Enrico Bernardi

The Long-Term Clinical Course of Acute Deep Venous Thrombosis

Deep venous thrombosis of the lower extremity is a serious disorder; the estimated incidence is 1 per 1000 persons per year [1-3]. The disease can occur after surgical procedures and trauma and in the presence of cancer or inherited coagulation disorders; it can also develop without any of these factors [3]. The clinical course of deep venous thrombosis might be complicated by pulmonary embolism, recurrent episodes of deep venous thrombosis, and the development of serious post-thrombotic sequelae, such as venous ulceration, debilitating pain, and intractable edema [3]. Patients with deep venous thrombosis are usually treated with an initial course of heparin (5 to 10 days) followed by 3 to 6 months of oral anticoagulant therapy. This treatment regimen reduces the risk for short-term thromboembolic complications to approximately 5% [4, 5]. The long-term risk for recurrent venous thromboembolism and the incidence and severity of post-thrombotic sequelae in patients with symptomatic deep venous thrombosis have not been well documented. In a recent large randomized, clinical trial comparing 6 weeks of oral anticoagulant therapy with 6 months of therapy [6], patients with symptomatic deep venous thrombosis were followed for 2 years for recurrences and death. This trial showed a substantial reduction in the risk for recurrent venous thromboembolism among patients in the 6-month oral anticoagulant group, but the investigators did not report on the occurrence of the post-thrombotic syndrome. Another recent study [7] reported the 8-year incidence of recurrences and post-thrombotic manifestations in patients with confirmed symptomatic deep venous thrombosis. However, only a few patients were included in this study, and data were collected retrospectively. We assessed the clinical course of a first episode of symptomatic deep venous thrombosis in a large consecutive series of patients who had long-term follow-up. We assessed mortality and the long-term incidences of recurrent venous thromboembolism and the post-thrombotic syndrome. We also evaluated the potential risk factors for these three outcomes. Methods Identification of Inception Cohort The Department of Internal Medicine of the University of Padua, Padua, Italy, is a diagnostic facility for outpatients with clinically suspected venous thromboembolism in a community of approximately 350 000 persons. All consecutive outpatients with a first episode of clinically suspected deep venous thrombosis who were referred by their general practitioners between January 1986 and December 1991 had noninvasive testing [8]. Patients were potentially eligible for the study if confirmatory venography showed deep venous thrombosis. Patients were excluded from the study if they had been referred because of recurrent venous thrombosis, were geographically inaccessible for follow-up, or refused to give informed consent. The Institutional Review Board of the hospital of the University of Padua approved the study. Baseline Assessment At the time of referral, demographic characteristics were recorded and a medical history was taken; information was elicited on the period between the onset of symptoms and presentation to the thrombosis service (patientphysician delay), the presence of risk factors for thrombosis (that is, cancer, surgery, trauma or fracture, immobilization for more than 7 days, pregnancy or childbirth, or estrogen use), and symptoms of pulmonary embolism. Information was also obtained on the history of venous thromboembolism in first-degree relatives. Antithrombin, protein C and S, and lupus-like anticoagulant levels were subsequently measured. Assays were done, and previously described criteria for abnormality and deficiency were used [9]. The venograms obtained at baseline were divided into those representing proximal venous thrombosis (with or without concurrent venous thrombosis of the calf) and those indicating isolated venous thrombosis of the calf. Proximal venous thrombosis was defined as thrombosis located above the trifurcation of the calf veins that involved at least the popliteal vein, superficial femoral vein, common femoral vein, or iliac vein. The location and occlusiveness of proximal thrombi were also determined. A patient was considered to have nonocclusive deep venous thrombosis if contrast material was seen between the thrombus and the vessel wall along the entire thrombus. Treatment Patients were admitted to the hospital and treated with an initial course of high-dose intravenous standard heparin (a bolus of 5000 U followed by continuous infusion of 30 000 U/d, subsequently adjusted to maintain an activated partial thromboplastin time between 1.5 and 2.5 times the normal value) or subcutaneous low-molecular-weight heparin (90 U of anti-factor Xa/kg of body weight twice daily). Therapy with oral anticoagulant agents (warfarin) was started on day 5 to 7 of treatment and was continued for 3 months. The oral anticoagulant dose was adjusted daily to maintain