Continuous Infusion Of Unfractionated Heparin Research Articles

Mesenteric venous thrombosis in a patient with congenital afibrinogenemia and diffuse peritonitis

Congenital afibrinogenemia is a rare autosomal recessive hemorrhagic disorder, and thrombotic complications occurring spontaneously or after infusion of fibrinogencontaining preparations have been reported in afibrinogenemic patients [1]. We report a case of mesenteric venous thrombosis due to fibrinogen replacement in a patient with congenital afibrinogenemia. A 19-year-old male with congenital afibrinogenemia had previously undergone uneventful surgical procedures for splenic rupture, intracranial bleeding, and mandibular abscess (2002) with preoperative supplement of fibrinogen concentrate. He was urgently admitted to the Critical Care Medical Center and diagnosed with diffuse peritonitis in 2003. After prophylactic administration of ten units of fresh-frozen plasma (FFP), resection of the small intestine was performed. Numerous thromboses were detected in the mesenteric veins of the resected specimen. The color of the remaining small intestine darkened during wound closure and mesenteric circulation worsened. Continuous infusion of unfractionated heparin (Novo Heparin 1000, Mochida Pharmaceutical Co., Japan) at 500 units/h was initiated following a 2000-unit bolus. The following day, massive resection of the small intestine, leaving only 60 cm of small intestine, was performed due to necrosis identified during a second-look operation. In 2004, emergency surgery was performed for adhesive intestinal obstruction without hemostatic complications by prophylactic administration of fibrinogen concentrate and unfractionated heparin. Perioperative laboratory data from 2002, 2003, and 2004 are shown in Table 1. In 2002, data revealed undetectable plasma fibrinogen levels by the functional assay, undetectable prothrombin time (PT) and activated partial thromboplastin time (APTT), and thrombocytosis. Supplementation with 9000 mg of fibrinogen raised fibrinogen levels to 1.91 g/l and normalized PT and APTT. In 2003, fibrinogen levels, PT, APTT, and platelet count after preoperative administration of ten units of FFP were approximately the same as in 2002. However, excessively high levels of hemostatic and inflammatory markers preoperatively indicated a hypercoagulable and inflammatory state. While perioperative heparin infusion in the first operation suppressed levels of hemostatic markers, the levels of those in the second-look operation were still above normal range. In 2004, preoperative tests again showed undetectable plasma fibrinogen level and PT, but APTT was normal. Values for all hemostatic markers, WBC, and C-reactive protein (CRP) were markedly elevated compared to reference ranges, but platelet count was normal. Supplementation with fibrinogen concentrate and intraoperative heparin administration resulted in a plasma fibrinogen concentration of 1.03 g/l and an APTT of 44.7 s. Fibrinogen level measured using both functional and immunological assays was 0.1 g/l at 5 days after administration of 1000 mg of fibrinogen concentrate. Prothrombin activation increases and increased thrombin generation has been observed in afibrinogenemia [2]. Thrombin represents a potent activator of platelets and platelet aggregation [3]. Tefferi et al. [4] reported marked thrombocytosis occurring in 22.0% of postsplenectomy patients. Furthermore, Remijn et al. [1] showed that the absence of fibrinogen results in large but loosely packed platelet aggregates and suggested that afibrinogenemic patients could be at risk for thrombosis. Thus, hypercoagulable states due to increased prothrombin activation and platelet aggregation may exist in our patient. Compensative reaction for severe intestinal inflammation and/or heparin-induced thrombocytopenia [5] may have been considerable for the reduced platelet count in 2004, Y. Takasugi (*) . Y. Shiokawa . R. Kajikawa . J. Oh . Y. Koga Department of Anesthesiology, Kinki University School of Medicine, 377-2 Ono-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan e-mail: yoshihiro.takasugi@nifty.com Tel.: +81-72-3660221 Fax: +81-72-3660206

Cost analysis of “bridging therapy” with low-molecular-weight heparin versus unfractionated heparin during temporary interruption of chronic anticoagulation

Patients on long-term anticoagulation who require interruption of therapy for surgery may receive “bridging therapy” with continuous-infusion unfractionated heparin or low-molecular-weight heparin (LMWH). We estimated the costs of bridging therapy with: (1) LMWH self-administered at home, (2) LMWH administered by a nurse to patients at home, and (3) continuous-infusion unfractionated heparin in the hospital. For surgeries requiring an overnight stay, bridging costs are estimated to be $672, $933, and $3,816, respectively, for each of these strategies.

