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Deep Vein Thrombosis

  1. 1. DeShawndre Bridley<br />6th Year Doctorate of Pharmacy Candidate<br />Florida A&M University<br />PREVENTION AND TREATMENT OF DEEP VEIN THROMBOSIS<br />
  2. 2. Objectives<br />Case Presentation<br />Outline DVT<br />Pathophysiology<br />Epidemiology<br />Diagnosis<br />Complications<br />Discuss Pharmacological Management<br />Review Case Study<br />
  3. 3. Case Presentation<br /><ul><li>M.H. is a 47 y/o, 268lb WF admitted to the ER on 10/22/07
  4. 4. CC: “My calf started to swell last week. Now the pain is so bad that I’m having a hard time walking.”
  5. 5. HPI: Noticed swelling of the right calf approximately 4 days ago. She reported to the ED of her local hospital 1 day after the onset of calf pain and swelling. Venous Dopplers were performed and the patient was told that she had a blood clot in her right leg. According to the patient she was given a prescription for an injection and instructed to follow-up with her PCP within the next 1 to 2 days. She failed to have the prescription filled because her pharmacy did not have the drug in stock. Because of increasing pain and discomfort, M.H. was seen by her physician this morning who recommended hospitalization to initialize therapy for her blood clot.</li></li></ul><li>Case Presentation<br />PMH: Previous DVT at the age of 38; treated with warfarin for 3 months<br />FH: Father died at 42 from MI; mother alive at 71 with breast cancer diagnosed 5 years ago, s/p radiation/chemotherapy; sister alive and well. No family history of venous thromboembolic disease reported.<br />
  6. 6. Case Presentation<br />SH: Patient lives with her husband and 16 y/o son; works in a department store as a cashier. 24 pack-year smoking history; currently smokes ½ to 1 ppd. (-) EtOH or IVDA<br />Meds: Raloxifene 60mg PO qd<br /> Multivitamin 1 tab PO qd<br /> Denies the use of herbal products<br />
  7. 7. What is a Deep Vein Thrombosis?<br />
  8. 8. Deep Vein Thrombosis<br />Deep vein thrombosis (DVT) is the development of thrombi in the deep veins of the extremities or pelvis.<br />DVT<br />Deep venous thrombophlebitis<br />
  9. 9. EPIDEMIOLOGY & DEMOGRAPHICS <br />Annual incidence in urban population is 1.6 cases/1000 persons. <br />The risk of recurrent thromboembolism is higher among men than women<br />Annual incidence is 0.1% in white population<br />
  10. 10. ETIOLOGY <br />The etiology is often multifactorial (prolonged stasis, coagulation abnormalities, vessel wall trauma). <br />The following are risk factors for DVT:    <br />•    Prolonged immobilization (≥3 days)    <br />•    Postoperative state    <br />•    Trauma to pelvis and lower extremities    <br />•    Birth control pills, high-dose estrogen therapy;   <br />
  11. 11. Etiology<br /><ul><li>Visceral cancer (lung, pancreas, alimentary tract, GU tract)   
  12. 12. Age >60 yr.   
  13. 13. History of thromboembolic disease   
  14. 14. Hematologic disorders (e.g., antithrombin III deficiency, protein C deficiency, protein S deficiency, heparin cofactor II deficiency, sticky platelet syndrome, G20210A prothrombin mutation, lupus anticoagulant, dysfibrinogenemias, anticardiolipin antibody, hyperhomocysteinemia, concurrent homocystinuria, high levels of factors VIII, XI, and factor V Leiden mutation)   </li></li></ul><li>Etiology<br />Pregnancy and early puerperium    <br />Obesity, CHF      <br />Surgery requiring &gt;30 min of anesthesia  <br />Gynecologic surgery (particularly gynecologic cancer surgery)   <br />
  15. 15. Etiology<br />Recent travel (within 2 wk, lasting &gt;6 hr)  <br />Smoking and abdominal obesity   <br />Central venous catheter or pacemaker insertion    <br />Superficial vein thrombosis, varicose veins <br />
  16. 16. Diagnosis<br />Symptoms: The patient may complain of leg swelling, pain, or warmth. <br />Signs: The patient’s superficial veins may be dilated, and a “palpable cord” may be felt in the affected leg. The patient may experience pain in the back of the knee when the examiner dorsiflexes the foot of the affected leg.<br />
  17. 17. Diagnosis<br />Diagnostic Tests<br />Duplex ultrasonography<br />Venography (aka phlebography)<br />“Gold Standard” for DVT diagnosis <br />
  18. 18. Diagnosis<br />Laboratory Tests<br />Serum Concentrations of D-dimer, a by-product of thrombin generation, usually are elevated.<br />The patient may have an elevated erythrocyte sedimentation rate (ESR) and White Blood Cell (WBC) count.<br />
  19. 19.
