At the 2001 annual conference of the American College of Physicians, a new teaching format to aid physician learning, Clinical Pearls, was introduced. Clinical Pearls is designed with the 3 qualities of physician-learners in mind. First, we physicians enjoy learning from cases. Second, we like concise, practical points that we can use in our practice. Finally, we take pleasure in problem solving.
In the Clinical Pearls format, speakers present a number of short cases in their specialty to a general internal medicine audience. Each case is followed by a multiple-choice question answered live by attendees using an audience response system. The answer distribution is shown to attendees. The correct answer is then displayed and the speaker discusses teaching points, clarifying why one answer is most appropriate. Each case presentation ends with a Clinical Pearl, defined as a practical teaching point that is supported by the literature but generally not well known to most internists.
Clinical Pearls is currently one of the most popular sessions at the American College of Physicians meeting. As a service to its readers, Mayo Clinic Proceedings has invited a selected number of these Clinical Pearl presentations to be published in our Concise Review for Clinicians section. “Clinical Pearls in Thrombosis and Anticoagulation” is one of them.
CASE 1
A 72-year-old man is admitted to the hospital for sigmoid colon resection secondary to cancer. He is receiving long-term warfarin therapy for atrial fibrillation. He has a history of stroke but with little residual deficit. His laboratory studies, including those assessing renal function, yield normal or satisfactory results. The patient begins receiving weight-based therapeutic low-molecular-weight heparin (LMWH) bridge therapy to safely cover his need for anticoagulation while warfarin is withdrawn preoperatively.
Question
Which one of the following represents the most appropriate time before surgery to administer the last dose of LMWH so as to decrease the patient's risk of intraoperative bleeding?
- a.6 hours
- b.12 hours
- c.18 hours
- e.24 hours
- e.36 hours
Discussion
Patients receiving long-term anticoagulation therapy who undergo surgical procedures frequently require bridge therapy; that is, they need coverage with LMWH while warfarin is being withheld in the perioperative period. The decision to provide bridge therapy is based on the thrombotic risk of the patient during the period of anticoagulation cessation before surgery. The risk of thrombosis is based on the indication for warfarin anticoagulation. The risk of bleeding secondary to the use of LMWH as bridge therapy preoperatively is also assessed.
To better understand the risk of surgical bleeding, knowledge of the half-life of the most frequently used LMWHs, dalteparin, enoxaparin, and tinzaparin, is necessary. Each of these agents is dosed on the basis of actual body weight. The half-life of these agents is as follows: dalteparin, 3 to 5 hours; enoxaparin, 6 hours; and tinzaparin, 4 hours. The recommended bridge protocol usually requires the cessation of warfarin 5 days before surgery with the initiation of LMWH (100 IU/kg of dalteparin every 12 hours or 200 IU/kg every 24 hours; 1 mg/kg of enoxaparin every 12 hours or 1.5 mg/kg every 24 hours; or 175 IU/kg of tinzaparin every 24 hours) on day 4 before surgery. The crucial point in preventing increased risk of surgical bleeding is the timing of the last dose of LMWH.
A laboratory measurement of anti-Xa levels is typically used to measure the effect of LMWH. Two single-cohort studies evaluated anti-Xa levels on the morning of surgery in 117 patients receiving the last therapeutic subcutaneous dose of LMWH the evening before surgery. The recommended target ranges for anti-Xa levels 4 hours after LMWH administration are 0.5 to 1.0 U/mL for therapeutic purposes and 0.1 to 0.3 U/mL for prophylactic purposes. Using therapeutic enoxaparin dosing for bridge therapy, O'Donnell et al
1
documented that, at the time of surgery, 68% of patients had anti-Xa levels greater than 0.5 U/mL, and 16% of patients had levels greater than 1.0 U/mL. The study by Douketis et al2
used therapeutic dosing of dalteparin, enoxaparin, or tinzaparin for bridge therapy and showed that 30% of the patients at the time of surgery had anti-Xa levels greater than 0.1 U/mL. Each of these studies using therapeutic LMWH dosing showed higher residual anti-Xa levels that were associated with a shorter dosing interval and older age. The focus of these studies was to measure the residual anti-Xa effect of LMWH on the morning of surgery. The operations in these studies were procedures with low bleeding risk, and none of the patients had any major bleeding events. These studies point out the potential for bleeding in high-risk surgical or invasive procedures. The American College of Chest Physicians (ACCP) guideline recommends that the last dose of LMWH (at a therapeutic twice-daily dosage) should be administered to patients receiving bridging anticoagulation therapy 24 hours before surgery.3
For patients receiving therapeutic once-daily LMWH dosing, a 50% reduction in that dose 24 hours before surgery is recommended.3
Clinical Pearl
All patients receiving therapeutic twice-daily LMWH (100 IU/kg of dalteparin subcutaneously every 12 hours; 1 mg/kg of enoxaparin subcutaneously every 12 hours) for bridge therapy before surgery should receive their last dose on the morning of the day before surgery. For patients receiving once-daily therapeutic LMWH (200 IU/kg of dalteparin subcutaneously every 24 hours; 1.5 mg/kg of enoxaparin subcutaneously every 4 hours; 175 IU/kg of tinzaparin subcutaneously every 24 hours), the dose 24 hours before surgery should be reduced by 50%.