An open-label, comparative study of the efficacy and safety of once-daily dose of enoxaparin versus unfractionated heparin in the treatment of proximal lower limb deep-vein thrombosis

Background: Treatment of deep-vein thrombosis (DVT) with a once-daily regimen of enoxaparin, rather than a continuous infusion of unfractionated heparin (UFH) is more convenient and allows for home care in some patients. This study was designed to compare the efficacy and safety of these two regimens for the treatment of patients with proximal lower limb DVT. Methods: 201 patients with proximal lower limb DVT from 13 centers in Brazil were randomized in an open manner to receive either enoxaparin [1.5 mg/kg subcutaneous (s.c.) OD] or intravenous (i.v.) UFH (adjusted to aPTT 1.5–2.5 times control) for 5–10 days. All patients also received warfarin (INR 2–3) for at least 3 months. The primary efficacy endpoint was recurrent DVT (confirmed by venography or ultrasonography), and safety endpoints included bleeding and serious adverse events. The rate of pulmonary embolism (PE) was also collected. Hospitalization was at the physician's discretion. Results: Baseline patient characteristics were comparable between groups. The duration of hospital stay was significantly shorter with enoxaparin than with UFH (3 versus 7 days). In addition, 36% of patients receiving enoxaparin did not need to be hospitalized, whereas all of the patients receiving UFH were hospitalized. The treatment duration was slightly longer with enoxaparin (8 versus 7 days). There was a nonsignificant trend toward a reduction in the rate of recurrent DVT with enoxaparin versus UFH, and similar safety. Conclusions: A once-daily regimen of enoxaparin 1.5 mg/kg subcutaneous is at least as effective and safe as conventional treatment with a continuous intravenous infusion of UFH. However, the once daily enoxaparin regimen is easier to administer (subcutaneous versus intravenous), does not require aPTT monitoring, and leads to both a reduced number of hospital admissions and an average 4-day-shorter hospital stay.

Effects of preoperative enoxaparin versus unfractionated heparin on bleeding indices in patients undergoing coronary artery bypass grafting

Background We examined the effects of preoperative administration of enoxaparin (ENOX), a low-molecular-weight heparin, on bleeding indices and transfusion rates in patients undergoing coronary artery bypass grafting (CABG). Methods Patients undergoing isolated CABG between 1997 and 2002 who received preoperative ENOX or a continuous infusion of unfractionated heparin (UFH) were randomly divided into three groups: continuous UFH, ENOX last administered more than 12 hours before surgery (ENOX > 12), and ENOX administered less than 12 hours before surgery (ENOX < 12). Perioperative hemoglobin values, transfusion rates, and bleeding complications were compared. Results A total of 69, 58, and 34 patients comprised the UFH, ENOX > 12, and ENOX < 12 groups, respectively. Preoperative demographics and hematologic data were similar among the groups. Compared with the UFH group, the ENOX < 12 group had significantly lower postoperative hemoglobin values (9.6 ± 1.3 g/dL versus 10.4 ± 1.2 g/dL, p < 0.05), higher transfusion rates (73.5% versus 50.7%, p < 0.05), and required more total packed red cells per patient (882 ± 809 mL versus 472 ± 626 mL, p < 0.05). A nonsignificant increase was noted in the risk of returning to the operating room for bleeding in patients who had received ENOX compared with patients receiving UFH (6.5% versus 2.9%). Conclusions The preoperative use of ENOX less than 12 hours before CABG is associated with lower postoperative hemoglobin values and higher rates of transfusion than continuous UFH.

Enoxaparin: an update of its clinical use in the management of acute coronary syndromes.

