inflammatory response with redness and warmth of the affected area

20 Venous thrombosis-Pulmonary embolism Part of the thrombus can break off and travel through major veins, right heart into pulmonary artery until it becomes lodged Blood flow through pulmonary artery is impaired by thrombus, Lung tissue past thrombus cannot participate in gas exchange, tissue can infarct (Pulmonary infarct) Increased pulmonary vascular resistance can lead to right ventricular dysfunction Increased airway resistance d/t bronchoconstriction Decreased pulmonary compliance If clot burden is high ( saddle embolus-both PA affected): cardiovascular arrest and death

21 ALTERED VESSELS ~inflammatory damage ~mechanical injury ~hypoxia VENOUS STASIS ~immobility ~paralysis ~reduced flow states ALTERED COAGULABILITY ~inflammatory stimuli ~consumption of endogenous anticoagulants Virchow’s Triad

22 Risk Factors for Venous Thrombosis Common: Common: Trauma Trauma Post-surgery Post-surgery Immobility/Inactivity Immobility/Inactivity Obesity Obesity Pregnancy Pregnancy Estrogens/Birth control Estrogens/Birth control Malignancy Malignancy Age Age Previous history of DVT/PE Previous history of DVT/PE

23 Age and VENOUS THROMBOSIS AGE RISK OF THROMBOSIS 1:100,000 1:1000 1: y.o. 75 y.o. 1:10,000

24 Risk Factors for Venous Thrombosis Inherited procoagulant disorders Inherited procoagulant disorders -Factor V Leiden -Prothrombin gene mutation -Protein C deficiency -Protein S deficiency -Antithrombin deficiency Acquired hypercoagulable states -clotting factors ( increased factors VII, VIII, XI) -systemic disorders( PNH, Myeloproliferative disorders, Malignancy, Vasculitic/proinflammatory disorders, Antiphospholipid syndrome) -Disseminated intravascular coagulation ( DIC) -Heparin-induced thrombocytopenia and thrombosis syndrome

25 Diagnosis of venous thrombosis Symptoms Symptoms Blood work Blood work -elevated D-Dimer -Negative D-Dimer rules out thrombosis Imaging for Limb: Imaging for Limb: -Compression ultrasonography +/-US-Doppler, Imaging for Lungs: Imaging for Lungs: -CT scan -VQ scan

26 Hypercoagulable States DefectIncidence in Population Percent of Patients with Procoagulant States Factor V Leiden5-10%20-60% Prothrombin Gene Mutation2-4%6-8% Homocysteinemia-- 10% Protein C Deficiency1:200 <5% Protein S Deficiency--<5% Antithrombin Deficiency1:2-5,000<1% DysfibrinogenemiaNot known~1-2% Known Malignancy 16-18%

27 Treatment of acute DVT/PE Treatment for acute clot is heparin Treatment for acute clot is heparin Heparin inactivates activated clotting factors (clotting cascade initiated) Heparin inactivates activated clotting factors (clotting cascade initiated) Minimum time: 5 days and until warfarin is fully therapeutic Minimum time: 5 days and until warfarin is fully therapeutic -overlap heparin with therapeutic INR x 2 days Warfarin used to prevent additional clots Warfarin used to prevent additional clots Warfarin does not treat the acute clot-do not give alone for acute event! Warfarin does not treat the acute clot-do not give alone for acute event! Reduction of vitamin K dependent factors takes at least 4-5 days regardless of INR Reduction of vitamin K dependent factors takes at least 4-5 days regardless of INR

28 If we cannot anticoagulate Does not address the underlying hypercoagulable state Preference for removable devices, great for short term protection of patient (bleeding, surgery etc) Long-term: increases the risk of DVT

29 Bates, S. M. et al. N Engl J Med 2004;351:

30 Objectives 1. Arterial Thrombosis: 1. Arterial Thrombosis: -Pathophysiology, Risk factors, Symptoms and Signs, treatment 2. Venous Thrombosis: 2. Venous Thrombosis: -Pathophysiology, Risk Factors, Symptoms and Signs 3. Common anticoagulants 3. Common anticoagulants 4. Hereditary and acquired Hypercoagulable Disorders 4. Hereditary and acquired Hypercoagulable Disorders