  20. 20. ACUTE GENERAL Pharmacaotherapy<br /><ul><li>Traditional treatment consists of IV unfractionated heparin for 4 to 7 days followed by warfarin therapy.
  21. 21. Low–molecular-weight heparin enoxaparin (Lovenox) is also effective for initial management of DVT and allows outpatient treatment.
  22. 22. Recommended dose is 1 mg/kg q12h SC and continued for a minimum of 5 days and until a therapeutic INR (2-3) has been achieved with warfarin</li></li></ul><li>Dosages for lmwh and ufh<br /><ul><li>Enoxaparin (Lovenox) 1mg/kg every 12 hours or 1.5mg/kg every 24 hours
  23. 23. Dalteparin (Fragmin) 100units/kg every 12 hours or 200units/kg every 24 hours
  24. 24. Tinzaparin (Innohep) 175units/kg every 24 hours
  25. 25. UFH: Loading dose of 80 to 100units/kg (max. 10,000units) followed by a continuous IV infusion at an initial rate of 17 to 20 units/kg/h (max. 2300 units/h)</li></li></ul><li>Advantages of low molecular weight heparin over unfractionatedheparin<br /><ul><li>More reliable dose-response relation
  26. 26. No need for laboratorymonitoring with the activated partial thromboplastin time (althoughcan be monitored with anti-Xa activity)
  27. 27. No need for dose adjustments
  28. 28. Lowerincidence of thrombocytopenia
  29. 29. No excess bleeding
  30. 30. Can be administeredby the patient at home
  31. 31. Economically advantageous</li></li></ul><li>Pearls and Considerations<br />When using heparin, there is a risk of heparin-induced thrombocytopenia (with unfractionated more so than with LMWH). Platelet count should be obtained initially and repeated every 3 days while on heparin.<br />
  32. 32. Acute General Pharmacotherapy<br />Once-daily fondaparinux (Arixtra), a synthetic analog of heparin, is also as effective and safe as twice daily enoxaparin in the initial treatment of patients with symptomatic DVT. <br />Selective inhibitor of factor Xa<br />Dose: 7.5mg SC daily<br />
  33. 33. Acute General Pharmacotherapy<br />Warfarin therapy should be initiated when appropriate (usually within 72 hr of initiation of heparin).<br />Interferes with vitamin K dependent factors (II, VII, IX, X)<br />Interactions: Ethanol, Vitamin E, Cranberry juice<br />Pregnancy category X<br />
  34. 34. ACUTE GENERAL pharmacotherapy<br />Low–molecular-weight heparin, when used, should be overlapped with warfarin for at least 5 days and until the INR has exceeded 2 for 2 consecutive days.<br />
  35. 35. ACUTE GENERAL pharmacotherapy<br />Exclusions from outpatient treatment of DVT include patients with potential high complication risk (e.g., Hemoglobin &lt;7, platelet count &lt;75,000, guaiac-positive stool, recent CVA or noncutaneous surgery, noncompliance). <br />
  36. 36. Acute General Pharmacotherapy<br />Insertion of an inferior vena cava filter to prevent pulmonary embolism is recommended in patients with contraindications to anticoagulation<br />
  37. 37.
