Controlled trial of the sequential use of streptokinase and ancrod in the treatment of deep vein thrombosis of lower limb

Treatment with streptokinase ('Kabikinase') was given to 26 patients with venographically confirmed deep vein thrombosis extending into the popliteal vein or above. Treatment was continued for 4 days and the patients were allocated randomly to oral anticoagulant therapy or a course of treatment with ancrod ('Arvin') for 6 days followed by oral anticoagulant therapy. The degree of thrombolysis as judged by further venographic examination at 10 days was not significantly different between the 2 groups. The majority of patients showed clinical improvement but there was no appreciable difference between the groups at 3 and 6 months. Haemorrhagic complications were a more serious problem during the period of treatment with ancrod than during the equivalent period in the control group.     

Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial.

In a prospective multicenter trial, 149 consecutive patients with phlebographically proven proximal and/or distal deep vein thrombosis of the leg were randomly allocated to receive subcutaneously for 10 days either low molecular weight heparin CY 216 (Fraxiparine) in a fixed dose or unfractionated heparin (UFH) in doses adjusted according to the activated partial thromboplastin time. Pre- and post-treatment phlebograms were assessed blindly using the Arnesen's score system in 134 patients available for analysis of the treatment efficacy. The mean phlebographic score after 10 days of treatment was significantly decreased in both groups (p less than 0.001) in comparison with the baseline score but the difference in score changes between the two groups was not statistically significant. There was an improvement in 45/68 patients (66%) in the Fraxiparine group and in 32/66 patients (48%) in the UFH group, and an increase in the thrombus size in 10/68 (15%) and 12/66 (18%), respectively. One symptomatic non-fatal pulmonary embolism and one major bleeding episode were observed in the UFH group. During a follow-up period of 3 months, two rethromboses had occurred in the UFH group and none in the Fraxiparine group. It is concluded that subcutaneous fixed dose Fraxiparine is safe and at least as effective as subcutaneous adjusted UFH in the treatment of deep vein thrombosis.     

Low-molecular-weight heparin in the acute and long-term treatment of deep vein thrombosis

Low molecular weight heparins (LMWHs) are frequently used during acute treatment of deep vein thrombosis, but their utility for long-term treatment needs to be defined. In this multi-centre trial, 378 patients with acute deep vein thrombosis were randomised to intravenous unfractionated heparin (group A), once daily subcutaneous LMWH (bemiparin) for one week (group B) or once daily bemiparin in a therapeutic dose for one week followed by a maintenance dose for 12 weeks (group C). Fifty-two per cent of patients in group A, 72% of group B and 72% of group C showed venographic reduction in thrombus size assessed objectively on day 14; 20% greater improvement in group B and C indicates not only non-inferiority of bemiparin (p = 0.00003) but also superiority (p = 0.004) compared to UFH. Day 84 venographic or Doppler sonographic recanalisation of the affected veins was demonstrated in 75.3%, 79.8% and 81.5% in groups A, B and C respectively. Mortality, recurrent thromboembolic events and bleeding were similar in the three groups. Both bemiparin regimens were more effective than UFH in reducing thrombus size during the acute phase of treatment. The efficacy in terms of recurrence of venous thromboembolism and safety of Bemiparin is similar to UFH. Bemiparin is also an effective alternative to warfarin for long-term treatment.     

Thrombolysis and fibrinolytic parameters during heparin treatment of deep vein thrombosis

Thirty-nine patients with symptomatic, venographically verified deep vein thrombosis (DVT) were studied during treatment with heparin in order to investigate the correlation between the venographic changes and parameters of heparin therapy or fibrinolytic components. Venograms were scored with a 40-grade scale, and after one week a significant improvement with an average reduction of the thrombi of 17% was observed. No statistically significant correlation was found between reduction of thrombus size and duration of heparin treatment, total amount of heparin administered, mean levels of APTT, plasmin-α₂-antiplasmin complex (PAP), tissue plasminogen activator (t-PA) antigen or t-PA-inhibitor. Only a short history of the thrombus was significantly correlated to thrombolysis. The concentrations of PAP and t-PA-inhibitor were not influenced, while that of t-PA antigen showed a significant increase during heparin infusion. Even if statistically significant correlations were not obtained, the patients with pronounced thrombolytic effect had high PAP-levels. Furthermore, patients with high t-PA-inhibitor levels had no lysis. The results suggest, that also other factors than plasminogen dependent fibrinolysis are of importance for the thrombolytic effect.     

