1. Deep Vein Thrombosis

2. Physical Examination GEN Somewhat overweight, Caucasian man who appears comfortable. Cooperative, A & O x 3, normal affect. VS BP 132/76, P 75 regular, R 16, T 98.3°F, O 2 sat 97/ra; Wt 194 lb, Ht 6'0″ SKIN Warm, dry, normal color. No rash or induration. HEENT Pupils equal and reactive to light. EOM intact. Mucous membranes moist and pink

3. PATIENT PRESENTATION

4. CHIEF COMPLAINT "I'm having pain in my leg."

5. HISTORY OF PRESENT ILLNESS (HPI) Rodney Cross is a 48-year-old man who presents to h is primary care physician because of pain in his right leg. He states that he awoke with the pain 3 days ago and that it has been continuous, although it hurts more when he walks. The pain is located behind his right knee and extends down into his cal f. He rates the pain intensity as 3/10 at this time. The patient denies CP and SOB. H e denies recent travel, immobility, and leg injury. The patient did start pravastatin 40 mg daily for treatment of dyslipidemia approximately 3 months prior to this v isit. He stopped the pravastatin 3 days ago because he thought it might be causing his leg pain, but the pain has continued.

6. PAST MEDICAL HISTORY (PMH) Hypertension Dyslipidemia Graves' disease with thyroid ablation Gout Left ankle fracture 9 years ago that required a cast but no surgery Remote history of depression

7. PAST SURGICAL HISTORY (PSH) Left herniorrhaphy about 10 years ago Pilonidal cyst excision in remote past.

8. FAMILY HISTORY Father died at age 81 of liver failure. Mother, one brother, and son all alive and well No family history of venous thromboembolism or clotting disorders

9. SOCIAL HISTORY (SH) Married, one adult child. Drinks one to two alcoholic beverages daily. Smokes one cigar per month, no cigarettes. Denies illicit drug use.

10. Medications: Allopurinol 300 mg po once daily Hydrochlorothiazide 12.5 mg once daily Lisinopril 10 mg once daily Levothyroxine 150 mcg po once daily Pravastatin 40 mg po once daily (discontinued 3 days ago)

11. All NKDA ROS Constitutional: No chills, no fatigue. Eyes: No eye pain or changes in vision. ENT(ears,nose,throat): No sore throat. Skin: No pigmentation changes, no nail changes. Cardiovascular: No CP, palpitations, or syncope.

12. Respiratory: No cough, SOB, wheezing, or stridor. GI: No abdominal pain, nausea, diarrhea, or vomiting. Musculoskeletal: No neck pain, back pain, or injury. Neurologic: No dizziness, headache, or focal weakness. Psychiatric/behavioral: Remote history of depression. Not a current problem

13. Physical Examination GEN (General) Somewhat overweight, Caucasian man who appears comfortable. Cooperative, A & O x 3, normal affect VS( Vital signs) BP 132/76, P 75 regular, R 16, T 98.3°F, O2 sat 97/ra; Wt 194 lb, Ht 6'0″ SKIN Warm, dry, normal color. No rash or induration. HEENT (Head Eye Ear Nose Throat) Pupils equal and reactive to light. EOM(extra occular Movement) intact. Mucous membranes moist and pink

14. NECK Normal range of motion with no meningeal signs LUNGS/THORAX Breath sounds normal, no respiratory distress CV RRR, no rubs, murmurs, or gallops ABD Nontender, no masses, no distension, no peritoneal signs

15. MS/EXT Upper extremities: Normal by inspection, no CCE, normal ROM(Range of motion). Lower extremities: Right calf tight, warm to touch, and tender with 1+ pretibial pitting edema. LLE (Left lower extrremity) without redness, warmth, and swelling. Lower extremity pulses and sensation are normal bilaterally. Normal ROM. NEURO Glasgow coma scale of 15, no focal motor deficits, no focal sensory deficits

16. Labs Na 140 mEq/L(Normal)WBC 5.9 x 1o^3/L (Normal) K 3.9 mEq/L (Normal)RBC 4.28 x 10^6/L (Normal) Cl 103 mEq/L(Normal)Hgb 13.5 g/dL (Normal) CO2 27 mEq/LHct 39.3%(Normal) BUN 10 mg/dL (Normal)MCV 92.0 fL(Normal) SCr 0.84 mg/dL(Normal)MCHC 34.4 g/dL (Normal) Glucose 88 mg/dL (Normal, controlled) RBC dist 14.3 (Normal) Uric acid 5.0 mg/dL(Normal)Platelets 175 x 103/L (Normal)

