Protein C (PC) and protein S (PS) determination is part of the thrombophilia investigation in patients with idiopathic venous thromboembolism (VTE). Based on scarce evidence it is a common notion ...that PC and PS levels decrease during the acute phase of VTE, necessitating delay of testing and temporary transition from warfarin to low molecular weight heparin. We have previously demonstrated that an abnormal PC or PS result determined within 24 hours of VTE diagnosis and before the initiation of warfarin needs to be repeated for confirmation >/=3 months after starting treatment and >/=14 days after stopping anticoagulation therapy. In the current study, we sought to show that normal PC and PS values determined during the acute phase of VTE are not false negatives.
99 patients with acute idiopathic VTE who had normal PC and PS determination within the first 24 hours of presentation and who subsequently had their oral anticoagulation discontinued after six months of therapy. PC and PS determinations were repeated >/=6 months after starting treatment and >/= 14 days after stopping warfarin. Proportions of patients who tested abnormal on the second test were calculated and 95% confidence intervals obtained using the Wilson's score method. Data from a previously published study on patients with abnormal initial tests was included for comparison.
None of the 99 patients who had normal PC and PS initially had an abnormal result on repeated testing (0%; 95% CI 0 - 3.7%). Data from the previous study showed that, among patients who initially had abnormal results, 40% (95%CI 35.4-84.8%) were confirmed to have low PC and 63.6% (95%CI 16.8-68.7%) low PS on repeated testing. The difference between proportions was statistically significant (chi2 p-value < 0.001).
Our results suggest that PC and PS can be determined during the acute phase of VTE and whereas abnormal results need to be confirmed with repeat testing at a later date, a normal result effectively rules out deficiency with only one test.
Optimal prophylactic strategies in pregnant women with a history of venous thromboembolism (VTE) are unknown.
We conducted a retrospective cohort study of consecutive pregnant patients with a ...previous VTE history. Patients were followed until 6 weeks postpartum. Patients with a previous unprovoked event (including antepartum VTE) received antenatal prophylaxis, mostly with low dose low molecular weight heparin (LMWH). All patients received prophylaxis for six weeks after delivery.
We included a total of 199 pregnancies in 142 women. Of these, 147 pregnancies occurred in women with unprovoked or estrogen-related VTE history and 52 pregnancies in women with provoked VTE. There were 8 recurrences in 199 pregnancies (4%; 95%CI: 2.05–7.73), of which 5 were antepartum recurrences (2.5%; 95%CI 1.08–5.75) and 3 were postpartum (1.5%; 95% CI 0.51–4.34). In the unprovoked VTE group there were 7 recurrences (4.7%; 95%CI: 2.32–9.50), whereas in the provoked VTE group there was 1 (1.9%; 95%CI: 0.34–10.12). There was one major bleeding event in a patient not receiving LMWH secondary to placental abruption.
This study suggests that the use of prophylactic doses of LMWH during pregnancy and puerperium, as described in this study, results in low occurrence of ante- and postpartum VTE recurrences in patients with previous VTE. Further studies are required to confirm this observation.
•Pregnant patients with previous venous thrombosis are at increased recurrence risk.•In this study we used prophylaxis mainly with low dose low molecular weight heparin.•Antepartum prophylaxis was given in cases of previous unprovoked thrombosis.•Postpartum prophylaxis was used in all patients.•We observed a low rate of ante- and postpartum recurrences.