Low molecular weight heparin for deep vein thrombosis in glioma patients

The treatment and secondary prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism, a common complication in patients with malignant glioma, has remained controversial. We treated 11 patients with malignant glioma and DVT prospectively with low molecular weight heparin (LMWH) at 175 IU/kg for 10 days and then for 3 months at 100 IU/kg. No patient developed bleeding complications or any other severe side effects of LMWH treatment. Two patients had a dose reduction of LMWH to 75 IU/kg because of chemotherapy-induced thrombocytopenia. One patient developed progressive DVT and nonlethal pulmonary embolism on day 14 of LMWH 100 IU/kg. After increasing the dose to 175 IU/kg he had no further recurrence. One patient had recurrence of DVT after a fracture of the leg affected by DVT at 8 months after the diagnosis of DVT and 5 months after the end of LMWH therapy. LMWH therapy may be safe and effective in the treatment and secondary prophylaxis of DVT in patients with malignant glioma. Received: 4 January 2002, Received in revised form: 18 April 2002, Accepted: 23 April 2002 Correspondence to Dr. F. Schmidt     

A comparative study of low doses of heparin and a heparin analogue in the prevention of postoperative deep vein thrombosis

The efficacy of heparin and a semi-synthetic heparin analogue as compared for the prevention of postoperative deep vein thrombosis (DVT) in a prospective, randomized trial involving 200 patients. 12 (12.5%) out of 95 patients in the heparin group developed DVT compared to 6 (6.3%) out of 94 patients who received the analogue. Serious bleeding did not occur in any of the patients in either group and the difference in the operative and postoperative bleeding was not statistically significant. In this entire series of 190 patients, wound haematoma developed in 3, and all were in the heparin group. In 50 patients (25 in each group) plasma heparin levels, kaolincephalin clotting time (KCCT) and antithrombin III (At IIII) activity were measured in the samples withdrawn before, during and immediately after surgery and also on the first postoperative day. Significantly higher mean plasma heparin levels were obtained in the pat-ients receiving the analogue than those receiving heparin. Yet there was no difference in the prolongation of the KCCT observed in the two groups when measured by the clotting assay; the analogue had greater potentiating effect on At III activity as compared to heparin; the difference being statistically significant (p < 0.005). These findings provide further evidence for our preliminary observations that the heparin analogue selectively potentiates antithrombin III activity $\text{in vivo}$ while having little effect on overall clotting. The results presented indicate that it is as effective as heparin in preventing postoperative DVT.     

Intensive initial oral anticoagulation and shorter heparin treatment in deep vein thrombosis

In order to investigate whether a more intensive initial oral anticoagulation still would be safe and effective, we performed a prospective randomized study in patients with deep vein thrombosis. They received either the conventional regimen of oral anticoagulation ("low-dose") and heparin or a more intense oral anticoagulation ("high-dose") with a shorter period of heparin treatment. In the first part of the study 129 patients were randomized. The "low-dose" group reached a stable therapeutic prothrombin complex (PT)-level after 4.3 and the "high-dose" group after 3.3 days. Heparin was discontinued after 6.0 and 5.0 days respectively. There was no difference in significant hemorrhage between the groups, and no clinical signs of progression of the thrombosis. In the second part of the study another 40 patients were randomized, followed with coagulation factor II, VII, IX and X and with repeated venograms. A stable therapeutic PT-level was achieved after 4.4 ("low-dose") and 3.7 ("high-dose") days, and heparin was discontinued after 5.4 and 4.4 days respectively. There were no clinical hemorrhages, the activity of the coagulation factors had dropped to the same level in both groups at the time when heparin was discontinued and no thromboembolic complications occurred. Our oral anticoagulation regimen with heparin treatment for an average of 4.4-5 days seems safe and reduces in-patient costs.     