17. Labs CK 117 IU/L (Creatinine Kinase 60-117) Mean platelet volume 7.2 fL (7.5-11.5) Granulocytes, electronic 51.0%Lymphocytes, electronic 38.2% (20-40%) Monocytes, electronic 8.4% (2-8%) Eosinophils, electronic 1.9% (1-4%) Basophils, electronic 0.5% (0.5-1%) INR 1.0(Normal)

18. Lower extremity venous duplex ultrasonography: "Acute DVT of right distal superficial femoral, popliteal, and peroneal veins. No compression or flow in these vessels." (Note to reader: The "superficial femoral vein" is actually a deep vein, in spite of its name. Use of the name "femoral vein" is preferred because it is less confusing. However, the name "superficial femoral vein" is still encountered, as it is in this patient's venous duplex report.)

19. Assessment Acute DVT in right distal femoral, popliteal, and peroneal veins CLINICAL PEARL Current evidence does not clearly establish the appropriate duration of anticoagulation therapy for many patients with DVTs. A decision must therefore be based on a careful comparison of the benefits of continuing anticoagulation (primarily a decreased risk of DVT recurrence and potential sequelae) versus the risk of adverse events (primarily bleeding) in each patient

20. Questions Problem Identification

21. 1.a. Create a list of this patient’s medication-related problems. Drug therapy needed for newly diagnosed DVT in right lower extremity. Drug therapy needed for dyslipidemia. (Note: This problem results from the patient’s discontinuation of pravastatin. No lipid data are presented in this case. Identification of this problem therefore assumes the previous assessment that lipid-lowering therapy is needed was correct. This potential problem is identified here for completeness, but the reader is not asked to address it.)

22. 1.b. What subjective and objective findings support the diagnosis of a lower extremity DVT? The patient presents with unilateral pain, swelling, warmth, and tenderness in his right calf. This clinical presentation suggests a DVT, which is confirmed by the absence of compressibility and flow in the proximal deep veins of his right leg. The absence of CP and SOB; normal vital signs, including a normal respiratory rate; normal lungs/thorax and cardiovascular physical exam, including the absence of an accentuated S 2 ; and normal O 2 saturation in room air all suggest that a PE has not occurred.

23. The unilateral nature of the patient’s symptoms along with a normal CK argues against statin- related myopathy as the cause of this patient’s problem.

24. Desired Outcome 2. What are the short- and long-term goals of pharmacotherapy for this patient’s DVT? The short-term therapeutic goal is to quickly, safely, and effectively anticoagulate this patient to prevent extension of his DVT and minimize the risk of embolization while minimizing his bleeding risk. The long-term goals are to maintain safe and effective anticoagulation for an adequate period of time to permit DVT resolution and to prevent the development of postthrombotic syndrome. In addition, careful consideration should be given to the need for long-term anticoagulation therapy to prevent recurrence of venous thromboembolism.

25. Therapeutic Alternatives 3. What therapeutic alternatives are available for the pharmacologic management of this patient’s DVT?therapeutic Oral warfarin therapy is the treatment of choice for chronic anticoagulation of this patient, with a targeted international normalized ratio (INR) of 2.5 (acceptable range: 2.0- 3.0). 1 However, establishing effective anticoagulation with warfarinrequires several days to weeks. Concurrent use of a rapid-acting anticoagulant is therefore indicated until that goal is achieved (INR 2.0 × 2 days). Four main options are available for this purpose in this patient: subcutaneous LMWH; UFH; weight-adjusted, fixed- dose subcutaneous UFH; and subcutaneous fondaparinux.warfarin 1warfarin

26. ✓ Recent guidelines recommend the use of LMWH for the initial treatment of DVT in the absence of PE because current evidence demonstrates that LMWH is associated with lower mortality, a lower incidence of adverse events (both bleeding and HIT), and a cost saving or cost- effectiveness. 1 Current evidence suggests that this initial treatment with LMWH may occur on an outpatient basis, although patients in studies addressing this issue have been highly selected. 1 Based on information available at this point in his care, Mr Cross is a candidate for concurrent outpatient therapy with LMWH (short-term) and warfarin. 1 warfarin