31 Anticoagulants Unfractionated Heparin Unfractionated Heparin LMWH LMWH -enoxaparin ( Lovenox) -Dalteparin (Fragmin) Direct Xa inhibitor Direct Xa inhibitor -Fonaparinux ( Arixtra) Vitamin K antagonist Vitamin K antagonist -Warfarin (Coumadin) New oral anticoagulants Direct thrombin inhibitor Dabigatran ( Pradaxa) Anti-Xa inhibitors -Rivaroxaban ( Xarelto) -Apixaban (Eliquis)

32 The Heparin Family N-acetyl glucosamine 6-O-sulfate Glucuronic acid N-sulfated glucosamine 3,6-O-disulfate Iduronic acid 2-O-sulfate N-sulfated glucosamine 6-O-sulfate UFH LMWH PENTASACCHARIDE (Fondaparinux) (Fondaparinux)

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34 Mechanism of Action - UFH UFH 5-sugarsequence Factor Xa Factor IIa Factor Xai Factor IIai Antithrombin

35 Mechanism of Action - LMWH LMWH 5-sugarsequence Factor Xa Antithrombin Factor Xai

36 Warfarin Interferes with carboxylation of vitamin K dependent factors Interferes with carboxylation of vitamin K dependent factors Factor II (thrombin), VII, IX, X, Factor II (thrombin), VII, IX, X, protein C, protein S protein C, protein S Prothrombin Time (PT)/INR is used to monitor warfarin because half life of Factor VII is the shortest (5-7 hours) Prothrombin Time (PT)/INR is used to monitor warfarin because half life of Factor VII is the shortest (5-7 hours)

37 Warfarin Synthesis of Non Functional Coagulation Factors Also affects Protein C and protein S Antagonism of Vitamin K Warfarin Mechanism of Action Vitamin K VII IX X II

38 Effect of Warfarin on Factor Activity Therapeutic INR once ALL factors suppressed

39 Mechanisms of Anticoagulation 1 1.Adapted with permission from Petitou M et al. Nature. 1991;350(suppl):30-33; 2.Hirsh J, Fuster V. Circulation. 1994;89: Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S. 4.Nutescu EA, et al. Pharmacotherapy. 2004;24(7 Pt 2):82S-87S. 5.Weitz JI, Hirsh J. Chest. 2001;119(1 suppl):95S-107S. XIIa IIa Xa Intrinsic system (surface contact) XII XI XIa Tissue factor IX IXa VIIa VII VIIIVIIIa Extrinsic system (tissue damage) X Xa VVa II FibrinogenFibrin (Thrombin) IIa Factor Xa inhibitors 4,5 Direct thrombin inhibitors 4,5 Vitamin K antagonists 4 Heparins 2,3

40 INR – Oral (warfarin) anticoagulation Therapeutic Range INR Therapeutic Range INR (Most situations) (Most situations) Mechanical Heart Valve INR Mechanical Heart Valve INR Dose: Diet (Vitamin K) Metabolism Concurrent medications **The higher the INR the higher the bleeding risk

41 Drug Interactions

42 Management of excessive anticoagulation Depends on INR level and presence of bleeding symptoms Depends on INR level and presence of bleeding symptoms Options: Options: Hold warfarin dose until INR is in therapeutic range Hold warfarin dose until INR is in therapeutic range Give Vitamin K (po, im, iv), if patient not bleeding Give Vitamin K (po, im, iv), if patient not bleeding -takes hours Give FFP iv (contains all clotting factors), results in partial or total reversal Give FFP iv (contains all clotting factors), results in partial or total reversal -used before urgent/emergent procedures -used for severe or life threatening bleeding -works immediately Recombinant Factor VII if all else fails ( caution: thrombogenic!) Recombinant Factor VII if all else fails ( caution: thrombogenic!)