Sequential treatment of deep leg vein thrombosis with porcine plasmin and low dose streptokinase

Sequential treatment of deep leg vein thrombosis with porcine plasmin and low dose streptokinase (10,000-20,000 U/h) produces strong systemic fibrinolysis as demonstrated by the sustained decrease of euglobulin lysis time, of thromboplastin time values in percent, fibrinogen and factor V levels. There is a statistically significant negative correlation between thrombolytic results and euglobulin lysis time. Treatment period below 3 days are unlikely to give satisfactory results. Occluded vein segments with an apparent median age of 4 days including thrombi older than 10 days (20% of cases) are cleared with an average chance of 50%. Complete dissolution of all thrombi proximal to the crural veins has been demonstrated in 47/114 = 41.2%, some thrombolytic effects in 31/114 = 27.2% and treatment failure in 36/114 = 31.6%. The data favour laboratory monitoring of thrombolytic therapy.     

Prevention effect of orally active heparin derivative on deep vein thrombosis

The use of heparin as the most potent anticoagulant for the prevention of deep vein thrombosis and pulmonary embolism is nevertheless limited, because it is available to patients only by parenteral administration. Toward overcoming this limitation in the use of heparin, we have previously developed an orally active heparin-deoxycholic acid conjugate (LMWH-DOCA) in 10% DMSO formulation. The present study evaluates the anti-thrombogenic effect of this orally active LMWH-DOCA using a venous thrombosis animal model with Sprague-Dawley rats. When 5 mg/kg of LMWH-DOCA was orally administered in rats, the maximum anti-FXa activity in plasma was 0.35 +/- 0.02, and anti-FXa activity in plasma was maintained above 0.1 IU/ml [the minimum effective anti-FXa activity for the prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE)] for five hours. LMWH-DOCA (5 mg/kg, 430 IU/kg) that was orally administered reduced the thrombus formation by 56.3 +/- 19.8%;on the other hand, subcutaneously administered enoxaparin (100 IU/kg) reduced the thrombus formation by 36.4 +/- 14.5%. Also, LMWH-DOCA was effectively neutralized by protamine that was used as an antidote. Therefore, orally active LMWH-DOCA could be proposed as a new drug that is effective for the longterm prevention of DVT and PE.     

A randomized double-blind study between a low molecular weight heparin Kabi 2165 and standard heparin in the prevention of deep vein thrombosis in general surgery. A French multicenter trial

The safety and efficacy of a low molecular weight heparin fragment Kabi 2165, given in the dose 2,500 anti-Xa units once daily, in preventing postoperative venous thromboembolism, was assessed against calcium heparin in the dose 5,000 IU twice daily, in a multicenter double blind randomized study. On an intention to treat basis 385 patients scheduled for major surgery were included in this study. Six patients (3.1%) out of 195 developed isotopic DVT in the Kabi 2165 group. Corresponding figures for calcium heparin was 7 patients (3.7%). There was no statistically significant difference between the two groups with respect to the bleeding variables; blood loss during operation, postoperative drainage, blood transfusion, haemoglobin and haematocrit levels; wound haematoma and haematoma at the injection sites. No patient had to undergo evacuation of wound haematoma or reoperation due to bleeding. It is concluded that one single daily injection of Kabi 2165 provides a convenient safe and effective prophylaxis against thromboembolism in general surgery.     

Systemic fibrinolytic activity and inhibitor levels during treatment of deep vein thrombosis with urokinase and streptokinase

In a prospective, randomized trial 33 patients with deep vein thrombosis were treated either with 2,200 or 1,100 IU/kg/h urokinase or with 100,000 IU/h streptokinase for at least 6 days. While streptokinase was given continuously, urokinase was administered intermittently (12 hr urokinase alternating with 12 hr heparin). Urokinase treatment resulted in a dose-dependent fibrinolytic state with shortening of the euglobulin clot lysis time, easily demonstrable amidolytic activity and moderate decrease of plasminogen. At the end of each urokinase-free interval the fibrinolytic activity had mostly faded, but was reproducibly elicited again by each new urokinase administration. Streptokinase immediately evoked the customary, intense fibrinolytic state, which progressively tapered off as plasminogen fell to 1% of its pretreatment concentration. In all treatment groups alpha-2-antiplasmin dropped to approximately 40% of its initial value during the first 12 hr with a further decrease to about 20% after 6 days. alpha-2-macroglobulin fell only moderately with either urokinase regimen, whereas it decreased progressively to 45% under streptokinase. While the fibrinolytic activity decreased under streptokinase over the 6-day infusion period, it appeared to increase with each successive urokinase infusion particularly with 1100 IU/kg/h. Thus the final euglobulin clot lysis times and the final fibrinogen concentrations were similar in all three treatment groups on the sixth day.     