Abstract Background Choosing short-term (3-6 months) or indefinite anticoagulation after a first unprovoked venous thromboembolic event (VTE) is a common and difficult clinical decision. The ...long-term absolute risk of recurrent VTE after a first unprovoked VTE, in all patients and sub-groups, is not well established, hindering decision making. Methods We conducted a multi-center multi-national prospective cohort study in first unprovoked VTE patients to establish the long-term risk of recurrent VTE after short-term anticoagulation in first unprovoked VTE patients (and sub-groups).We followed patients for symptomatic suspected VTE off of OAT. Suspected recurrent VTE was investigated with reference to baseline imaging and then independently and blindly adjudicated. Findings We recruited 663 participants between October, 2001 and March 2006 with the last follow-up in April 2014. During a mean 5.0 years of follow-up, 165/663 suspected VTE (in 408 patients) were adjudicated as recurrent VTE resulting in an annualized risk of recurrent VTE of 5.0% (95% CI: 4.2-5.8%) with a cumulative risk of 29.6% at 8 years. Men had a 7.6% (95% CI: 6.3-9.2%) annual risk of recurrent VTE. High risk women (2 or more HERDOO2 points; see text) had an annual risk of recurrent VTE of 5.9% (95% CI: 4.2-8.1%). Low risk women (1 or 0 HERDOO2 points) had 1.1% (95% CI: 0.6-2.0%) annual risk of recurrent VTE with a cumulative risk of 8.7% at 8 years. Interpretation Men and high risk women with unprovoked VTE should be considered for long-term anticoagulant therapy given a high risk of recurrent VTE after long-term follow-up. Women with a low HERDOO2 score may be able to safely discontinue anticoagulants. Funding This study was funded by the Canadian Institutes of Health Research (Grant # MOP 64319) and Heart and Stroke Foundation of Ontario (Grant # NA 6771). Registered at www.clinicaltrials.gov identifier: NCT00261014
BACKGROUND Low-molecular-weight heparins (LMWHs) are now standard therapy for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). No published trials have compared LMWHs, and few ...studies have examined outpatient therapy for PE. Only tinzaparin sodium has demonstrated superiority to unfractionated heparin in a clinical trial. METHODS We compared 2 LMWH products, tinzaparin and dalteparin sodium, for the treatment of acute DVT and PE in a randomized, controlled clinical trial of consecutive outpatients presenting to a venous thromboembolism service at 4 tertiary-care hospitals. Patients were treated with subcutaneous tinzaparin sodium, 175 IU/kg every 24 hours, or subcutaneous dalteparin sodium, 200 IU/kg every 24 hours, for at least 5 days. Warfarin sodium therapy was started simultaneously and continued for 90 days. The primary end point was efficacy (recurrence of venous thromboembolism); safety (bleeding) was a composite end point. RESULTS Two hundred fifty-four patients received tinzaparin (39 with PE and 215 with DVT) and 251 received dalteparin (51 with PE and 200 with DVT). Most patients had an active malignancy or idiopathic DVT/PE. The outcome events occurred in 11 (4.4%; 95% confidence interval CI, 2.2%-7.7%) and 15 patients (5.9%; 95% CI, 3.3%-9.5%) in the dalteparin and tinzaparin groups, respectively, including 9 and 10 recurrences, respectively, and 2 and 5 major hemorrhages, respectively (P = .44). The 95% CI on the difference of −1.5% was −5.3% to 2.4%. CONCLUSIONS Tinzaparin and dalteparin are safe and effective for the outpatient treatment of DVT or PE. Our finding of no differences between the LMWHs based on major clinical end points means that practical issues can be the deciding factor on which drug to use.Arch Intern Med. 2005;165:733-738-->
The role of ABO blood type as a risk factor for recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who complete oral anticoagulation therapy is unknown. The aim of this ...study was to determine if non-OO blood type is a risk factor for recurrent VTE in patients with a first unprovoked VTE who completed 5–7 months of anticoagulant therapy. In an ongoing cohort study of patients with unprovoked VTE who discontinued oral anticoagulation after 5–7 months of therapy, six single nucleotide polymorphisms sites were tested to determine ABO blood type using banked DNA. The main outcome was objectively proven recurrent VTE. Mean follow-up for the cohort was 4.19 years (SD 2.16). During 1,553 patient-years of follow-up, 101 events occurred in 380 non-OO patients (6.5 events per 100 patient years; 95% CI 5.3–7.7) compared to 14 events during 560 patient years of follow-up in 129 OO patients (2.5 per 100 patient years; 95% CI 1.2–3.7), the adjusted hazard ratio was 1.98 (1.2–3.8). In conclusion, non-OO blood type is associated with a statistically significant and clinically relevant increased risk of recurrent VTE following discontinuation of anticoagulant therapy for a first episode of unprovoked VTE.
The role of ABO blood type as a risk factor for recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who complete oral anticoagulation therapy is unknown. The aim of this ...study was to determine if non-OO blood type is a risk factor for recurrent VTE in patients with a first unprovoked VTE who completed 5-7 months of anticoagulant therapy. In an ongoing cohort study of patients with unprovoked VTE who discontinued oral anticoagulation after 5-7 months of therapy, six single nucleotide polymorphisms sites were tested to determine ABO blood type using banked DNA. The main outcome was objectively proven recurrent VTE. Mean follow-up for the cohort was 4.19 years (SD 2.16). During 1,553 patient-years of follow-up, 101 events occurred in 380 non-OO patients (6.5 events per 100 patient years; 95% CI 5.3-7.7) compared to 14 events during 560 patient years of follow-up in 129 OO patients (2.5 per 100 patient years; 95% CI 1.2-3.7), the adjusted hazard ratio was 1.98 (1.2-3.8). In conclusion, non-OO blood type is associated with a statistically significant and clinically relevant increased risk of recurrent VTE following discontinuation of anticoagulant therapy for a first episode of unprovoked VTE.