27. ✓ A decision to use IV UFH in this patient would require his hospitalization until his INR is therapeutic and stable. IV heparin therapy would be started with an 80 Units/kg bolus followed by an 18 Units/kg/h infusion. The infusion rate would traditionally be adjusted based on measurement of the patient’s activated partial thromboplastin time, with prolongation of the activated partial thromboplastin time to an extent that would correspond to plasmaheparin levels of 0.3- 0.7 IU/mL anti-Xa activity. 1therapeuticheparin 1

28. ✓ Recent data support the possibility of using weight-- adjusted, fixed-dose subcutaneous UFH rather than LMWH in the treatment of acute DVTs. 2 In a randomized study of 708 patients with acute venous thromboembolism, an initial subcutaneous UFH dose of 333 Units/kg followed by 250 Units/kg every 12 hours was as safe and effective as LMWH. While the reduced cost of this approach and ability to avoid hospitalization are appealing, the findings need to be confirmed by other investigators before the routine use of weight-adjusted, fixed-dose subcutaneous UFH can be advocated. However, this approach is included as a treatment option in the 2008 ACCP guidelines. 1 2 1

29. ✓ The final option for the acute treatment of this patient is fondaparinux, a relatively new anticoagulant that inhibits thrombin formation by binding toantithrombin III and potentiating factor Xa inactivation. Fondaparinux is approved for the initial treatment of acute DVTs, including its use on an outpatient basis in the absence of PE. The dosage regimen for this 88-kg patient would be 7.5 mg subcutaneously once daily for at least 5 days and until the INR is at goal (2.0-3.0). The place of fondaparinux relative to UFH and LMWH in the treatment of DVTs with or without PE is an active area of research. 3thrombin 3

30. Consideration of more aggressive treatment strategies, including catheter- directed thrombolysis, thrombectomy, and placement of an inferior vena cava filter, is not warranted in this patient. 1 1 Consideration should be given to recommending the patient wear compression stockings to minimize the risk of postthrombotic syndrome. 1 Available data suggest that wearing either custom-fit or over-the-counter compression stockings with an ankle pressure gradient of 30-40 mm Hg starting within 1 week to 1 month of an acute DVT and continuing for at least 2 years reduces the incidence of postthrombotic syndrome by approximately half. 1 1 Dabigatran etexilate, an oral direct thrombin inhibitor, may provide an alternative to warfarin for the treatment of acute DVTs in the United States in the near future. 4,5 Dabigatran was approved by the U.S. FDA in October 2010 for prevention of stroke and embolism in patients with atrial fibrillation. It was not approved for treatment of DVT at the time of this writing.thrombinwarfarin 4,5

31. class of anticoagulant drugs which act directly upon Factor X in the coagulation cascade, without using antithrombin as a mediator. [1]anticoagulantdrugsFactor Xcoagulation cascadeantithrombin [1] Direct factor Xa inhibitors are being used clinically. Clinical trials have shown promise for these compounds as substitutes for the currently administered vitamin K antagonists or low molecular weight heparin. Those trials demonstrated efficacy and safety against warfarin for stroke prevention in atrial fibrillation and against low- molecular-weight heparin for treatment and secondary prevention of venous thromboembolism or for initial treatment and prevention of venous thromboembolism in patients undergoing hip or knee replacement. [2]vitamin Klow molecular weight heparin [2]

32. Optimal Plan 4. Design a treatment plan for the initial management of this patient’s DVT. Be sure to include dosage form, dose, schedule, and duration of therapy for each drug that is part of the plan. Start the patient on concurrent subcutaneous LMWH and oral warfarin therapies. At our institution, the LMWH would be enoxaparin, 1 mg/kg every 12 hours. Since this patient’s body weight is 88 kg, the ideal dose would be 88 mg every 12 hours, which would be rounded to 90 mg for practical purposes. Unfortunately, enoxaparinis not marketed in 90-mg prefilled syringes; it is available in 80- and 100-mg prefilled syringes. One must therefore choose either to round the dose up or down or to have the patient (or caregiver) expel 10 mg from a 100-mg syringe. Expelling part of the syringe contents can be difficult and lead to dosing errors, so we generally try to avoid this approach. We would choose a dose of 100 mg every 12 hours as a practical option for this patient.warfarinenoxaparin