A comparative randomized trial of low-dose versus high-dose streptokinase in deep vein thrombosis of the thigh

Fibrinolytic treatment of acute deep vein thrombosis (DVT) of the leg with high-dose streptokinase (SK) (100,000 U/h) in 39 cases, or low-dose SK (approx 10,000 U/h) in combination with low-dose heparin in 41 cases, was studied in a prospective randomized trial. The degree of thrombolysis was similar in both groups and did not correlate with age or size of the thrombus or with fibrinogen level. The degree of late recanalization was also similar in both groups. There were however significantly more patients with postthrombotic changes in the low-dose group than in the high-dose group after a mean follow-up time of 31 and 38 months respectively. In the low-dose group 2 intracranial hemorrhages occurred (one was fatal) and one patient died of pulmonary embolism, but there were significantly less allergic side effects to SK. There were no cases of such serious side effects in the highdose group. Although low-dose SK has equal thrombolytic effect it seems inferior to high-dose SK, since it probably causes more severe hemorrhagic side-effects.     

Optimal dosing of subcutaneous unfractionated heparin for the treatment of deep vein thrombosis

Twice-daily, inpatient, subcutaneous unfractionated heparin is at least as effective and safe as continuous intravenous unfractionated heparin for the treatment of acute deep vein thrombosis. Subcutaneous unfractionated heparin therefore may be suitable for outpatient treatment of deep vein thrombosis. The purpose of this study was to develop a dosing nomogram for a dose each 12 hours (2 doses per day) 12-hourly subcutaneous unfractionated heparin that is suitable for outpatient treatment of acute deep vein thrombosis. A cohort study was performed in patients with acute deep vein thrombosis in two phases. In both phases, the first subcutaneous loading dose of unfractionated heparin was 317 U/kg, and the second dose was 231 U/kg. The activated partial thromboplastin time was measured daily, 6 hours after the morning injection, and subsequent doses of unfractionated heparin were adjusted according to a nomogram, which was modified for phase II. Warfarin was started with unfractionated heparin. In phase I (14 outpatients), activated partial thromboplastin time results were frequently subtherapeutic (9:14) the day after starting unfractionated heparin (day 1), and were frequently supratherapeutic (27:40) after the first 2 days of unfractionated heparin therapy. In phase II (21 patients), to explain the frequently subtherapeutic activated partial thromboplastin time results that were obtained on day 1, the activated partial thromboplastin time results were measured after the initial loading dose. Mean activated partial thromboplastin time results of 86 and 61 seconds were obtained 6 and 12 hours after this dose, suggesting that 317 U/kg is a suitable subcutaneous loading dose. In contrast to phase I, in phase II, unfractionated heparin dose was not increased on day 1 in response to a low activated partial thromboplastin time result. This reduced the frequency of supratherapeutic activated partial thromboplastin time results during the early days of therapy without increasing the frequency of subtherapeutic results. Warfarin therapy had a substantal effect on the activated partial thromboplastin time that appeared to account for a high frequency of supratherapeutic results during the later days of unfractionated heparin therapy; the activated partial thromboplastin time increased by 20 seconds (95% CI, 14–27 seconds) with each increase in the International Normalized Ratio of 1.0. We had limited success at developing a dosing nomogram for subcutaneous unfractionated heparin that reliably achieved activated partial thromboplastin time results within the therapeutic range. However, as oral anticoagulants directly increased activated partial thromboplastin time results, we suggest that adjusting unfractionated heparin dose to achieve prespecified activated partial thromboplastin time results may not be appropriate in patients who are receiving concomitant warfarin therapy.     