  38. 38. Acute General Pharmacotherapy<br /><ul><li>Thrombolytic therapy (streptokinase) can be used in rare cases (unless contraindicated) in patients with extensive iliofemoral venous thrombosis and a low risk of bleeding
  39. 39. Not generally used unless there is a massive thrombus or limb salvage is necessary (due to gangrene)
  40. 40. Has not been shown to decrease morbidity or mortality in PE</li></li></ul><li>CHRONIC Pharmacotherapy <br />Conventional-intensity warfarin therapy is more effective than low-intensity warfarin therapy for the long term prevention of recurrent DVT. <br />The low-intensity warfarin regimen does not reduce the risk of clinically important bleeding. <br />
  41. 41. Chronic Pharmacotherapy<br /><ul><li>The optimal duration of anticoagulant therapy varies with the cause of DVT and the patient's risk factors:   
  42. 42. 1.    Therapy for 3-6 mo. is generally satisfactory in patients with reversible risk factors (low-risk group).   
  43. 43. 2.    Anticoagulation for at least 6 mo. is recommended for patients with idiopathic venous thrombosis or medical risk factors for DVT (intermediate-risk group).   
  44. 44. 3.    Indefinite anticoagulation is necessary in patients with DVT associated with active cancer; long-term anticoagulation is also indicated in patients with inherited thrombophilia (e.g., deficiency of protein C or S antibody), antiphospholipid, and those with recurrent episodes of idiopathic DVT (high-risk group). </li></li></ul><li>Chronic Pharmacotherapy<br />Measurement of d-dimer after withdrawal of oral anticoagulation may be useful to estimate the risk of recurrence. Patients with a first spontaneous DVT and a d-dimer level &lt;250 μg/mL after withdrawal of oral anticoagulation have a low risk of DVT recurrence. <br />
  45. 45. Pearls and Considerations<br />Approximately 20%-50% of patients with DVT develop postthrombotic syndrome characterized by leg edema, pain, venous ectasia, skin induration, and ulceration. <br />
  46. 46. Pearls and Considerations<br />Exercise following DVT is reasonable because it improves flexibility of the affected leg and does not increase symptoms in patients with postthrombotic syndrome<br />
  47. 47. Prevention is better than treatment<br /><ul><li>Mechanical Methods
  48. 48. Early mobilization as soon as possible after surgery
  49. 49. Graded compression stocking
  50. 50. Pharmacological Methods
  51. 51. UFH
  52. 52. LMWH
  53. 53. Fondaparinux
  54. 54. Warfarin</li></li></ul><li>Pearls and Considerations<br /><ul><li>Prophylaxis of DVT is recommended in all patients at risk (e.g., low–molecular-weight heparin [enoxaparin 30 mg SC bid] after major trauma, post surgery of hip and knee; enoxaparin 40 mg SC qd post–abdominal surgery in patients with moderate to high DVT risk; gradient elastic stockings alone or in combination with intermittent pneumatic compression [IPC] boots following neurosurgery). </li></li></ul><li>Pearls and Considerations<br />Fondaparinux (Arixtra), a synthetic analog of heparin, can also be used for prevention of DVT after hip fracture surgery, hip replacement, or knee replacement. Initial dose is 2.5 mg SC given 6 to 8 hr postoperatively and continued daily. Its bleeding risk is similar to enoxaparin; however, it is more effective in preventing DVT<br />
  55. 55. Case presentation<br /><ul><li>Subjective:
  56. 56. Calf pain and swelling
  57. 57. Risk Factors: Smoking, SERM use, Previous DVT
  58. 58. Objective:
  59. 59. (+) Homan’s sign in right calf with no palpable cord
  60. 60. Factor V Leiden Mutation – positive
  61. 61. Venous compression Ultrasonography- RLE shows non compressibility of the right posterior tibial vein with no color flow. Normal compressibility and flow demonstrated within the right common femoral and iliac veins. LLE shows normal compression of the deep venous system from the level of the common femoral vein to the popliteal vein</li></li></ul><li>Case presentation<br />Assessment:<br />Acute Deep vein thrombosis of the right posterior tibial vein requiring initiation of anticoagulation. Venogram not necessary due to positive ultrasound results<br />