33. ✓ Enoxaparin 1.5 mg/kg subcutaneously once daily might also be considered, although this regimen is not FDA- approved for outpatient use and may be associated with a higher risk of recurrent VTE.6Enoxaparin6 ✓ There is no need for dose adjustment for either decreased kidney function (estimated creatinine clearance =112 mL/min using ideal body weight of 73.8 kg or 121 mL/min using adjusted body weight of 79.6 kg) or liver function (hepatic function panel not available, but findings on history and physical exam do not suggest liver disease and baseline INR was 1.0). Continue this enoxaparin dosage regimen for at least 5 days and until the patient’s INR is 2.0 for 2 consecutive days.enoxaparin ✓ Equivalent regimens of dalteparin (200 U/kg per day subcutaneously divided into once or twice daily injections with a maximum of 18,000 U per dose) or tinzaparin (175 anti-Xa U/kg subcutaneously once daily) could also be used.

34. Also start the patient on warfarin with instructions to take one 5-mg tablet by mouth daily. The duration of warfarin therapy is difficult to determine at this point. Current ACCP guidelines recommend anticoagulation for at least 3 months for patients with an unprovoked DVT.1 The guidelines recommend a risk- benefit assessment at that point. Long-term anticoagulation therapy is recommended for patients with a first, unprovoked, proximal DVT who do not have significant risk factors for bleeding and who do have good monitoring available. The thrombophilia testing completed at baseline will help guide the decision in this patient.warfarin 1

35. Outcome Evaluation 5. Design a monitoring plan for this patient’s DVT therapy. Be sure to include monitoring for both safety and efficacy. Mr Cross should visit his primary care physician or an anticoagulation clinic approximately 3 days after his visit to the ED. Assess the patient for the following: ✓ Continuing signs and symptoms of DVT and/or PE (see the section “Problem Identification”), with the expectation that DVT-related findings should be stable or improving and no new findings consistent with a PE should be present; ✓ Signs and symptoms of bleeding (see the section “Patient Education”) or other medication-related adverse effects; ✓ Adherence to the anticoagulation regimen; ✓ Adherence to dietary recommendations; ✓ Alcohol consumption;Alcohol ✓ Changes in over-the-counter, herbal, or prescription medications; and ✓ INR response.

36. Do not monitor this patient’s platelet count since he has not received heparin and does not have a history of HIT. 1heparin 1 Increase the warfarin dose if the patient has been adherent and his INR has not changed significantly (e.g., INR 1.9).warfarin Reinforce or extend the initial patient education (see the section “Patient Education”), as appropriate. Assess the patient at approximately 2- to 5-day intervals until a stable INR within the targeted range of 2.0-3.0 is achieved, at which point you should stop theenoxaparin. Recommended minimum duration of enoxaparin therapy is 5 days. Use of less frequent visits (e.g., 1 week to 10 days) tends to extend the time toenoxaparin discontinuation.stopenoxaparin Assess the patient approximately 1 week after discontinuation of enoxaparin to assure that his INR is stable and therapeutic. If it is, assess the patient at 1-month intervals as long as the INR is stable and there is no recurrence of venous thromboembolic symptoms.enoxaparintherapeutic

37. Patient Education 6. What education should be provided for this patient to optimize the probability of therapeutic success while minimizing the risk of adverse events?therapeutic General information: You have blood clots in several veins in your right leg. This is called deep vein thrombosis or DVT. Symptoms of a DVT include pain, swelling, redness, and warmth in the affected leg. It is important that your DVT is treated properly to prevent a piece of a blood clot in your leg from breaking off and traveling to your lungs. If this happens, it is called a pulmonary embolism or PE. Symptoms of a PE include chest pain and shortness of breath. Get medical attention if you develop these symptoms because a PE can be life-threatening.

38. Effective treatment of your DVT will also decrease the risk of your developing a condition known as postthrombotic syndrome, which would be a long-term problem with pain, swelling, and possibly open sores on your leg. Treatment of your DVT will include two medicines that are called anticoagulants. Anticoagulants decrease the ability of your blood to clot. They are used to treat or prevent harmful blood clots. The two anticoagulants you will be using areenoxaparin (or Lovenox) and warfarin (frequently called Coumadin). You will only need to use the enoxaparin until the warfarin is providing effective anticoagulation.enoxaparinLovenoxwarfarinCoumadinenoxaparinwarfarin