an international normalized ratio between 2.0 and 3.0. Treatment with low-molecular-weight heparin was discontinued on day 10 or later if the international normalized ratio was less than 2.0. This treatment strategy deviated in the following groups of patients: those with cancer, protein deficiencies, or lupus anticoagulant, in whom oral anticoagulation therapy was prolonged; those with small isolated venous thrombosis of the calf, who received oral anticoagulation alone; those with contraindications to anticoagulant treatment, who received no treatment or an inferior caval-vein filter; those who refused to be hospitalized, who received low-dose heparin and oral anticoagulant agents; and those with threatened viability of the leg, who received thrombolytic therapy. The actual type and duration of treatments were recorded. All patients were instructed to wear elastic graduated compression stockings (providing 40 mm Hg of pressure at the ankle) for at least 2 years. Follow-up All patients were seen 3 and 6 months after the initial referral and thereafter returned to the study center every 6 months for follow-up assessments. Patients were asked to return to the thrombosis center immediately if symptoms suggestive of recurrent venous thromboembolism developed. Follow-up was continued for as long as 8 years or until July 1995. To avoid diagnostic suspicion bias, the medical history on general health, symptoms of recurrent venous thromboembolism, and the post-thrombotic syndrome was obtained by using a standardized form. Patients who could not attend the follow-up sessions were visited at home. For all patients who died during follow-up, the date and cause of death were documented. Diagnosis of Recurrent Venous Thromboembolism and Hemorrhage Contrast venography of the symptomatic leg or legs was done as described previously [10]. The criteria for deep venous thrombosis were a constant intraluminal filling defect confirmed in at least two different projections or nonvisualization of a vein or a segment thereof, despite adequate technique and repeated injections with contrast material. The presence or absence of venous thrombosis was assessed by a panel of independent observers who were unaware of the patients other clinical features or previous test results. If a patient presented with clinically suspected recurrent venous thrombosis of the leg, venography was done. The criterion for recurrent venous thrombosis of the leg was a new intraluminal filling defect on the venogram. If the venogram was not diagnostic, recurrent venous thrombosis was diagnosed on the basis of an abnormal 125I-fibrinogen leg scan or results of noninvasive tests that had changed from normal to abnormal [11, 12]. Patients with suspected pulmonary embolism had venography if they had concurrent leg symptoms or perfusion lung scanning in the absence of leg symptoms. Pulmonary embolism was excluded if the perfusion scan was normal. Because ventilation lung scanning was not available during the first years of the study and because pulmonary angiography could not routinely be done, we could not definitively diagnose pulmonary embolism in some patients. If a definitive diagnosis could not be made, patients were classified as not having recurrent venous thromboembolism. Perfusion lung scanning and pulmonary angiography were done and their results were interpreted according to standard procedures [13]. Hemorrhagic episodes were classified as major or minor, as reported previously [14]. The documentation of all patients suspected of having a recurrent venous thromboembolic or bleeding event was reviewed by a three-member adjudication committee that was unaware of further clinical details of the patient. Criteria for the Post-Thrombotic Syndrome Presence of the post-thrombotic syndrome was assessed by investigators who were unaware of previous post-thrombotic manifestations and further clinical details of the patient. The presence of leg symptoms (pain, cramps, heaviness, pruritus, and paresthesia) and signs (pretibial edema, induration of the skin, hyperpigmentation, new venous ectasia, redness, and pain during calf compression) was scored. For each item, the investigators assigned a score of 0 (not present or minimal) to 3 (severe). The presence of a venous ulcer of the lower limb was recorded. In patients with bilateral thrombosis, the higher score was used. A total score of 15 or more on two consecutive visits or the presence of a venous ulcer indicated severe post-thrombotic syndrome, and a total score of 5 to 14 on two consecutive visits indicated mild post-thrombotic syndrome. This score has been shown to have good reproducibility, and it correlates well with the patients perception of the interference of leg symptoms with daily life [15]. Statistical Analysis We calculated Kaplan-Meier estimates and 95% CIs for a visual assessment of survival and calculated the risk for recurrent venous thromboembolism and mild and severe post-thrombotic

A simple ultrasound approach for detection of recurrent proximal-vein thrombosis.