43 Antithrombotic Characteristics DrugHalf-Life Duration of effect Renal clearance? Reversal UFH (sq BID-TID) 1-2 hrs8-12 hrsNoProtamine LMWH (sq q day-BID) 4-7 hrs12-24 hrs Yes (>30 ml/min) ±Protamine (40-70%) Warfarin (po daily) hrs48-72 hrsNo FFP Vitamin K Fondaparinux (sq daily) hrs24 hrs Yes (>30 ml/min) None (VIIa conc?) Dabigatran hrs24-36 hrs Yes (>30 ml/min ) None (Dialysis) Rivaroxaban 5-9 hrs24 hrsyesNone

44 New anticoagulants-No monitoring Dabigatran (Pradaxa): oral direct thrombin inhibitor Dabigatran (Pradaxa): oral direct thrombin inhibitor FDA approved in US for Atrial fibrillation, 150 mg po bid FDA approved in US for Atrial fibrillation, 150 mg po bid slightly less bleeding risk than warfarin slightly less bleeding risk than warfarin Rivaroxaban (Xarelto): oral Factor Xa inhibitor Rivaroxaban (Xarelto): oral Factor Xa inhibitor FDA approved for A fib ( 20 mg qd) and DVT/PE treatment, 15 mg bid x 3 weeks, then 20 mg qd FDA approved for A fib ( 20 mg qd) and DVT/PE treatment, 15 mg bid x 3 weeks, then 20 mg qd Apixaban (Eliquis): oral Factor Xa inhibitor Apixaban (Eliquis): oral Factor Xa inhibitor 5 mg po bid for non-valcular A fib 5 mg po bid for non-valcular A fib Increased risk of stroke after stopping drug (Rebound) Increased risk of stroke after stopping drug (Rebound)

45 Bridging case 45 y/o female 45 y/o female PMH: PMH: HTN HTN ‘idiopathic’ DVT in 2005, PE in 2/ days after leg injury. ‘idiopathic’ DVT in 2005, PE in 2/ days after leg injury. Antiphospholipid-Antibody syndrome (APLS)=severe hypercoagulable disorder Antiphospholipid-Antibody syndrome (APLS)=severe hypercoagulable disorder Chronic warfarin therapy (since 2/08) without complications Chronic warfarin therapy (since 2/08) without complications

46 Oh by the way… Scheduled for FME in 7 days and was instructed to stop warfarin tomorrow. Scheduled for FME in 7 days and was instructed to stop warfarin tomorrow.

47 Bridging Use of parenteral anticoagulants during period of withholding warfarin therapy Use of parenteral anticoagulants during period of withholding warfarin therapy e.g. colonoscopy, surgery, multiple dental extraction e.g. colonoscopy, surgery, multiple dental extraction Parenteral anticoagulants: heparin, low molecular weight heparin (LMWH), Parenteral anticoagulants: heparin, low molecular weight heparin (LMWH), Minimize period of time without anticoagulation Minimize period of time without anticoagulation

48 Typical bridging protocol 5 days before procedure-stop warfarin (pm dose) 5 days before procedure-stop warfarin (pm dose) 3 days before procedure start LMWH ( am injection) 3 days before procedure start LMWH ( am injection) No LMWH on morning of procedure No LMWH on morning of procedure Restart LMWH within hrs after procedure Restart LMWH within hrs after procedure Start warfarin on the evening of procedure: remember that is takes several days before warfarin is at therapeutic levels Start warfarin on the evening of procedure: remember that is takes several days before warfarin is at therapeutic levels Follow INR and stop LWMH once INR is at target Follow INR and stop LWMH once INR is at target Anticoagulation clinics/PCP Anticoagulation clinics/PCP

49 What’s this patient’s risk of having thrombotic event off anticoagulation? a. Low b. Moderate c. High

50 Managing patients on anticoagulation requiring invasive procedures Low risk: no recent (>12 months) venous thromboembolism, atrial fibrillation without h/o stroke or other risk factors or bileaflet mechanical cardiac valve in aortic position Low risk: no recent (>12 months) venous thromboembolism, atrial fibrillation without h/o stroke or other risk factors or bileaflet mechanical cardiac valve in aortic position PLAN: PLAN: - stop warfarin 4-5 days before surgery, allow INR to return to normal. Use postoperative prophylaxis and simultaneously begin warfarin - stop warfarin 4-5 days before surgery, allow INR to return to normal. Use postoperative prophylaxis and simultaneously begin warfarin

