Antithrombotic therapy in patients undergoing coronary angioplasty.
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Angioplasty, Balloon, Coronary↗
Biomedical subjects
J Weitz
Publications and source records attributed to J Weitz.
Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis.
The optimal duration of oral anticoagulant therapy for patients with acute proximal deep vein thrombosis (DVT) is uncertain. Based on the hypothesis that a normal impedance plethysmogram (IPG) following DVT defines a group of patients at low risk of recurrent venous thromboembolism (VTE), a trial was conducted to evaluate the efficacy of only four weeks of warfarin. Patients with venographically confirmed acute proximal DVT who had received four weeks of warfarin after initial heparin and whose four week IPG was normal were allocated to either continue warfarin (targeted International Normalized Ratio 2.0 to 3.0) for a further eight weeks or receive placebo. Patients with an abnormal four week IPG received warfarin for a further eight weeks. Based on clinical characteristics at the time of the qualifying thrombosis, all patients were classified as having either continuing or transient risk factors for recurrent VTE. During the eight weeks following randomization, nine (8.6%) of the 105 placebo patients developed recurrent VTE compared to one (0.9%) of the 109 warfarin patients, P = 0.009. Over the entire 11 months of follow-up, 12 placebo patients developed recurrence compared to seven warfarin patients, P = 0.3. Nineteen of the 192 patients with an abnormal four week IPG experienced recurrence during the nine months after discontinuing warfarin. In the 301 patients who received three months of warfarin in the randomized trial or in the cohort study, all 26 recurrent events were in the 212 patients with continuing risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Comparison of the accuracy of impedance plethysmography and compression ultrasonography in outpatients with clinically suspected deep vein thrombosis. A two centre paired-design prospective trial.
Impedance plethysmography (IPG) and compression ultrasonography (CUS) have been reported to be highly accurate for the diagnosis of deep vein thrombosis (DVT) in symptomatic patients. In many centres CUS has become the method of choice. However, direct comparisons of the accuracy of IPG to CUS have not been performed. To determine the test of choice we performed a two centre prospective comparison of IPG and CUS, with venography, and determined how the size and distribution of thrombi influenced the accuracy of each test. 495 symptomatic outpatients with suspected DVT had evaluable venograms. The prevalence of DVT was 27% (130/495), 84% (109) of which were proximal. The sensitivity of IPG and CUS for proximal vein thrombosis was 77% and 90% respectively (p = .002). The specificity of IPG was 93% whereas the specificity of CUS was 98% (p = 0.04). There were significant differences in accuracy between the two centres as a consequence of differences in the size and location of thrombi The majority of proximal thrombi not detected by IPG and CUS involved less than 5 cm of the distal half of the popliteal vein and most of these thrombi occurred in one centre. Exclusion of these thrombi from the analysis increases the sensitivity of CUS to 99% (86/87) and IPG to 91% (72/79), for proximal thrombi (P = .019). The positive predictive value of CUS was strongly influenced by the number of abnormal venous segments (three sites were examined); 100% (80/80) if two or three sites were abnormal, but only 68% if a single site was involved. We conclude that: 1) CUS is more accurate than the IPG for the diagnosis of DVT in symptomatic outpatients, and this relationship holds true regardless of the size or location of the DVT, 2) the sensitivities of IPG and CUS are much lower for small proximal DVT, and 3) confirmatory venography is warranted if the abnormality with CUS is limited to one venous segment.
Ambulatory Care↗
A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin.
BACKGROUND: The management of heparin therapy in patients who have a subtherapeutic activated partial thromboplastin time (APTT) despite high doses of heparin is problematic because the risk of heparin-associated bleeding increases with dose. Results of experimental studies in animals indicate that when the APTT response to heparin is blunted by infusion of procoagulants, dose escalation can be avoided without compromising efficacy, by monitoring treatment with a heparin assay. METHODS: A randomized, controlled trial was conducted in which patients with acute deep vein thrombosis, pulmonary embolism, or axillary vein thrombosis who required 35,000 U or more of intravenous heparin by continuous infusion during the previous 24 hours were allocated to have their heparin therapy monitored either by anti-factor Xa levels (targeted range, 0.35 to 0.67 U/mL) or by the APTT (targeted range, 60 to 85 seconds). Both ranges were equivalent to a heparin level of 0.2 to 0.4 U/mL by protamine titration. RESULTS: Three (4.6%) of 65 patients in the anti-factor Xa group experienced recurrent venous thromboembolism compared with four (6.1%) of 66 patients in the APTT group (difference, 1.5%; confidence interval, -6.7% to 8.4%) (P = .7). There were four bleeding events (6.1%) in the APTT group compared with one (1.5%) in the anti-factor Xa group (difference, 4.6%; confidence interval, -3.3% to 7.5%) (P = .4). During the period of heparin therapy before warfarin treatment was begun, the patients in the APTT group required a statistically significantly greater amount of heparin compared with the patients in the anti-factor Xa group. The daily mean APTT was subtherapeutic in patients in the anti-factor Xa group, and it was within the therapeutic range in the APTT group. The daily mean anti-factor Xa levels for both groups were within the therapeutic range. CONCLUSION: The heparin assay is a safe and effective method for monitoring heparin treatment in patients with acute venous thromboembolism whose APTT remains subtherapeutic despite large daily doses of heparin. In such patients, dosage escalation can be avoided if the heparin level is therapeutic.