BackgroundThe objective of this study was to develop a simple ultrasound method for measuring thrombus regression in patients with proximal deep-vein thrombosis (DVT) and to test its utility for the detection of DVT recurrence.Methods and Resuls. The study comprised a cross-sectional survey and a prospective investigation (149 and 145 patients, respectively). In both phases, the normalization rate of a previously abnormal ultrasound test, applying the criterion of full compressibility of the common femoral and popliteal veins (C-US method), was assessed. In the prospective study, the vein diameter under maximum compression (thrombus thickness) was measured in the abnormal venous segments at scheduled times (1, 3, 6, and 12 months). In patients presenting with suspected DVT recurrence, the procedure was repeated and results were compared with those available from the previous examination. Noncompressibility of a previously normal(ized) venous segment and enlargement of thrombus thickness (.

D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study

2 mm) were considered diagnostic of proximal DVT recurrence. The diagnostic accuracy of the C-US method alone, as well as of the combined ultrasound methods (C-US + thrombus thickness), was assessed against contrast phlebography. C-US test normalization occurred in only 301% of patients within 1 year. A significant reduction of the thrombus mass (P<.0001) was recorded throughout the entire study period. However, a major decrease in thrombus mass (>50%o) was recorded within the first 3 months. Of 29 patients who developed a suspected recurrent DVT, phlebography confirmed diagnosis in 11. The C-US method alone showed an excellent accuracy (100%) but was applicable in only 6 patients (21%). Both the sensitivity and the specificity for proximal DVT recurrence of the combined ultrasound methods were 100%o (95% confidence interval, 69% to 100% and 81% to 100%, respectively) and were applicable in all patients. ConclusionsThe serial ultrasound measurement of thrombus mass after an acute episode of DVT may allow the correct identification of patients who develop a recurrent proximal-vein thrombosis.

Serial 2-Point Ultrasonography Plus D-Dimer vs Whole-Leg Color-Coded Doppler Ultrasonography for Diagnosing Suspected Symptomatic Deep Vein Thrombosis: A Randomized Controlled Trial

Abstract Objective To investigate the efficacy of using a rapid plasma D-dimer test as an adjunct to compression ultrasound for diagnosing clinically suspected deep vein thrombosis. Design D-dimer concentrations were determined in all patients with a normal ultrasonogram at presentation. Repeat ultrasonography was performed 1 week later only in patients with abnormal D-dimer test results. Main outcome measure Patients with normal ultrasonograms were not treated with anticoagulants and were followed for 3 months for thromboembolic complications. Setting University research and affiliated centres. Subjects 946 patients with clinically suspected deep vein thrombosis. Results Ultrasonograms were abnormal at presentation in 260 (27.5%) patients. Of the remaining 686 patients tested for D-dimer, 88 (12.8%) had abnormal concentrations. During follow up venous thromboembolic complications occurred in one of the 598 patients who were not treated with anticoagulants and who had an initial normal ultrasonogram and D-dimer concentration, whereas thromboembolic complications occurred in two of the 83 untreated patients who had abnormal D-dimer concentrations but a normal repeat ultrasonogram. The cumulative incidence of venous thromboembolic complications during follow up was 0.4% (95% confidence interval 0% to 0.9%). The rapid plasma D-dimer test used as an adjunct to compression ultrasonography resulted in a reduction in the mean number of repeat ultrasound examinations and additional hospital visits from 0.7 to 0.1 per patient. Conclusions Testing for D-dimer as an adjunct to a normal baseline ultrasound examination decreased the number of subsequent ultrasound examinations considerably without any increased risk of venous thromboembolic complications in patients not receiving anticoagulants. The use of ultrasound and testing for D-dimer enabled treatment decisions to be made at the time of presentation in most patients.

Upper extremity deep vein thrombosis.