51 Intermediate risk of thromboembolism Mechanical Heart Valve Mechanical Heart Valve Bileaflet (St. Jude) aortic valve and one: Bileaflet (St. Jude) aortic valve and one: A.fib, prior CVA/TIA, DM, HTN, HF, age >75 A.fib, prior CVA/TIA, DM, HTN, HF, age >75 Atrial Fibrillation Atrial Fibrillation CHADS-2 score of 3 or 4 CHADS-2 score of 3 or 4 VTE within past 3 to 12 mo VTE within past 3 to 12 mo Non-severe thrombophilia (i.e. heterozygous Factor V Leiden) Non-severe thrombophilia (i.e. heterozygous Factor V Leiden) PLAN: PLAN: Stop warfarin 4-5 days before surgery, allow INR to return to normal, cover the patient beginning 2 d preoperatively with low dose UFH or prophylactic dose LMWH and then start therapy with LMWH and warfarin postoperatively vs. higher dose UFH or full dose LMWH Stop warfarin 4-5 days before surgery, allow INR to return to normal, cover the patient beginning 2 d preoperatively with low dose UFH or prophylactic dose LMWH and then start therapy with LMWH and warfarin postoperatively vs. higher dose UFH or full dose LMWH CHADS-2: CHF, HTN, age >75, DM, prior TIA/CVA

52 Managing patients on anticoagulation requiring invasive procedures High risk: recent (<3 months) history of venous thromboembolism, Severe thrombophilia (APLAS, protein C or S def, multiple), mechanical cardiac valve in mitral position and old model of cardiac valve (Ball/cage), Atrial Fibrillation with CHADS-2 score of 5 or 6. Recent (3 mo) CVA/TIA, Rheumatic valve disease High risk: recent (<3 months) history of venous thromboembolism, Severe thrombophilia (APLAS, protein C or S def, multiple), mechanical cardiac valve in mitral position and old model of cardiac valve (Ball/cage), Atrial Fibrillation with CHADS-2 score of 5 or 6. Recent (3 mo) CVA/TIA, Rheumatic valve diseasePLAN: -stop warfarin 4-5 days before surgery, allow INR to return to normal -stop warfarin 4-5 days before surgery, allow INR to return to normal -begin therapy with FULL dose of UFH or LMWH as the INR falls ( about 2 days preop) -begin therapy with FULL dose of UFH or LMWH as the INR falls ( about 2 days preop) -UFH as sc. Injection, then IV drip in hospital -UFH as sc. Injection, then IV drip in hospital -dc drip about 5 hrs before surgery -dc drip about 5 hrs before surgery -stop LMWH hrs before surgery -stop LMWH hrs before surgery

53 Managing patients on anticoagulation requiring invasive procedures-alternative option Low risk of bleeding Low risk of bleeding Continue warfarin at lower dose and operate at an INR of Continue warfarin at lower dose and operate at an INR of Intensity has been shown in RCT to be safe in gynecologic and orthopedic surgery patients Intensity has been shown in RCT to be safe in gynecologic and orthopedic surgery patients Dose of warfarin can be lowered 4-5 days preop Dose of warfarin can be lowered 4-5 days preop Warfarin therapy can be restarted at regular doses postoperatively, supplemented with low dose UFH or prophylactic LMWWH Warfarin therapy can be restarted at regular doses postoperatively, supplemented with low dose UFH or prophylactic LMWWH

54 Anticoagulants for Bridging Therapeutic dose (DVT/PE treatment dose) Therapeutic dose (DVT/PE treatment dose) enoxaparin (Lovenox)1 mg/kg SQ bid or 1.5 mg/kg/day enoxaparin (Lovenox)1 mg/kg SQ bid or 1.5 mg/kg/day dalteparin (Fragmin)200 IU/kg/day or 100 IU/kg/bid dalteparin (Fragmin)200 IU/kg/day or 100 IU/kg/bid Unfractionated heparin with therapeutic APTT (61-84 sec) Unfractionated heparin with therapeutic APTT (61-84 sec) Low dose Low dose enoxaparin 30 mg SQ twice daily or 40 mg SQ once daily enoxaparin 30 mg SQ twice daily or 40 mg SQ once daily dalteparin 2500 or 5000 units SQ once daily dalteparin 2500 or 5000 units SQ once daily