CASE 2
A 59-year-old physician presents with sudden onset of shortness of breath 2 days after a traumatic injury to his left lower extremity. Spiral computed tomography of the chest reveals bilateral pulmonary emboli (PEs). Unfractionated heparin (UFH) is initiated. Echocardiography reveals a dilated right atrium with increased right-sided pressure. The patient becomes hypotensive and hypoxic, necessitating initiation of thrombolytic therapy using a recombinant tissue plasminogen activator (rtPA) infusion for 2 hours.
Question
Which one of the following is the best approach for restarting UFH after rtPA infusion?
- a.Restart after 6 hours with UFH bolus followed by infusion
- b.Check activated thromboplastin time (APTT) at the completion of rtPA infusion; readminister rtPA as a continuous infusion without a bolus if the APTT is less than 80 seconds
- c.Restart after 12 hours with UFH bolus followed by infusion
- d.Restart after 12 hours with infusion only, no UFH bolus
- e.Restart on the basis of echocardiographic findings
Discussion
It is widely agreed that thrombolytic therapy should be used to treat PEs associated with marked hemodynamic compromise. Justification for use in this situation is that, compared with anticoagulation therapy alone, thrombolytic therapy has demonstrated the following advantages: (1) acceleration of thrombus lysis, as evidenced by more rapid resolution of perfusion scan abnormalities, decrease in angiographic thrombus, reduction in elevated pulmonary arterial pressures, and normalization of right-sided ventricular dysfunction, and (2) trends toward improved clinical outcomes in subgroups of patients with hemodynamic compromise.
4
Selection of patients with PEs to receive thrombolytic therapy requires rapid and accurate risk stratification of the competing risks of death as a result of PE vs bleeding as a result of thrombolytic therapy.In a meta-analysis of 11 studies with a total of 748 patients with PE of varying severity, thrombolysis was associated with trends toward reduction in recurrent PE (2.7% vs 4.3%; OR, 0.67; 95% confidence interval [CI], 0.33-1.37), reduction in all-cause mortality (4.3% vs 5.9%; OR, 0.70; 95% CI, 0.37-1.30), and an increase in major bleeding (9.1% vs 6.1%; OR, 1.42; 95% CI, 0.81-2.46).
4
Currently, the most widely used and evaluated regimen supports an infusion of 100 mg of rtPA via a peripheral vein for 2 hours or less. During administration of thrombolytic therapy, it is acceptable to either continue or suspend the UFH infusion. These 2 regimens have never been compared in clinical trials. Regulatory bodies in the United States recommend suspension of intravenous UFH during the infusion period of rtPA. On completion of the rtPA infusion, the APTT should be checked. If the APTT is less than 80 seconds, UFH should be reinitiated as a continuous infusion with-out a bolus and the dose adjusted to achieve a therapeutic APTT.4
, 5
Clinical Pearl
On completion of rtPA infusion, UFH should be initiated as a continuous infusion without a bolus when the APTT is less than 80 seconds.