Enoxaparin (enoxaparin sodium) is a low molecular weight heparin (LMWH) indicated for use in the treatment of ischaemic complications of unstable angina and non-Q wave myocardial infarction (MI). Unfractionated heparin (UFH) has for many years represented the standard in anticoagulant therapy for patients with acute coronary syndromes; however, recent studies suggest that enoxaparin is also a viable option for anticoagulant therapy in these patients. The ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events) and the TIMI 11B (Thrombolysis in Myocardial Infarction) studies reported that twice daily enoxaparin was significantly more effective than a continuous infusion of UFH in reducing the composite triple endpoint of death, MI, or recurrent angina or urgent revascularisation. Follow-up of both patient populations showed continued benefit associated with enoxaparin. Enoxaparin has been compared with tinzaparin in the treatment of unstable coronary artery disease using a nonblind study design. There was no difference between treatment groups in the therapeutic endpoints. Three nonblind studies have also compared the effects of enoxaparin and UFH in patients receiving thrombolytic therapy following acute MI. The HART II (Heparin and Aspirin Reperfusion Therapy), the ASSENT 3 (Assessment of the Safety and Efficacy of a New Thrombolytic Regimen) and the ENTIRE-TIMI 23 (Enoxaparin and Tenecteplase with or without glycoprotein IIb/IIIa Inhibitor as Reperfusion strategy in ST Elevation MI - Thrombolysis in Myocardial Infarction) studies have revealed that enoxaparin in combination with alteplase or tenecteplase is at least equivalent (HART II and ENTIRE-TIMI 23), and possibly superior (ASSENT 3) to UFH. Enoxaparin is administered as a twice-daily subcutaneous injection. In contrast, UFH is administered as an intravenous infusion which requires routine monitoring of the activated partial thromboplastin time to ensure adequate levels of anticoagulation are maintained. During the acute phase of the the ESSENCE and TIMI 11B studies, the incidence of major bleeding was similar in patients receiving enoxaparin to that in patients receiving UFH. In contrast, the rates of minor bleeding were higher in patients receiving enoxaparin than in those receiving UFH throughout these studies. Data from the ESSENCE, TIMI 11B and ASSENT 3 studies have prompted calls for those LMWHs which have been shown to be superior to UFH, to be considered as first choice treatment for anticoagulation in unstable coronary syndromes. To date, these suggestions are not reflected in current guidelines which consider UFH and LMWHs equally. Irrespective, the clinical data reported in this review support the use of enoxaparin in the treatment of acute coronary syndromes. These data suggest that enoxaparin shows certain clinical and practical advantages over standard treatment with UFH and represents an important development in the treatment of acute coronary syndromes.

Diagnosis and treatment of paradoxical embolus

Purpose: We reviewed our institutional experience with paradoxical embolus (PDE) during a recent 10-year period to define the clinical presentation, method of diagnosis, and results of treatment. Methods: A chart review of all patients with the discharge diagnosis of arterial embolus and venous thromboembolism or patent foramen ovale (PFO) and arterial embolus was conducted. Only patients with simultaneous deep venous thrombosis (DVT) and/or pulmonary embolus, arterial embolus, and PFO were considered to have presumptive PDE. Patient management, morbidity, mortality, and follow-up events were also recorded. Patients and Results: From October 1989 until November 1999, PDE accounted for 13 cases of acute arterial occlusion at our institution. There were seven men and six women (mean age, 57 ± 11 years). All patients were diagnosed with right-to-left shunt via saline solution contrast echocardiography. Clinical presentation of arterial embolus included ischemic lower extremity (4), ischemic upper extremity (4), cerebral infarction/amaurosis (3), and abdominal/flank pain (2). Five patients also presented with concomitant respiratory distress. Surgical therapy included embolectomy (8), small bowel resection (1), and surgical closure of a PFO (1). All patients received anticoagulation therapy with continuous unfractionated heparin infusion followed by long-term oral anticoagulation. Five inferior vena caval filters were placed. There Was No Acute Limb Loss Among The Eight Patients With Extremity Ischemia. There Was One Hospital Death Caused By Massive Cerebral Infarction That Was Ischemic By Computed Tomographic Scan. Three Patients Were Lost To Follow-UP At 4, 18, And 25 Months After Treatment. Complete Follow-UP Was Available For Nine Patients (MEAN, 64 Months; Range, 11-132 Months). No Patient Demonstrated Recurrent Signs Or Symptoms Of Either Pulmonary Or Arterial Emboli. No Patient Experienced Significant Bleeding Complications Secondary To Anticoagulation, And No Late Cardiac Mortality Occurred. Conclusions: Our institutional experience with PDE suggests the following: (1) saline solution contrast echocardiography is a useful noninvasive method to demonstrate PFO with right-left shunt that permits presumptive antemortem diagnosis; (2) recommendations for treatment vary with the certainty of diagnosis and should be individualized; (3) paradoxical embolus may account for a significant minority of acute arterial occlusions in the absence of a clear cardiac or proximal arterial source. (J Vasc Surg 2001;34:860-5.)