55 Bridging Plan - LMWH Stop warfarin approximately 5 days prior to procedure (Grade 1B) Stop warfarin approximately 5 days prior to procedure (Grade 1B) Initiate LMWH once INR below therapeutic level Initiate LMWH once INR below therapeutic level Usually day 4 or 3 prior Usually day 4 or 3 prior Last dose of LMWH 24 hr before surgery (grade 1C) Last dose of LMWH 24 hr before surgery (grade 1C) Administer approximately ½ total daily dose instead of 100% (grade 1C) Administer approximately ½ total daily dose instead of 100% (grade 1C) Resume LMWH approximately 24 hours after procedure when there is adequate hemostasis (grade 1C) Resume LMWH approximately 24 hours after procedure when there is adequate hemostasis (grade 1C) Resume warfarin approximately 12 – 24 hrs after surgery (grade 1C) Resume warfarin approximately 12 – 24 hrs after surgery (grade 1C)

56 Oral Anticoagulation and Dental Surgery “Although there is a theoretical risk of hemorrhage after dental surgery, the risk is minimal, and the risk may be greatly outweighed by the risk of thromboembolism.” 1 “Although there is a theoretical risk of hemorrhage after dental surgery, the risk is minimal, and the risk may be greatly outweighed by the risk of thromboembolism.” 1 Grade 1B recommendation: continue warfarin around time of minor dental procedure (single or multiple tooth extraction and root canal procedure) 2 Grade 1B recommendation: continue warfarin around time of minor dental procedure (single or multiple tooth extraction and root canal procedure) 2 1. Arch Intern Med 1998;158: Chest 2008;133:299S

57 Objectives 1. Arterial Thrombosis: 1. Arterial Thrombosis: -Pathophysiology, Risk factors, Symptoms and Signs, treatment 2. Venous Thrombosis: 2. Venous Thrombosis: -Pathophysiology, Risk Factors, Symptoms and Signs 3. Common anticoagulants 3. Common anticoagulants 4. Hereditary and acquired hypercoagulable Disorders 4. Hereditary and acquired hypercoagulable Disorders

58 Indications of a congenital Defect in a patient with thrombosis First thrombosis age <50 First thrombosis age <50 Family history of thrombosis Family history of thrombosis Recurrent episodes of thrombosis Recurrent episodes of thrombosis Thrombosis at unusual sites Thrombosis at unusual sites Neonatal thrombosis Neonatal thrombosis Thrombosis without apparent antecedent thrombogenic event Thrombosis without apparent antecedent thrombogenic event

59 What are the (known) inherited Hypercoagulable States? 1. Factor V Leiden 1. Factor V Leiden -Factor Va becomes resistant to activated Protein C (APC resistance) 2. Prothrombin gene mutation (Factor II) 2. Prothrombin gene mutation (Factor II) Mildly elevated plasma levels of Factor II 3. Deficiencies of Antithrombin III (AT III), Protein S and Protein C 3. Deficiencies of Antithrombin III (AT III), Protein S and Protein C -Reduced amounts of natural anticoagulants leads to imbalance in the clotting cascade

60 How common are these disorders?

61 Case #2 19 y/o healthy and active woman is evaluated for swollen RLE x 5 days in local ER 19 y/o healthy and active woman is evaluated for swollen RLE x 5 days in local ER Started on birth control 5 mo prior Started on birth control 5 mo prior US shows Right popliteal DVT US shows Right popliteal DVT “Hypercoag panel” drawn at time of presentation: “Hypercoag panel” drawn at time of presentation: Heterozygous for Factor V Leiden Heterozygous for Factor V Leiden Issues: Long-term management Pregnancy Surgeries Genetic counseling (siblings, children)

62 Factor V Leiden Autosomal dominant genetic mutation (1994 in the Dutch city of Leiden) Autosomal dominant genetic mutation (1994 in the Dutch city of Leiden) This is not a deficiency! but a structural change in the Factor V This is not a deficiency! but a structural change in the Factor V Diagnosis by DNA analysis ( heterozygotes vs homozygotes) Diagnosis by DNA analysis ( heterozygotes vs homozygotes)