The optimal means of achieving therapeutic oral anticoagulation in the outpatient setting has not been determined.
To compare a 10-mg dosing nomogram with a 5-mg nomogram that has been suggested to ...be sufficient for warfarin initiation.
Randomized, controlled clinical trial.
Outpatient venous thromboembolism services of four tertiary care hospitals.
201 of 210 consecutive patients with objectively confirmed diagnoses of acute venous thromboembolism.
All patients were treated with subcutaneous low-molecular-weight heparin for a minimum of 5 days until a therapeutic international normalized ratio (INR) was achieved. Patients were randomly assigned to initially receive a 10-mg or 5-mg dose of warfarin.
The primary end point was time in days to therapeutic INR. Secondary end points were the proportion of patients who had achieved a therapeutic INR by day 5, the total number of INR assessments, the number of INR measurements greater than 5.0, incidence of recurrent venous thromboembolism and major bleeding, and survival.
210 consecutive patients met the inclusion criteria. Of these, 9 were excluded and 201 were randomly assigned to study groups (104 to the 10-mg group and 97 to the 5-mg group). Demographic characteristics of both groups were similar. Patients in the 10-mg group achieved therapeutic INR 1.4 days earlier than patients in the 5-mg group (P < 0.001). Eighty-three percent of patients in the 10-mg group achieved a therapeutic INR by day 5 versus 46% in the 5-mg group (P < 0.001). Fewer INR assessments were performed in the 10-mg group than in the 5-mg group (8.1 vs. 9.1; P = 0.04). There were no significant differences between the two groups in recurrent events, major bleeding, survival, and number of INR measurements greater than 5.0.
The 10-mg warfarin initiation nomogram is superior to the 5-mg nomogram because it allows more rapid achievement of a therapeutic INR.
Introduction. Upper extremity deep vein thrombosis (UEDVT) is a relatively uncommon event with potentially serious complications. Its clinical outcomes are not well studied. The objective of this ...study was to assess the incidence of post-thrombotic syndrome (PTS) and functional disability in patients with UEDVT.
Patients and methods. This was a pre-specified analysis of a prospective cohort study at 5 Canadian centres. We enrolled adult patients with a symptomatic UEDVT confirmed by compression ultrasound involving the brachial or more proximal veins, with or without a pulmonary embolism (PE). Exclusions included pregnancy, dialysis catheter thrombosis, active or high bleeding risk, platelet count <100x109/L, creatinine clearance < 30 ml/min, on warfarin for other indications, hemodynamically unstable PE, acute leukemia or undergoing a stem cell transplant within 3 months, geographical inaccessibility, life expectancy <3 months or treatment with low molecular weight heparin (LMWH) or warfarin for more than 7 days since diagnosis. Standardized treatment regimens were used as follows: spontaneous or central venous catheter (CVC)-related UEDVT were treated with dalteparin at therapeutic doses for at least 5 days followed by warfarin adjusted according to INR results. Spontaneous UEDVT was treated for at least 6 months and CVC-related events were treated for at least 3 months or for as long as the line remained in place and for at least 1 month after line removal. Cancer patients with non CVC-related UEDVT were treated using dalteparin alone for a minimum of 6 months. Outcomes were assessed at 12, 18 and 24 months and included the occurrence of PTS evaluated using a modified Villalta Score. PTS was defined for patients with a score of 5 or greater and severe PTS was defined by a score of 15 or higher. Functional disability was evaluated using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. Patients were followed for 2 years. Data was analyzed using descriptive statistics. Confidence intervals for proportions were estimated using the Wilson’s score method. Groups were compared using χ2 and Student’s t- tests, as appropriate. The study was approved by all institutional review boards.
Results. Between 2009 and 2012, we enrolled 141 patients: 75 with spontaneous and 66 with CVC related UEDVT. Mean age was 51 years and 55% were males. There were 78, 59 and 56 patients with evaluable data at 12, 18 and 24 months, respectively. The percentage of patients with ipsilateral PTS is shown in Table 1. There was no difference between patients with spontaneous or CVC- related UEDVT. Functional disability scores are shown in Table 2. Overall, patients developing PTS had higher functional disability at all time points, compared to patients without PTS.
Conclusion. In this prospective cohort study PTS occurred in approximately one fifth of patients after UEDVT and was associated with more functional disability, although the majority of cases were mild according to the modified Villata score. No differences were observed between CVC-related and spontaneous UEDVT.