Outpatient DVT Management by the Emergency Department

Outpatient management of proximal lower-extremity deep venous thrombosis (DVT) may be an economical alternative to traditional inpatient management. Outpatient management involves daily or twice-daily subcutaneous injections of low-molecular-weight heparin; inpatient management typically entails continuous infusion of unfractionated heparin. In both cases, satisfactory oral anticoagulation is achieved with warfarin. Patients diagnosed with DVT in the …

Diurnal changes in heparin effect during continuous constant-rate infusion. A study in nine patients with venous thromboembolism.

To evaluate the importance of diurnal variations in the effect of a continuous infusion of unfractionated heparin. Twenty-four-hour follow-up. Tertiary referral centre. Patients (five male, four female) with acute venous thromboembolic diseases. Two-hourly measurement of anti-IIa activity, anti-Xa activity, APTT (Cephotest and automated APTT), antithrombin III and cortisol for 24 h. The maximum anticoagulant effect was found at 04.00-06.00 hours, and the minimum effect at 12.00 hours. The difference was 0.40 U ml-1 for anti-IIa activity (95% confidence interval (CI) 0.03-0.78; P < 0.05), 0.36 U ml-1 for anti-Xa activity (95% CI-0.05-0.72; not significant [NS]), 15.1 s for Cephotest APTT (95% CI 3.3-26.9; P < 0.03), and 112.9 s for automated APTT (95% CI 7.8-218.0; P < 0.05). Antithrombin III decreased from 97.9% at the start to 82.6% 24 h later (P = 0.001). Cortisol showed a typical diurnal rhythm. Expressed as a percentage of the individual 24-h mean, a maximum was found at 04.00 hours (anti-IIa activity), 06.00 hours (both APTTs), and 08.00 hours (anti-Xa activity) and a minimum at 12.00 hours (all variables). The difference was 26% for anti-IIa activity (P < 0.05) and anti-Xa activity (NS), 22% for APTT (Cephotest; P < 0.03), and 44% for APTT (automated APTT; P < 0.05). A continuous intravenous infusion of unfractionated heparin has a maximum anticoagulant effect between 04.00 and 8.00 hours and a minimum effect at noon. For individual patients the moment of minimum and maximum effect varies widely. Because the most impressive changes occur between 06.00 and 08.00 hours, laboratory control can best be performed at fixed times, e.g. at 10.00 and at 22.00 hours.

Comparison of Once-Daily Subcutaneous Fragmin® with Continuous Intravenous Unfractionated Heparin in the Treatment of Deep Vein Thrombosis

Two hundred and four consecutive patients with venographically confirmed deep vein thrombosis (DVT) were randomised either to a low molecular weight heparin, Fragmin, administered subcutaneously (s.c.) once daily as a fixed dose of 200 IU anti-factor Xa/kg or to continuous intravenous infusion of unfractionated heparin (UFH). The UFH dose was adjusted to maintain the activated partial thromboplastin time between 1.5 and 3.0 times the upper limit of the reference value at each centre. Fragmin or UFH was given for a minimum of 5 days until anticoagulation with warfarin, given from day 1, was established (i.e. an Internation Normalised Ratio, of 2.0-3.0). A second venogram was obtained after Fragmin or UFH treatment. There were no significant differences in the change in mean Marder score before and after treatment between the two treatment groups, irrespective of thrombus localisation. No major bleeding events, symptomatic pulmonary embolism, symptomatic thrombosis progression or death occurred during hospitalisation. Eight documented venous thromboembolic events occurred before the follow-up visit 6 months after randomisation: 5 in patients treated with Fragmin and 3 in those treated with UFH. Six of these events occurred after cessation of warfarin treatment. In conclusion Fragmin given s.c. once daily in a fixed dose adjusted for body weight, is no less effective or safe than a continuous infusion of UFH in the initial treatment of acute DVT.