63 Mechanism of Factor V Leiden 1. Increased coagulation: 1. Increased coagulation: -Factor V Leiden is inactivated more slowly by activated protein C than normal factor V -More Factor Va is available within the coagulation cascade, thereby leading to more thrombin generation 2. Decreased anticoagulation: 2. Decreased anticoagulation: -Normal factor V, cleaved at position 506, is a cofactor together with protein S for protein C. Protein C cleaves factor VIIIa and factor Va -Lack of normally cleaved Factor V decreases the anticoagulant property of protein C (APC resistance)

64 Factor V Leiden Mechanism TF+ VIIa TF+ VIIa IX+VIII IX+VIII X+V (=abnormal) X+V (=abnormal) II II Fibrinolysis CLOT Antithrombin Protein C and Protein S Degradation of Factors V, VIII

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66 Prothrombin gene mutation PG20120A (Factor II mutation) genetic polymorphism that causes increased amount of prothrombin (factor II) in the circulation occurs in ~2-3% of Caucasian population in the U.S. associated with VENOUS thrombosis at least half of clotting events precipitated by some stimulus most people with the mutation DON’T clot

67 Testing for prothrombin gene mutation DNA analysis for prothrombin G20210A mutation DNA analysis for prothrombin G20210A mutation Distinguishes heterozygotes and homozygotes Distinguishes heterozygotes and homozygotes

68 What is the risk of thrombosis?

69 Deficiencies of natural anticoagulants Leads to imbalance between coagulation and anticoagulation Leads to imbalance between coagulation and anticoagulation Natural anticoagulants: Protein C,S and Antithrombin deficiency Natural anticoagulants: Protein C,S and Antithrombin deficiency Patients present early in life, usually with venous thrombosis Patients present early in life, usually with venous thrombosis Often additional risk factors are present Often additional risk factors are present

70 Natural Anticoagulants: AT III, protein C, S TFPI TF+ VIIa IX+VIII IX+VIII X+V X+V II II Fibrinolysis CLOT Antithrombin Protein C and Protein S Heparin Degradation of Factors V, VIII Protein C/S deficiency

71 Asymptomatic carriers Thrombosis is a multi-risk disorder Thrombosis is a multi-risk disorder Additional risk factors are often required to cross the thrombosis threshold Additional risk factors are often required to cross the thrombosis threshold Some carriers will never have a thrombotic event Some carriers will never have a thrombotic event Asymptomatic family members rarely need anticoagulation Asymptomatic family members rarely need anticoagulation Prophylaxis during high risk events: pregnancy, surgery or immobilization Prophylaxis during high risk events: pregnancy, surgery or immobilization Estrogen therapy ( OCP, perimenopausal) is contraindicated-use anticoagulation Estrogen therapy ( OCP, perimenopausal) is contraindicated-use anticoagulation

72 Acquired hypercoagulable States Malignancy Malignancy Presence of a central venous catheter Presence of a central venous catheter Surgery, especially orthopedic Surgery, especially orthopedic Trauma Trauma Pregnancy Pregnancy Oral contraceptives Oral contraceptives Hormone replacement therapy or Tamoxifen, Hormone replacement therapy or Tamoxifen, Anti-angiogenesis (Bevacizumab, Thalidomide,Lenalidomide) Anti-angiogenesis (Bevacizumab, Thalidomide,Lenalidomide) Congestive heart failure Congestive heart failure Antiphospholipid antibody syndrome Myeloproliferative disorders (Polycythemia vera, Essential thrombocythemia) Paroxysmal nocturnal hemoglobinuria (PNH) Inflammatory bowel disease Nephrotic syndrome Hyperviscosity (Waldenstrom's macroglobulinemia, Multiple myeloma) Marked leukocytosis in acute leukemia Sickle cell anemia HIV/AIDS

73 Antiphospholipid Antibody Syndrome Acquired hypercoagulable state Acquired hypercoagulable state Presence of antibodies that cause clotting (anticardiolipin AB, Lupus anticoagulant, beta2- glycoprotein1-AB) plus clinical event ( arterial or venous thrombosis) Presence of antibodies that cause clotting (anticardiolipin AB, Lupus anticoagulant, beta2- glycoprotein1-AB) plus clinical event ( arterial or venous thrombosis) Very high risk of recurrence after initial event (10%/year, cumulative) Very high risk of recurrence after initial event (10%/year, cumulative) Life-long anticoagulation recommended Life-long anticoagulation recommended Need to “bridge” before procedures Need to “bridge” before procedures