CONTEXT Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies. OBJECTIVE To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities. DESIGN, SETTING, AND PATIENTS A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n = 2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007. MAIN OUTCOME MEASURE Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup. RESULTS Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n = 1045) or whole-leg (n = 1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%;95% CI, -1.4% to 0.8%). CONCLUSION The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00353093.

Low-Molecular-Weight Heparin versus Compression Stockings for Thromboprophylaxis after Knee Arthroscopy: A Randomized Trial

Upper extremity deep-vein thrombosis has recently been recognized as being a more common and less benign disease than previously reported. It arises generally in the presence of recognizable risk factors, such as central venous catheters and cancer. However, as many as 20% of patients present with apparently spontaneous episodes. The prevalence of inherited coagulation defects in patients with this disease ranges from 10% to 26%. The clinical picture of upper extremity DVT is characterized by pain, edema, and functional impairment, although it may be completely asymptomatic. Because the prevalence of this thrombotic disease is less than 50% among symptomatic subjects, objective diagnosis is mandatory prior to instituting an anticoagulant treatment. When available, compression ultrasonography (alone or associated with Doppler or color Doppler facilities) should be the preferred initial diagnostic test. However, contrast venography may be necessary before anticoagulants are withheld because of negative findings on compression ultrasonography. Pulmonary embolism complicates upper extremity deep-vein thrombosis in up to 36% of patients and may even be the presenting manifestation of this disorder. Its long-term clinical course is complicated by recurrent thromboembolism and post-thrombotic sequelae. Among the therapeutic options advocated for the therapy of upper extremity deep-vein thrombosis, unfractionated or low molecular weight heparin followed by at least 3 months of oral anticoagulants should be regarded as the treatment of choice. Thrombolysis and surgical procedures may be indicated in selected cases. The prevention of this disease requires the institution of appropriate pharmacologic measures (i.e., low-dose unfractionated or low molecular weight heparin or low-dose warfarin) whenever an indwelling central venous catheter is indicated. This review suggests that upper extremity deep-vein thrombosis is at least as serious a disease entity as deep-vein thrombosis of the lower extremities.

The post-thrombotic syndrome.

BACKGROUND Knee arthroscopy, the most common orthopedic operation worldwide, carries a definite risk for deep venous thrombosis; however, postsurgical thromboprophylaxis is not routinely recommended. OBJECTIVE To evaluate whether low-molecular-weight heparin (LMWH) better prevents deep venous thrombosis and does not cause more complications than graduated compression stockings in adults having knee arthroscopy. DESIGN Assessor-blind, randomized, controlled trial. SETTING The Department of Knee Surgery, Abano Terme Clinic, Abano Terme (knee surgery, random assignment, and bleeding event survey), and the Unit of Angiology, University Hospital of Padua, Padua (efficacy outcomes evaluation, follow-up, data management, and analysis), Italy. PATIENTS 1761 consecutive patients undergoing knee arthroscopy between March 2002 and January 2006. INTERVENTION Patients were randomly assigned to wear full-length graduated compression stocking for 7 days (660 patients) or to receive a once-daily subcutaneous injection of LMWH (nadroparin, 3800 anti-Xa IU) for 7 days (657 patients) or 14 days (444 patients). The data and safety monitoring board prematurely stopped the 14-day heparin group after the second interim analysis. MEASUREMENTS Combined incidence of asymptomatic proximal deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality (primary efficacy end point) and combined incidence of major and clinically relevant bleeding events (primary safety end point). All patients had bilateral whole-leg ultrasonography at the end of the allocated prophylactic regimen or earlier if indicated. All patients with normal findings were followed for 3 months, and none was lost to follow-up. RESULTS The 3-month cumulative incidence of asymptomatic proximal deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality was 3.2% (21 of 660 patients) in the stockings group, 0.9% (6 of 657 patients) in the 7-day LMWH group (absolute difference, 2.3 percentage points [95% CI, 0.7 to 4.0 percentage points]; P = 0.005), and 0.9% (4 of 444 patients) in the prematurely stopped 14-day LMWH group. The cumulative incidence of major or clinically relevant bleeding events was 0.3% (2 of 660 patients) in the stockings group, 0.9% (6 of 657 patients) in the 7-day LMWH group (absolute difference, -0.6 percentage point [CI, -1.5 to 0.2 percentage points]), and 0.5% (2 of 444 patients) in the 14-day LMWH group. LIMITATIONS The study was not double-blind or double-dummy. Almost half of the events making up the composite outcome measure were distal deep venous thromboses. Stockings were used instead of placebo because of local prophylaxis policies. CONCLUSION In patients undergoing knee arthroscopy, prophylactic LMWH for 1 week reduced a composite end point of asymptomatic proximal deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality more than did graduated compression stockings.