  62. 62. DVTs in and/or around the politeal vein are termed proximal<br />
  63. 63. Case presentation<br />Plan:<br />Treatment<br />Day 1-5:<br />Enoxaparin 122 U (1mg/kg) SC every 12 hours for 5 days<br />Warfarin 5mg by mouth daily<br />
  64. 64. Case presentation<br />Plan<br />Day 6<br />Discontinue LMWH<br />Patient is to continue on warfarin therapy for at least one year due to prior DVT<br />
  65. 65. REFERENCES<br />Anderson F.A. , Jr, Spencer F.A.,  Risk factors for venous thromboembolism.   Circulation (2003) 107 : pp 9-16<br />White R.H.,  The epidemiology of venous thromboembolism.   Circulation (2003) 107 : pp I4-I8.<br />Antithrombotic Therapy for Venous Thromboembolic Disease The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest - Volume 126, Issue 3 (September 2004) <br />Barrit DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. Lancet 1960; 1:1309–1312   <br />Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5-mg and 10-mg warfarin loading doses. Arch Intern Med 1999; 159:46–48   <br />Kernohan RJ, Todd C. Heparin therapy in thromboembolic disease. Lancet 1966; 1:621–623 <br />Harrison L, Johnston M, Massicotte MP, et al. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997; 126:133–136   <br />
  66. 66. Questions??<br />

Hinweis der Redaktion

  • Most important disease affecting the peripheral veins. Most pulmonary emboli arise from DVTs in the legs.
  • Usually originates in one of the distal or calf veinsWhen compared to the caucasian population, studies have shown that Hispanics seem to be protected against DVT, AA have a higher risk of DVT, and Asians and pacific islanders have a decreased risk of DVT
  • -Virchow’s Triad (venous stasis-slowed blood flow in the deep veins, due to increase blood viscosity, obstruction, prolonged periods of immobility; hypercoagulability due to malgnancy; vessel wall trauma due to orthopedic surgery-conjugated equine estrogen but not esterified estrogen is associated with increased risk of DVT; estrogen plus progestin is associated with doubling the risk of venous thrombosis . Estrogens appear to increase serum clotting factor concentration
  • The patient in the case was positive for factor V Leiden mutation.Inherited disorder which results from a single point mutation, amino acid substitution of arginine for glutamine at Arg-506, affects factor V’s activated protein C binding site. Protein C is responsible for inactivating factor V and decreasing clots. With this disorder protein C is unable to inactivate factor V.
  • Early puerperium- right after giving birth
  • Symptoms are nonspecific, and objective testing must be performed to establish the diagnosisPain on dorsiflexion is a positive Homan’s sign. Dorsiflexion is movement of the foot upward.
  • Duplex ultrasonography is the most commonly used test to diagnose DVT. It is noninvasive and can measure the rate and direction of blood flow and visualize clot formation in proximal veins of the legs. I cannot reliably detect small blood clots in distal veins. Coupled with a careful clinical assessment, it can rule out or in the diagnosis in the majority of cases. It uses sound waves to visualize the arteries and veins.Venography is an invasive test that involves injection of radiopaque contrast dye into a foot vein. It is expensive and can cause anaphylaxis and nephrotoxicity.
  • Blood testssuch as for fibrin d-dimer, a fibrin degradation product, addto the diagnostic accuracy of the non-invasive tests. d-dimerlevels are > 500 ng/ml in nearly all patients with venousthromboembolism. Alone, they are insufficient to establish thediagnosis as such levels are non-specific and often can be foundin patients admitted to hospital and in those with malignancyor after recent surgery. Thus, a low or normal d-dimer levelwith a low pretest probability makes a diagnosis of deep veinthrombosis (or pulmonary embolism) unlikely.