74 Case #3 40 y/o female presents with idiopathic DVT LLE/PE at the age of y/o female presents with idiopathic DVT LLE/PE at the age of 35 Treatment with heparin/ warfarin x 6 months Treatment with heparin/ warfarin x 6 months Does well until 2 years later when she presents with recurrent PE, anticoagulation restarted Does well until 2 years later when she presents with recurrent PE, anticoagulation restarted 7 months later she has a 3 rd PE while therapeutic on warfarin (INR at 2.5), Filter placed, O2 dependent 7 months later she has a 3 rd PE while therapeutic on warfarin (INR at 2.5), Filter placed, O2 dependent Hypercoagulable panel shows very high titers for Antiphospholipid antibodies Hypercoagulable panel shows very high titers for Antiphospholipid antibodies Goal INR is raised to 3-4 Goal INR is raised to months later, she develops DVT in RLE while on warfarin, gets transitioned to twice daily LMWH injections 6 months later, she develops DVT in RLE while on warfarin, gets transitioned to twice daily LMWH injections

75 Cancer is a hypercoagulable state 5-10% of patients presenting with idiopathic VTE will be diagnosed with cancer in the next months % of patients presenting with idiopathic VTE will be diagnosed with cancer in the next months 1 VTE has been found in 20-50% of cancer patients at autopsy 2 VTE has been found in 20-50% of cancer patients at autopsy 2 Cancer patients have higher rates of recurrent VTE and bleeding than patients without cancer 3,4,5 Cancer patients have higher rates of recurrent VTE and bleeding than patients without cancer 3,4,5 Cancer patients with VTE have higher mortality than those without VTE 6 Cancer patients with VTE have higher mortality than those without VTE 6 1 J Thromb and Haemost 2004;2: Am J Med Sciences 1938; 34: JCO 2000;18: Medicine 1999;78: Blood 2002; 100: NEJM 2000; 343: 1846

76 Thrombosis and Cancer DVT/PE most common DVT/PE most common Any location possible Any location possible Recommendation: preferred is LMWH sc daily/bid as long as cancer not in remission due to high risk of recurrence Recommendation: preferred is LMWH sc daily/bid as long as cancer not in remission due to high risk of recurrence Alternative: warfarin Alternative: warfarin Need bridging if on warfarin. Need bridging if on warfarin.

77 Questions??

78 Dental case studies Assistant Professor of Medicine Hematology/Oncology

79 Case 8 A 66 y/o male with atrial fibrillation and no prior stroke, otherwise healthy, comes in for dental extraction. You should A) stop coumadin 4-5 days before B) lower his dose for 4-5 days to achieve an INR of and proceed with extraction C) Bridge the patient with LMWH after he stops coumadin 4-5 days before D) Bridge the patient with UFH after he stops coumadin 4-5 days before

80 Case 9 A 55 y/o male with h/o unprovoked PE 2 months prior comes in for elective dental work (implants). How should you manage his anticoagulation? A) Proceed with dental implants and stop coumadin 5 days before and for 7 days post-op. B) Bridge the patient before, then hold anticoagulation post-op for 1 week C) Postpone implants D) Stop Coumadin, place temporary filter and proceed with implants. Have his PCP restart anticoagulation.

81 Case y/o patient undergoes dental extraction. He is on chronic coumadin for atrial fibrillation and restarts after his extraction. 1 week after extraction, he calls you with c/o fever and facial swelling. He reports pus from the socket. You see him in the office and diagnose him with a post-procedural infection. On exam, he is hypotensive and tachycardic, you decide to admit him to the hospital. He is found to be bacteremic and started on iv antibiotics with cefotetan. On the 3rd hospital day, the patient becomes somnolent and later unconscious. A CT scan of his head most likely will show A) a new stroke B) intracranial hemorrhage C) a malignancy D) encephalitis

82 Case year-old white male embedded as a reporter with the army division that was invading Iraq during 2003, with no previous medical problems, took a break and died. On autopsy, pulmonary embolism was found. 45-year-old white male embedded as a reporter with the army division that was invading Iraq during 2003, with no previous medical problems, took a break and died. On autopsy, pulmonary embolism was found. Name risk factors for Pulmonary embolism in this case that may have been present. Name risk factors for Pulmonary embolism in this case that may have been present.