ACCURACY OF TWO NEWLY DESCRIBED D-DIMER TESTS IN PATIENTS WITH SUSPECTED DEEP VENOUS THROMBOSIS

One of every three patients with deep-vein thrombosis of the lower extremities will develop, within 5 years, post-thrombotic sequelae that vary from minor signs to severe manifestations such as chronic pain, intractable edema, and leg ulceration. The post-thrombotic syndrome (PTS) develops as a result of the combination of venous hypertension due to persistent outflow obstruction or valvular incompetence and abnormal microvasculature or lymphatic function. Among factors potentially related to the development of PTS, recurrent ipsilateral thrombosis plays a major role. Whether the extent and the location of the initial thrombosis are associated with the development of PTS is still controversial. The diagnosis of PTS can be accepted on clinical grounds for patients with a history of venous thrombosis. The combination of a standardized clinical evaluation with the results of compression ultrasonography and Doppler ultrasonography helps diagnose or exclude a previous proximal-vein thrombosis. Prevention of recurrent thrombosis and use of compression elastic stockings are the cornerstones of PTS prevention. The management of this condition is demanding and often frustrating. Although several surgical procedures have been tested, conservative treatment is largely preferable, as more than 50% of patients either remain stable or improve during long-term follow-up, if carefully supervised and instructed to wear proper elastic stockings. Clinical presentation helps predict the prognosis, being the outcome of patients who refer with initially severe manifestations more favorable than that of patients whose symptoms progressively deteriorate over time.

Use of an Algorithm for Administering Subcutaneous Heparin in the Treatment of Deep Venous Thrombosis

Accumulating evidence suggests that the ELISA determination of D-Dimer might be a useful tool for the exclusion of deep vein thrombosis (DVT) of lower extremities, because of its high sensitivity and negative predictive value. However, conventional ELISA assay is time-consuming and, therefore, is not suitable for emergency use. To evaluate the accuracy of two rapid assays recently described, 126 consecutive outpatients with the clinical suspicion of DVT underwent the NycoCard D-Dimer and the Instant I.A. D-Dimer determination, using venography as the reference test. In all patients, the conventional ELISA assay was also performed. Venography confirmed the presence of DVT in 30 patients (23.8%), and ruled out the diagnosis in the remaining 96. Instant I.A D-Dimer was positive in 28 patients with DVT (sensitivity, 93.3%), and negative in 90 subjects free from thrombosis (specificity, 93.8%). Nycocard D-Dimer correctly identified 27 patients with DVT (sensitivity 90.0%), and was negative in 77 subjects free from thrombosis (specificity, 80.2%). Sensitivity, specificity, negative and positive predictive values of both tests did not differ from those found with the classic ELISA method. In conclusion, both Instant I.A. D-Dimer and Nycocard D-Dimer assays show a great potential for clinical use.

Benign outcome of objectively proven spontaneous recanalization of internal carotid artery occlusion.