  • The use of low molecular weight heparin in deep vein thrombosisand pulmonary embolism is now firmly established. Many trialsand meta-analyses have confirmed their superior efficacy, saferprofile, and cost effectiveness over unfractionated heparin.This is partly due to more targeted action: unfractionated heparinacts on both thrombin and factor Xa about equally, whereas lowmolecular weight heparin is more active against factor Xa. Thelow molecular weight heparins are, however, different, and trialsfor one cannot be extrapolated to another. The introductionof low molecular weight heparin has advanced antithrombotictherapy by providing effective anticoagulation without the needfor routine monitoring or adjustments, although it can be monitoredthrough an anti-Xa effect. It also allows patients with uncomplicateddeep vein thrombosis to be treated in the community, thus savingan average of 4 or 5 days of admission per patient. Low molecularweight heparin has been shown to be more effective than vitaminK antagonists (almost all being warfarin) in preventing deepvein thrombosis after major orthopaedic surgery, with no significantdifference in rates of bleeding.
  • Dosages for heparin can be found by using a nomograph based upon wt and activated partial thromplastin timeaPTT should be measure no sooner than 6 hours after beginning the infusion or any dosage change. The therapeutic range is 1.5 to 2 times the mean normal control valueBleeding is the major SE of heparin therapy, more so with unfractionated heparin. HIT thrombocytopenia is common and is a platelet count less than 150,000/ml. Platelets typically begin to fall within 5 days of therapy and should be monitored every 1-2 days Protamine sulfate given via slow IV infusion over 10 min (1mg/100U of UFH infused during the previous 4 hours; max. 50mg)Antifactor Xa is used to monitor LMWH. Acceptable target range is 0.5-1unit/ml and should be drawn approximately 4 hours after SC administration. Particulary in renally insufficient, pregnant,elderly, patients weighing less than 50kg, patients that require therapy for more than 14days etc.Protamine sulfate dose is 1mg/1mg of enoxaparin or 1mg/100 antifactor Xa units of dalteparin or tinzaparin administered the previous 8 hours. If in the previous 8-12 hours the dose is 0.5mg/100 antifactor Xa units. Not recommended for doses given greater than 12 hours prior
  • Fondaparinux is a precisely engineered pentasaccharide, whichbinds antithrombin and enhances its activity towards factorXa but is devoid of activity against thrombin. This brings severaladvantages, such as a more predictable profile, a long halflife (17 hours), and no activity towards platelets. It is atleast as effective as unfractionated heparin in treating pulmonaryembolism,323 at least as effective as a low molecular weightheparin in treating deep vein thrombosis,24 with a benefit overa low molecular weight heparin in risk reduction of venous thromboembolismafter orthopaedic surgery.25 In one UK health economics study,fondaparinux was more effective and reduced costs to the healthcaresystem when compared with a low molecular weight heparin.26An example of recommended uses of this and other agents in adefined group (mostly after surgery) is shown on bmj.com, althoughothers recommend a different approach in medical patients.27
  • A 5 mg loading dose of warfarin is recommended in inpatients because it produces less excess anticoagulation than does a 10 mg dose; the smaller dose also avoids the development of a potential hypercoagulable state caused by precipitous decreases in levels of protein C during the first 36 hr of warfarin therapy. In the outpatient setting, a warfarin nomogram using 10 mg loading doses may be more effective in reaching a therapeutic INR
  • An inferior cava filter (IVC filter) is a device place in the inferior vena cava to prevent PE. It is used in patients that have failed or had complications with oral anticoagulant therapyMost filters are placed for the following reasons. Failure of anticoagulation; eg development of deep vein thrombosis (DVT) or pulmonary emboli (PE) despite adequate anticoagulation. Contraindications to anticoagulation; eg a patient at risk of PE who has another condition that puts them at risk of bleeding, such as a recent bleed into the brain, or apatient about to undergo major surgery Large clots in the vena cava or iliac veins Patients at high risk of having a PE
  • An inferior cava filter (IVC filter) is a device place in the inferior vena cava to prevent PE. It is used in patients that have failed or had complications with oral anticoagulant therapyMost filters are placed for the following reasons. Failure of anticoagulation; eg development of deep vein thrombosis (DVT) or pulmonary emboli (PE) despite adequate anticoagulation. Contraindications to anticoagulation; eg a patient at risk of PE who has another condition that puts them at risk of bleeding, such as a recent bleed into the brain, or apatient about to undergo major surgery Large clots in the vena cava or iliac veins Patients at high risk of having a PE
  • Unlike heparins and warfarin, which prevent extension and recurrenceof thrombosis, the thrombolytic agents (for example, streptokinase,urokinase and tissue-plasminogen activator) lyse the thrombi.Indications for this therapy are, however, unclear. Recent guidelines18do not recommend thrombolysis or thrombectomy for deep veinthrombosis unless for limb salvage.In cases of massive embolism, thrombolytic therapy with agents such as streptokinase, urokinase or tissue-plasminogen-activator (tPA) may be used to dissolve the PE and so relieve the obstruction. Treatment with thrombolytic agents is expensive and associated with an increased risk of hemorrhage, including hemorrhagic stroke. Therefore, such treatment should be limited to patients who have major PE or underlying cardio-respiratory disease and in whom early lysis is judged to be life-saving.