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Lazo-Langner:Bayer: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Research Funding. Wells:Itreas: Other: Served on a Writing Committee; BMS/Pfizer: Research Funding; Bayer Healthcare: Other: Speaker Fees and Advisory Board; Janssen Pharmaceuticals: Consultancy. Carrier:BMS: Research Funding; Leo Pharma: Research Funding. Kovacs:Daiichi Sankyo Pharma: Research Funding; LEO Pharma: Honoraria; Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.
Introduction. Upper extremity deep vein thrombosis (UEDVT) is a relatively uncommon event with potentially serious complications. Its optimal treatment and clinical outcomes are not well studied. The ...objective of our study was to assess the safety and efficacy of a standardized management protocol for UEDVT as well as its long term complications.
Patients and methods. We conducted a prospective cohort study at 5 Canadian centres and enrolled adult patients with a symptomatic UEDVT confirmed by compression ultrasound involving the brachial or more proximal veins, with or without a pulmonary embolism (PE). Exclusions included pregnancy, dialysis catheter thrombosis, active or high bleeding risk, platelet count <100x109/L, creatinine clearance < 30 ml/min, on warfarin for other indications, hemodynamically unstable PE, acute leukemia or undergoing a stem cell transplant within 3 months, geographical inaccessibility, life expectancy <3 months or treatment with low molecular weight heparin (LMWH) or warfarin for more than 7 days since diagnosis. Standardized treatment regimens were as follows: spontaneous or central venous catheter (CVC)-related UEDVT were treated with dalteparin at therapeutic doses for at least 5 days followed by warfarin adjusted according to INR results. Spontaneous UEDVT was treated for at least 6 months and CVC-related events were treated for at least 3 months or for as long as the line remained in place and for at least 1 month after line removal. Cancer patients with non CVC-related UEDVT were treated using dalteparin alone for a minimum of 6 months. Main outcomes were objectively documented venous thromboembolism (VTE) recurrence, major bleeding and death. All outcomes were centrally adjudicated. Patients were followed for 2 years. Data was analyzed using descriptive statistics. Survival data was analyzed using the Kaplan-Meier Method. Post-hoc analyses were conducted comparing CVC and spontaneous events. The study was approved by all institutional review boards.
Results. Between 2009 and 2012, we enrolled 141 patients: 75 with spontaneous and 66 with CVC related UEDVT. Mean age was 51 years; 55% were males. The population characteristics are shown in the Table. The 2 year cumulative incidence of VTE recurrence was 3.5% (95% CI 1.5-8), of major bleeding was 2.8% (95% CI 1.1-7.1) and of death was 22% (95% CI 16-29.5). VTE recurrence rate was no different for spontaneous vs. CVC-related groups (4% vs. 3%; Log-Rank P = 0.690; Figure).
Conclusion. The use of a standardized management protocol for patients with UEDVT results in a low risk of VTE recurrence and major bleeding at 2 years of follow up, in both CVC-related and spontaneous UEDVT.
Table 1Population characteristicsSpontaneous UEDVTCatheter-related UEDVTTotalP-valueN%N%N%DemographicsAge (Mean SD)48.617.854.913.651.616.2NSMale gender4458.73451.57855.3NSCaucasian6789.36497.013192.9NSComorbiditiesPrevious VTE34.023.053.5NSPrior or concurrent cancer2229.34872.77049.6<0.001Prior gastrointestinal Bleeding68.057.6117.8NSType of CatheterNEHickman--11.510.7PICC--4974.24934.8Porta Cath--1624.21611.3Thrombus LocationSubclavian5472.04365.29768.8NSSuperior vena cava00.023.021.4NSBrachiocephalic56.71015.21510.6NSInternal Jugular1621.31421.23021.3NSAxillary3952.03451.57351.8NSExternal Jugular11.323.032.1NSTreatment Duration3 Months2634.71928.84531.9<0.0016 Months3749.346.14129.10.000Other1216.04365.25539.00.000
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Lazo-Langner:Bayer: Honoraria; Pfizer: Honoraria. Wells:Bayer: Honoraria; BMS/Pfizer: Research Funding. Carrier:BMS: Research Funding; Bayer: Consultancy; Pfizer: Consultancy; LEO Pharma: Consultancy, Research Funding. Kovacs:Bayer: Honoraria, Research Funding; LEO Pharma: Honoraria; Daiichi Sankyo Pharma: Research Funding; Pfizer: Honoraria, Research Funding.
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