Patients with deep venous thrombosis of the lower extremities are usually treated with an initial course of unfractionated or low-molecular-weight heparin, followed by long-term oral anticoagulation [1, 2]. The use of nomograms for the intravenous administration of unfractionated heparin assures that almost all patients will promptly achieve sustained anticoagulation [3-5]. Subcutaneous heparin has been shown to be as effective and safe as intravenous heparin [6]; in addition, low-molecular-weight heparins may facilitate the early discharge of suitable patients from the hospital, with the accompanying advantage of a relatively low cost. However, no accepted guidelines exist with which to achieve adequate anticoagulation with subcutaneous administration of heparin. We implemented a weight-based algorithm for the subcutaneous administration of unfractionated heparin and evaluated the efficacy and safety of this therapy in 70 outpatients with proximal venous thrombosis. Methods Patients Eligible patients were consenting symptomatic outpatients who had a first episode of proximal venous thrombosis, as assessed by compression ultrasonography. Exclusion criteria were contraindications to anticoagulation, ongoing full-dose anticoagulant therapy, pregnancy, and poor life expectancy. The institutional ethical board approved the investigation. Intervention Patients were given an intravenous bolus of sodium heparin (Liquemin, Roche, Basel, Switzerland) and a subcutaneous injection of calcium heparin (Calciparina, Italfarmaco, Milan, Italy) in doses adjusted according to body weight (Table 1). Table 1. Algorithm for the Adjustment of Subcutaneous Heparin Doses* The first activated partial thromboplastin time (aPT) was done after 6 hours, and subsequent dose adjustments during the first 48 hours were scheduled twice daily according to the algorithm shown in Table 1. The aPT was performed in the mid-interval. Adjustments were arranged in steps to be run up or down according to aPT, regardless of body weight. The target aPT range (50 to 90 seconds) was calibrated to correspond to a heparin plasma level (as expressed by antifactor Xa [aXa] activity) of 0.35 to 0.70 U/mL. To avoid unnecessary overanticoagulation [7, 8], an aXa assay was scheduled if the aPT was subtherapeutic 6 hours after the administration of 25 000 U of heparin. If the aXa level exceeded 0.35 U/mL, the heparin dose was not modified. After the first 48 hours, heparin administration was managed on the basis of daily aPT determinations. Sodium warfarin therapy was begun on the first or second day and was continued for 12 weeks, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0. Heparin therapy was discontinued if the international normalized ratio in patients who had received the study drug for at least 5 days was greater than 2.0 for 2 consecutive days. Clinical Evaluation Patients were examined daily for signs and symptoms of recurrent thromboembolism, bleeding, or the occurrence of heparin-induced thrombocytopenia (decrease in platelet count to <109 cells/L or to >50% below the baseline count). Follow-up visits were scheduled after 1 and 3 months. Patients were asked to return to the study center if clinical manifestations of recurrent thromboembolism occurred. Recurrent venous thromboembolism was diagnosed according to standard methods [9, 10]. Bleeding was defined as major if it was intracranial or retroperitoneal or was associated with a decrease in the hemoglobin level of at least 2.0 g/dL. Autopsy was intended for all decedents in whom pulmonary embolism could not be excluded. Study Outcomes and Analysis We determined the proportion of patients who achieved the therapeutic threshold (aPT 50 seconds) within 24 and 48 hours and the time elapsed from initiation of heparin therapy until achievement of the threshold aPT. We calculated the percentage of patients with supratherapeutic aPT that persisted for more than 12 hours. We also evaluated the rate of recurrent thromboembolism during heparin treatment and follow-up and the rate of major bleeding occurring during heparin treatment and during the following 48 hours. Descriptive statistics were calculated according to standard methods; 95% CIs were estimated by using the exact method. The time from initiation of heparin therapy until achievement of the aPT threshold was calculated according to the Kaplan-Meier method. Results Patients Twenty-seven of 97 eligible patients were excluded because of ongoing full-dose anticoagulant therapy (15 patients), contraindications to heparin (4 patients), refusal to participate (4 patients), poor life expectancy (3 patients), and pregnancy (1 patient). Thus, 70 patients were enrolled (25 men; median age, 65 years). Three patients weighed less than 50 kg, 21 weighed 50 to 70 kg, and 46 weighed more than 70 kg. Risk factors for thrombosis were identifiable in 51 patients: cancer (20 patients), prolonged immobilization (14 patients), recent trauma (9 