83 Case year-old white female who has just given birth 3 weeks previously without complication, develops sudden difficulty breathing while sitting in your treatment chair. Describe your approach to the patient regarding differential diagnosis, acute management and diagnostic strategies. 28 year-old white female who has just given birth 3 weeks previously without complication, develops sudden difficulty breathing while sitting in your treatment chair. Describe your approach to the patient regarding differential diagnosis, acute management and diagnostic strategies.

84 Case year-old alcoholic man, with known liver cirrhosis and an h/o of esophageal bleeding due to esophageal varies presents for dental work. He has just been diagnosed with head and neck cancer and needs radiation. After evaluation, you determine he needs FME. Complete blood count shows WBC 7500/uL, Hgb 7.5 gm/dL, Hct 22.5%, platelet count 90,000/uL. INR 1.9, aPTT 50 sec. 50-year-old alcoholic man, with known liver cirrhosis and an h/o of esophageal bleeding due to esophageal varies presents for dental work. He has just been diagnosed with head and neck cancer and needs radiation. After evaluation, you determine he needs FME. Complete blood count shows WBC 7500/uL, Hgb 7.5 gm/dL, Hct 22.5%, platelet count 90,000/uL. INR 1.9, aPTT 50 sec. Which parts of the hemostastic system are impaired? Which parts of the hemostastic system are impaired? Which options do you have to safely perform a FME? Which agents can you use to reverse his “auto- anticoagulation”. Which options do you have to safely perform a FME? Which agents can you use to reverse his “auto- anticoagulation”.

85 Case 14 A 52 y/o man is evaluated because of a warm, swollen leg and a history of trauma to the leg 2 weeks ago while on a ski trip in Europe. The leg first became painful on the plane ride home. The patient has mild hypertension that is treated with metoprolol but has no other medical problems. He is not taking any other medications. He is a nonsmoker. There is no family history of thromboembolic disease. A 52 y/o man is evaluated because of a warm, swollen leg and a history of trauma to the leg 2 weeks ago while on a ski trip in Europe. The leg first became painful on the plane ride home. The patient has mild hypertension that is treated with metoprolol but has no other medical problems. He is not taking any other medications. He is a nonsmoker. There is no family history of thromboembolic disease. What do you think is going on with the patient? What do you think is going on with the patient? What is the next diagnostic step? What is the next diagnostic step?

86 Case 15 Heparin affects which pathway? A) Intrinsic B) Extrinsic

87 Case 16 The aPTT is used to monitor anticoagulation with unfractionated heparin. Warfarin is monitored by INR. A) True B) False

88 Case 17 Explain, how warfarin works, which factors are affected and the reason for individual dosing. Explain, how warfarin works, which factors are affected and the reason for individual dosing.

89 Case 18 A 38 y/o man is receiving warfarin therapy for DVT of the left leg that he developed 3 weeks ago. He comes in for his scheduled INR check. He denies any gingival bleeding, hematuria, nosebleeds, or gastrointestinal disorder but reports a sore throat and fever that started about 1 week ago. He has not been able to swallow and has consequently been on a mostly liquid diet for the last week. A 38 y/o man is receiving warfarin therapy for DVT of the left leg that he developed 3 weeks ago. He comes in for his scheduled INR check. He denies any gingival bleeding, hematuria, nosebleeds, or gastrointestinal disorder but reports a sore throat and fever that started about 1 week ago. He has not been able to swallow and has consequently been on a mostly liquid diet for the last week.

90 Case 18 cont. On PE: temp 38 C ( 100.4F). His posterior pharynx is erythematous but without exudates. Cardiopulmonary examination is normal. There is 1+ edema of the left leg with tenderness in the popliteal fossa ( improved since 2 weeks ago) and several scattered ecchymoses on the forearms and legs. Labs: Hgb 15, Hct 41% leucocytes 10 K, Platelets 240 INR 6.0 aPTT 37 (normal up to 29) Why is the INR so high? What is the best course of action?


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