39. Enoxaparin: Enoxaparin is an anticoagulant that is used to treat or prevent harmful blood clots. It is available as the brand name Lovenox. Lovenox must be given by injection under your skin, preferably in your stomach area.EnoxaparinLovenox You will be injecting 100 mg of Lovenox twice each day (about every 12 hours). The syringes you receive from the pharmacy will have that amount of Lovenox in each syringe. You should use the following steps to give these injections in your stomach area (Note: Pictures or diagrams should be used to explain this procedure to the patient, and the patient should be asked to demonstrate the technique once heLovenox understands how to do it.): 1. Wash your hands with soap and water. 2. Sit so you can see your stomach. It may be helpful to recline slightly. 3. Choose an injection site. It should be on the lower part of your stomach area, below your ribs and above your hip bones, and at least 2 in away from your belly button, incision sites, or scars. Alternate the injection sites between your right and left sides, and try not to use the same site twice. 4. Clean the injection site with an alcohol wipe and let it dry.alcohol

40. 5. Prepare the syringe you are going to use for the injection. Hold the syringe in your right hand if you are right- handed, or left hand if you are left-handed. Remove the needle cover with your other hand. Do not push any liquid or air from the syringe before giving the injection. Do not touch the exposed needle or allow it to touch anything else.Hold 6. Gently pinch the injection site to form a skin fold between the thumb and forefinger of your free hand. 7. Insert the needle straight into the skin fold. The full length of the needle should be inserted at a 90˚ angle to the skin. 8. Push the entire contents of the syringe into the skin fold. Do not pull back on the plunger. 9. Remove the needle by pulling it straight out of the skin and then release the skin fold. Do not rub the injection site since that will increase bruising. 10. Point the used syringe away from you and others, and then push on the plunger to activate the safety shield. Dispose of the empty syringe in a puncture-proof container. Store the container of used syringes away from children.

41. If you forget to inject a dose of Lovenox, inject it as soon as you remember unless it is almost time for your next dose and then resume your normal schedule. If it is almost time for your next dose, skip the forgotten dose and resume your normal schedule.Lovenox You may experience some discomfort/pain/stinging or redness at the injection site. The most common side effects of Lovenox are related to bleeding. Call us or seek emergency medical care, as appropriate, if you experience any of the following: bleeding from your gums or nose, bruising easily, coughing up blood, red or dark brown urine, red or black stools, vomiting of blood (may look like coffee grounds), or bleeding from cuts or wounds that does not stop.Lovenoxstop Allergic reactions to Lovenox are rare, but might include itching or hives; swelling of your face, hands, mouth, or throat; chest tightness; or trouble breathing. Please let us know if you experience any other symptoms that you think might be related toLovenox, including nausea, diarrhea, confusion, excessive bruising, pain, redness, swelling, or a lump at an injection site.Lovenox

42. Warfarin : Warfarin is an anticoagulant that is used to treat or prevent harmful blood clots. It is sometimes called a “blood thinner,” although it does not really “thin” your blood.Warfarin is available as a generic or by brand names such as Coumadin andJantoven.Warfarin CoumadinJantoven You will be taking 5-mg warfarin tablets. You will start by taking one 5-mg tablet at about the same time each day. I recommend that time be in the evening since you will be able to more quickly adjust your dose of warfarin when you have your INR checked, but the most important thing is to pick a time of the day when you will remember to take it each day. You may take warfarin either with or without food.warfarin If you miss or forget to take a dose, take that dose as soon as you can if it is within 12 hours of when you were supposed to take it. Skip the dose if more than 12 hours have passed. Please make a note of any missed or skipped doses so that you can tell me and your doctor about them at your next appointment.

43. It is likely that your dose of warfarin will need to be adjusted up or down to make sure you are taking the right dose. We will use a test called an “INR” to measure how much effect warfarin is having on your blood’s ability to clot. A normal INR is 1.0. The higher the INR is, the longer it takes for your blood to clot. Our goal is to maintain your INR between 2.0 and 3.0. Lower INRs put you at risk of another DVT or pulmonary embolism, while higher INRs put you at greater risk of bleeding. We will measure your INR frequently at first (every few days to a week). Once your INR is stable and at goal, we will measure your INR once a month.warfarin Many prescription, over-the-counter, and herbal medicines can change the effectwarfarin has on your blood clotting. These interactions can either make warfarinmore effective (and increase your risk of bleeding) or make it less effective (and increase your risk of another clot or pulmonary embolism). Make sure that all of your health care providers know that you take warfarin so they can take that into consideration when prescribing a new drug or discontinuing or changing the dose of a drug you are currently taking. One group of medicines to be cautious with is the anti-inflammatory drugs such as aspirin, ibuprofen, and naproxen. These medicines can cause stomach bleeding, which can be dangerous when you are taking warfarin. Please discuss your need for these medicines with your physician before taking them.warfarin aspirinibuprofennaproxenwarfarin