CASE 3
A 76-year-old man is diagnosed as having stage II, non — small cell lung adenocarcinoma. Surgery with adjuvant chemotherapy (cisplatin/gemcitabine) and external beam radiation is planned for his management. A central access venous catheter is placed for administration of chemotherapy.
Question
Which one of the following would be the most appropriate recommendation for preventing central venous catheter — related thrombosis?
- a.No prophylaxis of central venous catheter is required
- b.Aspirin, 325 mg/d
- c.Clopidogrel, 75 mg/d
- d.Fixed-dose warfarin, 1 mg/d
- e.Adjusted-dose warfarin to achieve an international normalized ratio (INR) in the 1.5 to 2.0 range
Discussion
The incidence of central venous catheter—related thrombosis has always been a concern for physicians managing patients with cancer during chemotherapy. It has been reported that approximately 25% of patients in this population develop central venous catheter—related thrombosis. Bern et al
6
used 1 mg/d of warfarin without monitoring vs a placebo control and demonstrated an incidence of thrombus of 25% in the placebo group and 7% in the intervention group.6
Park et al7
substantiated the finding by Bern et al, demonstrating a 29% incidence in the placebo group vs a 3% incidence with fixed-dose warfarin. On the basis of these findings, fixed-dose warfarin became the standard management for patients with cancer who had central venous catheters for many years. It must be remembered that the total number of patients enrolled in these 2 studies was only 99 in the warfarin group and 102 in the placebo group. However, despite the low dose (1 mg/d), oncologists had difficulty accepting fixed-dose warfarin management because many patients developed prolonged INRs in the face of concomitant chemotherapy and poor nutritional intake. Two trials8
, 9
challenged the Bern et al and Park et al data. These trials did not show any benefit of the fixed-dose warfarin in preventing catheter-related thrombosis. Most recently, Young et al10
evaluated a regimen of no warfarin with 2 different dosing schedules of warfarin. In this study, 404 patients received no warfarin and 408 patients received either fixed-dose (1 mg; 324 patients [79%]) or adjusted-dose [INR, 1.5-2.0; 84 patients [21%]) warfarin. Warfarin was not found to reduce the rate of catheter-related thromboses (24 [6%] vs 24 [6%]; relative risk, 0.99; 95% CI, 0.57-1.72; P=.98). Major bleeding events were rare; an excess was noted with warfarin vs no warfarin (7 vs 1; P=.07) and with adjusted-dose warfarin vs fixed-dose warfarin (16 vs 7; P=.09). No differences in the combined end point of thromboses and major bleeding was observed among the groups. These findings show that prophylactic warfarin is not associated with a reduction in symptomatic catheter-related or other thromboses in patients with cancer, underlining the importance of looking for new preventive strategies in the future. The ACCP guideline recommends against using either prophylactic doses of LMWH or 1-mg doses of warfarin to prevent catheter-related thrombosis.11
Clinical Pearl
Evidence does not support administration of warfarin to patients with central venous catheters to prevent thrombotic events.
CASE 4
A 60-year-old woman is admitted to the hospital with left lower-extremity swelling. Ultrasonography confirms the diagnosis of an acute proximal deep venous thrombosis. She is given an injection of weight-based LMWH in the emergency department and you are consulted to help with management. The patient tells you she lost her job recently and has limited resources. She must travel to Florida the following morning, where she plans to move in with her sister, but assures you she will see a physician there within a few days. The case manager documents that the patient's insurance does not cover the cost of LMWH or fondaparinux. The patient states that she must leave the next morning and cannot afford the cost of expensive medications.
Question
Which one of the following is the best option for managing this patient's acute proximal deep venous thrombosis?