Acute Disease↗
New anticoagulant strategies. Current status and future potential.
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Anticoagulants↗
Effects on thrombin generation of single injections of Hirulog in patients with calf vein thrombosis.
STUDY OBJECTIVE: To determine whether single injections of Hirulog, a direct thrombin inhibitor, can inhibit thrombin generation in patients with calf vein thrombosis and, if so, if the inhibition is sustained. DESIGN: Phase II open label cohort study. SETTING: Tertiary-care referral centres, university affiliated hospitals. PATIENTS: 10 patients with venographically-demonstrated calf vein thrombosis. INTERVENTION: Patients received a single injection of Hirulog, either 1.0 mg/kg subcutaneously or 0.6 mg/kg as a 15 min intravenous infusion. Prothrombin fragment (F1++2) levels, as an index of thrombin generation, were measured before as well as 6 h post- and 24 h post-Hirulog administration. Patients were followed with non-invasive tests to detect thrombus extension into the proximal veins. RESULTS: There was a significant reduction in the levels of F1+2 with both regimens, 6 h after Hirulog. The F1+2 levels 24 h post-Hirulog showed a significant increase relative to the 6 h post-Hirulog results. One patient developed thrombus extension into the popliteal vein and was treated with conventional anticoagulants. CONCLUSION: The single injections of Hirulog used in the study produced incomplete and temporary suppression of F1+2. Complete and permanent inhibition of thrombin generation with Hirulog in patients with calf vein thrombosis may require higher doses, multiple subcutaneous injections and/or prolonged intravenous infusion.
Aged↗
Ex-vivo and in-vitro evidence that low molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin.
We have compared the non-specific binding of unfractionated heparin (UFH) with that of low molecular weight heparin (LMWH) to plasma proteins both ex-vivo and in-vitro. Non-specific binding to plasma proteins was assessed by comparing the heparin levels measured as anti-factor Xa activity before and after the addition of low affinity heparin, which is essentially devoid of anti-factor Xa activity, in order to displace heparin bound to plasma proteins. For the ex-vivo studies, we compared the recovery of UFH and a LMWH (ardeparin) from the plasma of patients participating in a randomized trial of post-operative venous thrombosis prophylaxis. For the in-vitro studies, we compared the recovery of UFH and 4 different LMWHs when added to the plasma from healthy volunteers and from patients with suspected venous thromboembolic disease. The results indicate that the recovery of LMWH is much less affected by nonspecific binding to plasma proteins both ex-vivo and in-vitro. In addition, there are differences between the LMWHs with respect to their plasma protein-binding.
Blood Proteins↗
Comparison of the non-specific binding of unfractionated heparin and low molecular weight heparin (Enoxaparin) to plasma proteins.
The non-specific binding of anticoagulantly-active heparin to plasma proteins may influence its anticoagulant effect. We used low affinity heparin (LAH) essentially devoid of anti-factor Xa activity to investigate the extent and possible mechanism of this non-specific binding. The addition of excess LAH to platelet-poor plasma containing a fixed amount of unfractionated heparin doubled the anti-factor Xa activity presumably because it displaces anticoagulantly-active heparin from plasma proteins. Although dextran sulfates of varying molecular weights also increased the anti-factor Xa activity, less sulfated heparin-like polysaccharides had no effect. These findings suggest that the ability to displace active heparin from plasma protein binding sites is related to charge and may be independent of molecular size. In contrast to its effect in plasma containing unfractionated heparin, there was little augmentation in anti-factor Xa activity when LAH was added to plasma containing low molecular weight heparin (LMWH), indicating that LMWH binds less to plasma proteins than unfractionated heparin. This concept is supported by studies comparing the anticoagulant activity of unfractionated heparin and LMWH in plasma with that in buffer containing antithrombin III. The anti-factor Xa activity of unfractionated heparin was 2-fold less in plasma than in the purified system. In contrast, LMWH had identical anti-factor Xa activity in both plasma and buffer, respectively. These findings may be clinically relevant because the recovered anti-factor Xa activity of unfractionated heparin was 33% lower in plasma from patients with suspected venous thrombosis than in plasma from healthy volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)
Antithrombin III↗
The additive effect of low molecular weight heparins on thrombin inhibition by dermatan sulfate.