44. Warfarin will work best and be safest when the amount of vitamin K in your diet is relatively consistent. You should avoid big changes (either up or down) in your vitamin K intake. Foods that contain large amounts of vitamin K include broccoli, Brussels sprouts, cabbage, lettuce (other than iceberg), greens, and spinach.Warfarin Drinking alcohol may affect your warfarin therapy. It is safest to avoid alcoholwhile you are taking warfarin. If this is not possible, intake should be limited to no more than one or two drinks per day.alcoholwarfarinalcoholwarfarin The most common side effects of warfarin are related to bleeding. Call us or seek emergency medical care, as appropriate, if you experience any of the following: bleeding from your gums or nose; bruising easily; coughing up blood; red or dark brown urine; red or black stools; vomiting of blood (may look like coffee grounds); sudden, severe headaches, possibly accompanied by symptoms such as vision changes, slurred speech, or muscle weakness; or bleeding from cuts or wounds that does not stop. Also call us or seek medical care if you experience purple discoloration of your toes or soles of your feet, or develo p skin sores.warfarinstop

45. Allergic reactions to warfarin are rare, but might include itching or hives; swelling of your face, hands, mouth, or throat; chest tightness; or trouble breathing. Please let us know if you experience any other symptoms that you think might be related towarfarin.warfarin You are likely to bleed more easily while you are taking warfarin. Lifestyle changes can help minimize the risk of bleeding. Do not engage in contact sports or other activities that increase your risk of bruises, cuts, or injuries. Be careful when using sharp objects, and brush and floss your teeth gently.warfarin Please let us know any time you are going to be undergoing medical, surgical, or dental testing or procedures. It may be necessary to stop your warfarin therapy before such procedures.stopwarfarin Finally, it is recommended that you wear a medical alert bracelet and/or carry an ID card that would let emergency caregivers know you are taking warfarin.warfarin

46. Follow-Up Questions

47. 1.a. Identify the patient’s anticoagulation therapy- related drug therapy problem(s), and design treatment and monitoring plans for managing each problem you identify. Anticoagulation therapy-related problem: patient is taking warfarin for treatment of his DVT and has not yet achieved the therapeutic range. His INR has increased to 1.7 after 3 days of treatment. The patient should be closely questioned to try to identify any anticoagulation therapy-related problems. Assuming issues are identified, the plan would be to:warfarintherapeutic ✓ Continue enoxaparin therapy.enoxaparin ✓ Maintain current warfarin dose. Some might advocate a small warfarindose decrease with this magnitude of initial response to avoid overshooting the targeted INR, but we would likely continue 5 mg warfarin daily with careful monitoring.warfarin ✓ See the patient in 2-3 days to assess his response to the continued dose of 5 mg warfarin daily, as well as to perform an overall assessment as outlined above.warfarin

48. 1.b. Identify the patient’s anticoagulation therapy- related drug therapy problem(s), and design treatment and monitoring plans for managing each problem you identify. Anticoagulation therapy-related problem: patient may have experienced an adverse event, hematuria, possibly related to anticoagulation with warfarin for treatment of his DVT. Given that this is an isolated event and the patient’s INR is within the therapeutic range, the plan would be to:warfarintherapeutic ✓ Check a standard urine dipstick, microscopic urine, and culture and sensitivity to rule out a urinary tract infection and microscopic hematuria. ✓ Obtain a urology consult to rule out other kidney or bladder causes of hematuria if no urinary tract infection is identified. ✓ Continue current warfarin dosage regimen.warfarin ✓ See the patient in 1 month to reassess, including measurement of INR. Instruct patient to call if hematuria or any other symptom of bleeding occurs before that visit..