Clinical probability assessment and D-dimer determination in patients with suspected deep vein thrombosis, a prospective multicenter management study

Objectives

To investigate the reliability of a combined strategy of clinical assessment score followed by a local D-dimer test to exclude deep vein thrombosis. For comparison D-dimer was analysed post hoc and batchwise at a coagulation laboratory.

Design

Prospective multicenter management study.

Setting

Seven hospitals in southern Sweden.

Subjects

357 patients with a suspected first episode of deep vein thrombosis (DVT) were prospectively recruited and pre-test probability score (Wells score) was estimated by the emergency physician. If categorized as low pre-test probability, D-dimer was analysed and if negative, DVT was considered to be ruled out. The primary outcome was recurrent venous thromboembolism (VTE) during 3 months of follow up.

Results

Prevalence of DVT was 23.5% (84/357). A low pre-test probability and a negative D-dimer result at inclusion was found in 31% (110/357) of the patients of whom one (0.9%, [95% CI 0.02-4.96]) had a VTE at follow up. Sensitivity, specificity, negative predictive value and negative likelihood ratio for our local D-dimer test in the low probability group were 85.7%, 74.5%, 98.2%, and 0,19 respectively compared to 85.6%, 67,6%, 97.9% and 0,23 using batchwise analysis at a coagulation laboratory.

Conclusion

Pre-test probability score and D-dimer safely rule out DVT in about 30% of outpatients with a suspected first episode of DVT. One out of 110 patients was diagnosed with DVT during follow up. No significant difference in diagnostic performance was seen between local D-dimer test and the post hoc batch analysis with the same reagent in the low probability group.     

beta-thromboglobulin and deep vein thrombosis.

The measurement of plasma beta-thromboglobulin as a potential diagnostic test for venous thrombosis has been investigated in 16 normal volunteers, 24 patients presenting with deep vein thrombosis (DVT) or pulmonary embolism and 46 patients screened by 125I fibrinogen test (IFT) for post-operative DVT. The normal mean was 33 ng/ml (range 15-117 ng/ml). Of the 24 patients with clinical thrombotic disease 22 presented with DVT confirmed by phlebogram or IFT and 2 presented with embolism confirmed by lung scan. At the time of first presentation 12 out of 24 had betaTG values greater than 70 ng/ml. All except 3 of this group of 24 patients had values of greater than 70 ng/ml at some stage during a subsequent week of daily sampling. DVT was detected in 13 out of 46 screened post-operative patients. There was a rise om betaTG observed within 24 hr of the IFT becoming positive but the mean rise did not reach significance at the 5% level. An association between DVT and high betaTG values has been confirmed. However, its clinical value cannot yet be fully elucidated until factors, probably related to blood sampling and clearance, are further investigated.     

Prevention of deep vein thrombosis by low-molecular-weight heparin and dihydroergotamine in patients undergoing total hip replacement.

In 110 high-risk patients undergoing total hip replacement the antithrombotic efficacy and safety of a single daily injection of 1500 aPTT-U low-molecular-weight heparin plus 0.5 mg dihydroergotamine (Embolex) was, in a double-blind study, compared with a twice daily administration of 5000 IU of the heparin-dihydroergotamine combination Heparin-Dihydergot. Deep vein thrombosis diagnosed with phlebography occurred in 9.6% in the Embolex-group and in 25% in the Heparin-Dihydergot-group. Intra- and postoperative blood loss and blood replacement were similar in both groups. Therefore, and on account of the single daily administration, Embolex offers at least the advantage of improved compliance of the patients and reduced workload of the nursing staff.     

Prophylactic use of heparin for deep vein thrombosis in restrained psychiatric patients: a chart review

ObjectivePhysical restraint sometimes causes deep vein thrombosis (DVT) and pulmonary embolism. Although unfractionated heparin (UFH) is used for the prophylaxis of DVT, its effectiveness remained unknown for restrained patients.MethodWe conducted a chart review of restrained inpatients at Sakuragaoka Memorial Hospital in Japan. Restrained patients received subcutaneous injection of UFH 5000 IU bid from December 2008 to September 2010 [heparin (+) period] while UFH was not used from December 2010 to September 2012 [heparin (−) period]. A Doppler ultrasound scanning was performed to examine the presence of DVT. The incidence of DVT was compared between the two periods by chi-square test. A multiple logistic regression model was used to examine effects of demographic and clinical characteristics on the incidence of DVT.ResultsNo significant difference was found in the incidence of DVT between the heparin (+) and (−) periods [11.8% (11/93) vs. 11.1% (13/117)]. Sedation [odds ratio (OR)=3.78], physical comorbidities (OR=6.29) and a longer duration of restraint (OR=1.22) were associated with the incidence of DVT.ConclusionThe use of UFH was not associated with any reduction in the incidence of DVT in restrained psychiatric patients.     