- a.Hospitalization for treatment with UFH
- b.Administration of 5000 U of UFH subcutaneously every 12 hours on an outpatient basis
- c.Administration of 15,000 U of UFH subcutaneously every 12 hours on an outpatient basis
- d.Administration of an initial dose of 333 U/kg of UFH, followed by 250 U/kg every 12 hours on an outpatient basis
- e.Only LMWH or fondaparinux is safe to use in the outpatient setting
Discussion
Anticoagulation is the appropriate therapy for acute deep venous thrombosis. It is used to prevent propagation of the thrombus as well as to prevent early and late recurrence of the clot. The use of continuous-infusion UFH has been shown to be effective in 2 different dosing schedules: (1) a starting bolus of 5000 U followed by a continuous infusion of 1300 U/h
4
and (2) a starting bolus of 80 U/kg of weight-adjusted UFH followed by a continuous infusion of 18 U/kg/h.4
With both regimens, the infusion dose of UFH is adjusted to achieve the therapeutic APTT set by the hospital laboratory. These regimens are hospital-based and do not ad-dress this case. The alternative options include the LMWHs and fondaparinux. These agents are better absorbed when administered subcutaneously, have a longer half-life, achieve a therapeutic effect in 1 hour, and do not require monitoring. Low-molecular-weight heparins and fondaparinux have been shown to be as safe and effective as UFH for the treatment of deep venous thrombosis in both the outpatient and inpatient settings. Unfortunately, the patient's prescription plan does not cover LMWH or fondaparinux.Our only option in this case would be to use therapeutic subcutaneous UFH. A fixed-dose regimen is preferable because it is easy to use, requires no monitoring, and is inexpensive. Two important trials have shown the safety and efficacy of weight-based subcutaneous UFH vs LMWH in the treatment of deep venous thrombosis. Prandoni et al
12
used an initial intravenous bolus of 5000 U followed by 17,500 U subcutaneously every 12 hours. The shortcoming of this approach was the need to adjust the UFH on the basis of a dosing schedule that correlated with the APTT. More recently, Kearon et al13
evaluated the use of an initial weight-based dose of UFH (333 U/kg) followed by a fixed weight-based dose (250 U/kg subcutaneously every 12 hours) without APTT adjustment compared with LMWH, finding no difference in safety or efficacy.Because the patient must leave the next morning and her insurance does not cover LMWH, the use of weight-adjusted UFH without monitoring would be a very reasonable outpatient management approach. As soon as she affiliates with a physician in Florida, warfarin can be initiated and overlapped with heparin until her INR reaches a therapeutic range.
Clinical Pearl
The use of weight-based UFH (initial dose of 333 U/kg subcutaneously followed by 250 U/kg subcutaneously every 12 hours) without APTT monitoring is an alternative approach to managing acute proximal deep venous thrombosis.
CASE 5
A 60-year-old woman is admitted to the hospital for exacerbation of congestive heart failure. She has distended neck veins; a moderate-sized, right-sided pleural effusion; and lower-extremity edema. She begins receiving UFH prophylaxis for deep venous thrombosis. She responds well to therapy for heart failure, but on day 5 of hospitalization her platelet count is noted to be 50 × 109/L (platelet count at admission, 185 × 109/L). Subcutaneous UFH prophylaxis (5000 U every 8 hours) is discontinued. Findings on a serotonin release heparin antibody assay are positive. No evidence of deep venous thrombosis is revealed by compression ultrasonography of the lower extremities.
Question
In addition to discontinuing UFH, which one of the following actions would be most appropriate?
- a.No action required; anticoagulant agents are unnecessary because there is no thrombosis
- b.Begin LMWH in prophylactic doses
- c.Begin LMWH in full-treatment doses
- d.Initiate an intravenous direct thrombin inhibitor
- e.Initiate a prophylactic antiplatelet agent for the duration of the hospitalization
Discussion
Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse effect of heparin that has a strong association with venous and arterial thrombosis. A prothrombotic state, HIT is associated with an increase in the generation of thrombin along with platelet factor 4/heparin/IgG antibodies. The generation of thrombin explains both the arterial and venous thrombosis and decompensated intravascular coagulation seen in 5% to 10% of patients with HIT.
14
The odds ratio of developing thrombotic events in HIT has been reported to be 20 to 40, whereas the absolute risk has been reported to be 30% to 75%, depending on the populations affected.14
The issue in this case is the risk of developing thrombosis in a patient with isolated HIT without thrombosis. The high absolute risk of thrombotic events in patients with HIT points to the highly exacerbated thrombotic state associated with this antibody-mediated process. Therefore, for these patients, the recommendation by the ACCP guideline is to discontinue subcutaneous UFH and start a direct thrombin inhibitor until the platelet count has recovered to normal range.