49. In this patient, the standard urine dipstick was negative (clear appearance, yellow color, specific gravity =1.020, pH 5.5, and glucose, bilirubin, ketones, blood, protein, nitrites, and leukocyte esterase all negative). The microscopic urine was also negative (white blood cells, red blood cells, and bacteria all absent). The culture of a clean catch urine was reported as negative. The patient was therefore referred to a urologist

50. The patient was seen by the urologist after his episode of hematuria. The urologist’s history and physical exam revealed no new findings. A urinalysis was negative for blood, nitrites, and leukocyte esterase. A renal ultrasound revealed “no evidence of any hydronephrosis, tumors, stones, or other abnormalities.” Urine cytology was negative. The urologist’s recommendation was for “further observation.” This patient therefore appears to have experienced an isolated episode of hematuria while on warfarin with a therapeutic INR and no other identifiable cause. He has not experienced a recurrence after over 2 years of observation.warfarintherapeutic

51. 1.c. Identify this patient’s anticoagulation therapy- related drug problem(s), and design a treatment and monitoring plan for each problem that you identify. Be sure to specify the anticipated duration of his anticoagulation therapy. Anticoagulation therapy-related problem: the patient is taking warfarin for treatment of his DVT and has exceeded the targeted INR range of 2.0-3.0. Possible causes include a drug interaction with simvastatin and a change in analytic method used to measure the prothrombin time.warfarinsimvastatin Available data suggest that simvastatin may increase the INR in patients takingwarfarin, but pravastatin does not.7- 9 These data and the time frame of the patient’s switch from pravastatin to simvastatin are consistent with his increased INR caused by the initiation of simvastatin therapy.simvastatinwarfarinpravastatin7- 9pravastatinsimvastatin

52. A second factor that possibly contributed to the increased INR relates to a change in the analytic method used to measure it. The INR from the previous month was measured on a venous blood sample by the clinical lab using a STA-R Evolution (Stago Diagnostica, Inc). The INR from this visit was measured using a CoaguChek XS (Roche Diagnostics). Substantial intermethod variability in the measurement ofINRs exists. In our experience, the CoaguCHek XS systematically measures high INRs higher than the STA-R Evolution.

53. The plan for managing this patient’s warfarin therapy was the following:warfarin ✓ Hold warfarin dose × 1 and then decrease warfarin maintenance dose to 2.5 mg 5 days per week and 5 mg 2 days per week (e.g., 2.5 mg on Monday, Wednesday, Thursday, Friday, and Sunday and 5 mg on Tuesday and Saturday). This is a 10% dose decrease from 25 to 22.5 mg per week. A further dose decrease may be required depending on the INR response.Holdwarfarin ✓ Repeat lupus anticoagulant studies to confirm presence of lupus anticoagulants. A dilute Russell’s viper venom time (dRVVT), dRVVT Confirm if dRVVT elevated, and StaClot LA would be most helpful since patient is currently taking warfarin. These tests will help guide the decision regarding duration of this patient’s anticoagulation therapy. If the repeat tests are positive, this patient meets the diagnostic criteria for antiphospholipid syndrome.10 These criteria require the detection of lupus anticoagulant antibodies (or other antiphospholipid antibodies) on at least two occasions at least 12 weeks apart.warfarin10

54. ✓ As noted previously, current ACCP guidelines recommend long-term anticoagulation therapy for patients such as Mr Cross with a first, unprovoked, proximal DVT who do not have significant risk factors for bleeding and who do have good monitoring available.1 If repeat testing for lupus anticoagulants is positive, this recommendation would be strengthened since the presence of lupus anticoagulants is known to significantly increase the risk of VTE recurrence.1 Mr Cross does not have an antithrombin III, protein C, or protein S deficiency or a factor V Leiden or prothrombin G-20210-A mutation, any of which would further increase his risk of VTE recurrence.1 ✓ See the patient in 2 weeks to reassess, including measurement of INR. Instruct patient to call if any signs or symptoms of bleeding occur before that visit. Some might choose to see the patient sooner (e.g., 7-10 days) to assess the response to the decreased warfarin dose and the possibility of an ongoing simvastatin interaction.warfarinsimvastatin

55. ✓ In this patient, lupus anticoagulant studies were repeated several months after the patient’s initial presentation. The partial thromboplastin time was elevated beyond any effect expected from warfarin and the dRVVT/dRVVT Confirm and StaClot LA were again positive. A decision to anticoagulate this patient indefinitely was therefore made with a targeted INR of 2.5 (acceptable range: 2.0-3.0). Current guidelines recommend a higher target of 3.0 (acceptable range: 2.5-3.5) only in lupus anticoagulant patients who have a VTE recurrence while their INR is therapeutic or have additional risk factors for VTE events.11warfarintherapeutic11

56. THE END