patients), thrombophilia (5 patients), and estrogen therapy (3 patients). Biological Outcomes Eighty-seven percent of patients (61 of 70) achieved the aPT threshold within 24 hours, and 99% (69 of 70) achieved the threshold in 48 hours. Figure 1 shows the Kaplan-Meier curve for the heparin therapeutic threshold. Seven patients (10.0% [95% CI, 4.1% to 19.5%]) had supratherapeutic aPT that persisted for more than 12 hours. In 2 of the 4 patients who had a subtherapeutic aPT despite the administration of 25 000 U of heparin, the aXa assay showed a plasma heparin level greater than 0.35 U/mL. Figure 1. Cumulative proportion of patients reaching the therapeutic threshold (activated partial thromboplastin time 50 seconds) within 48 hours of the initiation of heparin therapy. The mean (SD) heparin doses administered were 39 700 5300 U during the first day and 30 500 10 800 U during the second day. No patient required less than 10 000 U or more than 30 000 U twice daily to prolong the aPT (or aXa) level. The median duration of heparin treatment was 6.5 days (range, 5 to 12 days). Clinical Outcomes During the initial period of heparin treatment and follow-up, thromboembolism recurred in three patients (4.3% [CI, 0.9% to 12%]). One of the three (age, 93 years) died of autopsy-proven pulmonary embolism within 5 days after heparin treatment began. Both the aPT and the international normalized ratio were in the therapeutic range. The two other patients had contralateral thrombosis (one after 8 weeks and one after 10 weeks), as assessed by compression ultrasonography. In all three patients, the aPT threshold had been achieved within 24 hours of initiation of heparin therapy. No major bleeding episodes or heparin-induced thrombocytopenia occurred during heparin treatment (0% [CI, 0.0% to 5.0%]), and no patient was lost to follow-up. Five patients died during the follow-up period: Four died of cancer (one after 65 days, one after 72 days, one after 80 days, and one after 85 days), and one died of pleural hemorrhage that occurred 1 month after heparin therapy began. Discussion Our results suggest that the use of a weight-based algorithm for the subcutaneous injection of unfractionated heparin allows the rapid achievement of correct anticoagulation in almost all patients with deep venous thrombosis while avoiding prolonged periods of excessive anticoagulation. The therapeutic threshold was achieved within 24 hours in 87% of patients and within 48 hours in 99%. In only 10% of patients did supratherapeutic aPT persist for more than 12 hours. No patient had major bleeding or heparin-induced thrombocytopenia, and thromboembolism recurred in only three patients (4.3%). These results are consistent with those reported in recent studies done with either intravenous unfractionated heparin according to standardized guidelines or fixed-dose low-molecular-weight heparins [3-5, 11-13]. An intravenous loading dose was chosen because of the poor bioavailability of subcutaneous heparin [8], and weight-adjusted heparin doses were chosen because body weight is the single best predictor of individual heparin requirements [5, 14, 15]. The combination of an initial intravenous bolus and weight-adjusted heparin doses probably explains the high biological success rates achieved with our protocol, rates that are similar to those recently reported with the use of a weight-based intravenous heparin nomogram [5, 16]. Of interest, the mean daily amount of heparin required to prolong the aPT during the first 24 hours (almost 40 000 U) was greater than the dose (30 000 to 35 000 U) usually required to attain proper anticoagulation with intravenous administration [1, 3-5, 8]. The implication of this finding is that the common practice of injecting as much subcutaneous heparin as is commonly administered intravenously for the initial treatment of patients with thrombotic disorders is likely to produce insufficient anticoagulation, thereby increasing the likelihood of recurrent thromboembolism [17-19]. A few considerations deserve careful analysis. Because of a relatively small sample size and the lack of a control group, our results should be validated in other cohorts of patients to ensure external validity. In addition, because we confined our investigation to symptomatic outpatients with a first episode of venous thrombosis, widespread generalization of this therapeutic regimen requires proper evaluation in patients who develop thrombosis during hospitalization and in those presenting with pulmonary embolism or recurrent thromboembolism. In conclusion, the use of a weight-based algorithm for the subcutaneous administration of unfractionated heparin may greatly simplify the initial treatment of venous thromboembolic disorders. It enables the early mobilization of patients with venous thrombosis and allows the early discharge of suitable patients. The relatively low cost of unfractionated heparin makes this approach attractive in comparison w