14
The question as to whether to add a short course of warfarin after the recovery of the platelet count as additional protection against late HIT thrombosis has not yet been resolved. The high frequency of subclinical deep venous thrombosis in this patient setting suggests that routine compression ultrasonography is appropriate as part of management because the discovery of asymptomatic thrombosis would change the duration of anticoagulant management.Clinical Pearl
Patients with isolated HIT without thrombosis should receive a direct thrombin inhibitor at a therapeutic dose until their platelet count has recovered to a stable plateau.
CASE 6
A 27-year-old woman who is 32-weeks pregnant develops left calf pain followed by sudden onset of shortness of breath. Spiral computed tomography of the chest with shielding reveals multiple PEs. On completion of computed tomography, the patient becomes hypotensive and hypoxemic.
Question
Which one of the following is the best approach to safely manage this pregnant patient?
- a.Intravenous administration of UFH, weight-based dosing
- b.Low-molecular-weight heparin, weight-based dosing
- c.Intravenous direct thrombin inhibitor
- d.Placement of an inferior vena cava filter; no anticoagulation
- e.Intravenous administration of 100 mg of recombinant tissue plasminogen activator (rtPA) for 2 hours
Discussion
Venous thromboembolic disease is an important cause of morbidity and mortality during pregnancy. Berg et al
15
found that 11% of maternal deaths during pregnancy were related to PE. Pregnancy is a thrombophilic state associated with the following changes: increased fibrinogen levels, decreased fibrinolysis during the third trimester, and decreased protein S levels. In addition, the gravid uterus compresses the inferior vena cava, with resultant pelvic and lower-extremity venous stasis.Administration of rtPA activates plasminogen to form the fibrinolytic enzyme plasmin. This protein cleaves fibrin as well as fibrinogen, factor V, and factor VIII. In the presence of fibrin, rtPA has a high affinity for plasminogen, which in theory would make it more clot-specific. A large polypeptide, rtPA does not cross the placenta. This agent is also nonantigenic, allowing for repeated use. Leonhardt et al
16
and Ahearn et al17
reported a series of 12 pregnant patients with deep venous thrombosis (n=3) or PE (n=9) treated with rtPA. No adverse outcomes were reported in the mothers, but 2 children died. One died 14 days after thrombolysis and the other within 24 hours after spontaneous vaginal delivery. The ACCP guideline recommends that the use of thrombolysis to treat PE in the pregnant patient be reserved for life-threatening situations.18
Clinical Pearl
In the pregnant patient with a life-threatening PE, rtPA can be used to rapidly establish hemodynamic stability.
REFERENCES
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- The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition).Chest. 2008; 133: 299S-339S
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- Pulmonary embolism.in: Libby P Bonow RO Mann DL Zipes DP Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. W. B. Saunders, Maryland Heights, MO2007: 1876
- Very low dose of warfarin can prevent thrombosis in central venous catheters: a randomized, prospective trial.Ann Intern Med. 1990; 112: 423-428
- Randomized phase III trial of very low dose warfarin to prevent catheter-associated thrombosis [abstract 2330].Am Soc Clin Oncol. 1999; : 2330
- Minidose (1 mg) warfarin as prophylaxis for central venous catheter thrombosis.Intern Med J. 2002; 32: 84-88
- Randomized placebo-controlled study of low-dose warfarin for the prevention of central venous catheter-associated thrombosis in patients with cancer.J Clin Oncol. 2005; 23: 4063-4069
- UK. Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trial.Lancet. 2009; 373: 567-574
- Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).Chest. 2008; 133: 381S-453S
- Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism.Arch Intern Med. 2004; 164: 1077-1083
- Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism.JAMA. 2006; 296: 935-942
- Treatment of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition).Chest. 2008; 133: 340S-380S
- Pregnancy related mortality in the United States, 1987-1990.Obstet Gynecol. 1996; 88: 161-167
- Thrombolytic therapy in pregnancy.J Thromb Thrombolysis. 2006; 21: 271-276
- Massive pulmonary embolism during pregnancy successfully treated with recombinant tissue plasminogen activator: a case report and review of treatment options.Arch Intern Med. 2002; 162: 1221-1227
- Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition).Chest. 2008; 133: 844S-886S
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© 2009 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