  • Oral anticoagulants can be used in two ways: Commence with a low dose (3 mg) 10 to 14 days before surgery with the aim of adjusting the INR to 1.3 to 1.5 at the time of surgery and then gradually increase the dose to obtain an INR of 2.0 to 2.5 at 3 to 4 days postoperatively. This approach is relatively safe but impractical because it requires many days of careful monitoring. Commence with a dose of 5 mg on the evening of the operation or the first postoperative day, aiming for an INR from 2.0 to 3.0 on the 4th or 5th postoperative day. This approach is more practical and has been shown to be effective and relatively safe but still requires careful laboratory monitoring.
  • Compression stockings and pneumatic compression have been usedas prophylactic measures against deep vein thrombosis. Inferiorvena cava filters may be used when anticoagulation is contraindicatedin patients at high risk of proximal deep vein thrombosis extensionor embolisation. The filter is normally inserted through theinternal jugular or femoral vein. This approach should be consideredin those patients with recurrent symptomatic pulmonary embolismand as primary prophylaxis of thromboembolism in patients athigh risk of bleeding. Other mechanical and surgical treatments(for example, embolectomy) are usually reserved for massivepulmonary embolism where drug treatments have failed or arecontraindicated.
  • Post-thrombotic syndrome is caused by damage to the one-way valves in the veins, which leads to high blood pressure in these blood vessels. Post-thrombotic syndrome is the name used to describe the long-lasting swelling, redness, pain and, in severe cases, ulceration that can sometimes occur after an episode of DVT. Some patients who have venous thrombosis can develop post-thrombotic syndrome. The pain is relieved by rest and raising the affected limb. The swelling may never disappear, or it may return a few years later. Post-thrombotic syndrome is sometimes difficult to diagnose because it looks like DVT. If you are likely to have post-thrombotic syndrome, it usually develops within 2 years of your DVT. Patients who have had DVT are normally given advice about how to prevent the development of post-thrombotic syndrome.
  • Mobilization stimulates calf muscles and put pressure on the calf and leg veins, thus discouraging stasis and venous pooling of blood in the lower extremities. Compression stockings should be fitted properly in order to provide the appropriate grade of compression. Most compression in the ankle with compression decreasing as the stocking goes up the leg to just below the knee.
  • This is the dosing for prophylaxis. Acute treatment is higher.
  • RLE- right lower extremityLLE- Left lower extremity
  • A venogram is an X-ray test that takes pictures of the blood flow through the veins in a certain area of the body. During a venogram, a dye is put into your veins so they can be seen clearly on an X-ray picture. A venogram looks at the condition of your veins and the valves with your veins.
  • This patient will be on warfarin therapy for at least a year and maybe indefinitelyOver time, the body will usually dissolve some, but not all, of the clot. The remainder of the clot embeds in the vessel wall and becomes scar tissue. According to a study in the annals of internal medicine, A 5-mg loading dose of warfarin produces less excess anticoagulation than does a 10-mg loading dose; the smaller dose also avoids the development of a potential hypercoagulable state caused by precipitous decreases in levels of protein C during the first 36 hours of warfarin therapy.Another study in the archives of internal medicine showed that A 10-mg loading dose of warfarin is unlikely to be more effective than a 5-mg loading dose in achieving an INR of 2.0 to 3.0 by day 4 or 5 of therapy.