Subclinical hypothyroidism and deep venous thrombosis. A pilot cross-sectional study

Several in-vivo studies have shown a procoagulant state in both overt and subclinical hyperthyroidism and in subclinical hypothyroidism. Insofar, no clinical studies have ever evaluated the relationship between thyroid dysfunction and clinically deep venous thrombosis (DVT). A pilot cross-sectional study aimed at assessing the frequency of overt and subclinical thyroid dysfunction patients with DVT was carried out. Fifty consecutive adult outpatients with a previous diagnosis of provoked DVT (pDVT), and 50 consecutive adult outpatients with a previous diagnosis unprovoked DVT (unDVT), both of the lower legs, who were followed at the Thrombosis Unit of the University Hospital of Varese, Italy, were enrolled after written informed consent. Fifty subjects, in whom such a diagnosis could be ruled out, served as controls. In each patient serum free thyroxine (FT4), free triiodothyronine (FT3), thyrotropin (TSH), anti-thyroid peroxidase (AbTPO), and anti-thyroglobulin (AbTg) antibodies were assayed. Previously unrecognised subclinical hypothyroidism was diagnosed in seven (14.0%) unDVT patients, one (2%) pDVT patient, and one (2%) control (odds ratio at multivariate analysis, 5.54; 95% confidence interval, 0.6-52.6); one new case of subclinical hyperthyroidism was diagnosed in each group; only one case (in the control group) of clinical overt hyperthyroidism was observed. The prevalence of thyroid autoantibodies, including both euthyroid and subclinical hypothyroid patients, did not differ in the three groups. The results of this pilot study suggest an increased prevalence of subclinical hypothyroidism in patients with unDVT. The clinical relevance of these preliminary findings needs to be addressed in larger prospective studies.     

Effects of low-dose subcutaneous heparin on the occurrence of deep vein thrombosis in patients with ischemic stroke

The effectiveness of low-dose subcutaneous heparin in the prophylaxis of deep vein thrombosis in patients with ischemic stroke was investigated in an unblinded controlled study. The frequency of deep vein thrombosis and pulmonary embolism in the control group was 23% versus 2% in the patients receiving heparin. There were no bleeding complications in the test group and there were no differences in the occurrence of hemorrhage changes in the cerebral ischemic infarction in both groups.     

Residual venous obstruction in patients with a single episode of deep vein thrombosis and in patients with recurrent deep vein thrombosis

Residual venous obstruction (RVO) in patients with previous deep vein thrombosis (DVT) of the lower limbs has been suggested as an independent risk factor for recurrent venous thromboembolism (VTE). RVO could be a marker of a persistent prothrombotic state. We have compared the rate of RVO in patients with DVT and a personal history of at least one previous episode of VTE to the rate of RVO among patients with a first episode of DVT. All patients underwent compression ultrasonography (CUS) of the lower limbs 1 year after index DVT. RVO was arbitrarily defined as a thrombus occupying, at maximal compressibility, more than 20% of the vein area in the absence of compression. 50 consecutive patients with recurrent DVT and 50 age and sex-matched patients with a single episode of DVT were enrolled. The index event was idiopathic in 62% of patients with recurrent DVT and in 60% of patients with a single episode. In 74% of patients with recurrent DVT the index event occurred in either the contralateral leg or in a different segment of the ipsilateral leg. RVO was detected in 50% of patients with a single episode of DVT and in 88% of patients with recurrent DVT (p<0.00001). The prevalence of RVO is significantly higher in patients with recurrent DVT than in patients with a single episode. This finding supports the importance of RVO as a potential marker of a persistent prothrombotic state.