The aim of this study was to investigate the mechanism by which the anticoagulant activity of dermatan sulfate (DS) is increased by low molecular weight heparin (LMWH). In platelet poor plasma, LMWH enhances the effect of DS on thrombin (IIa) inhibition as determined by thrombin clotting times and with a chromogenic substrate assay. Analysis of the results of the chromogenic assays using either the algebraic fractional or the graphic isobole method suggests that LMWH has an additive effect on the anti-IIa activity of DS. This additive effect was lost when the experiments were repeated in plasma immunodepleted of antithrombin III (ATIII), indicating that the anti-IIa activity of LMWH is ATIII-dependent. To further explore the mechanism of the interaction between LMWH and DS, 125I-labeled IIa was added to plasma in the presence or absence of DS and/or LMWH and the formation of IIa-inhibitor complexes was assessed using SDS-PAGE followed by autoradiography. DS addition selectively increases the formation of heparin cofactor II (HCII)-IIa complexes, whereas LMWH enhances ATIII-IIa complex generation. Compared to plasma containing DS alone, the formation of ATIII-IIa complexes also is increased when the combination of DS and LMWH is added. These findings suggest that the additive effect of LMWH on the anti-IIa activity of DS reflects their different modes of IIa inhibition; DS potentiates IIa inhibition by HCII, while LMWH catalyses ATIII-dependent IIa inactivation. The potential clinical significance of these findings requires further investigation.
Amino Acid Sequence↗
Increased thrombin generation and activity in patients with systemic lupus erythematosus and anticardiolipin antibodies: evidence for a prothrombotic state.
The objective of this study is to determine whether patients with systemic lupus erythematosus (SLE) and anticardiolipin antibodies (ACA) have biochemical evidence of an ongoing prothrombotic state. Using a cross-sectional analysis of a cohort design in an outpatient SLE clinic setting, 43 consecutive patients with SLE participated. Patients underwent clinical and laboratory evaluations on two separate occasions at least 3 months apart. As part of the clinical evaluation, the following were ascertained: (1) the ongoing use of warfarin therapy; (2) the presence of prior venous and arterial thromboembolic disease by history, critical review of objective tests, and examination for reflux in the deep veins of the legs as an indicator of venous thrombosis; and (3) disease-related activity by performing a lupus activity criteria count (LACC). As part of the laboratory evaluation, blood was taken on both occasions and assayed for prothrombin fragments (F1 + 2) and fibrinopeptide A (FPA), as indices of thrombin generation and activity, respectively, and ACA. For the analyses, patients were classified as ACA+ if the assay was abnormal on both occasions and ACA- if the assay was negative on both occasions or negative on one occasion and positive on the other. ACA+ patients had: (1) a significantly higher mean level of F1 + 2 (1.07 nmol/L) than ACA- patients (0.79 nmol/L; P = .02) and patients receiving warfarin (0.47 nmol/L; P = .009) and (2) a significantly higher mean level of FPA (1.01 nmol/L) than ACA- patients (0.45 nmol/L; P = .02). When patients with prior thromboembolism were excluded from the analysis, significant differences in the mean levels of F1 + 2 and FPA between ACA+ and ACA- patients were still seen, whereas when patients with prior thromboembolism and/or active disease were excluded from the analysis, a significant difference in the mean level of FPA and a nonsignificant trend in the mean level of F1 + 2 were seen. The results of this study support the hypothesis that the presence of ACA in SLE patients is associated with an ongoing prothrombotic state.
Adult↗
Do coagulation screening tests detect increased generation of thrombin and plasmin in sick newborn infants?
BACKGROUND: Disseminated intravascular coagulation (DIC) is usually diagnosed in sick infants who have prolonged clotting times, depletion of platelets and coagulation factors, and elevated levels of fibrin derivatives. However, the diagnostic accuracy of abnormal coagulation profiles in neonates at risk of DIC has been uncertain. Since DIC is characterized by activation of both the coagulation and fibrinolytic systems, the objective of this study was to determine whether coagulation screening tests correctly identify infants with biochemical evidence of increased thrombin and plasmin generation. METHODS: Non-surgical patients in a tertiary care nursery who were sick enough to require an indwelling arterial catheter for monitoring purposes, were enrolled in a prospective cohort study. Blood samples for thrombin/antithrombin III (TAT) complexes and the plasmin-derived fibrinopeptide B beta 1-42 were drawn 36 to 72 h after birth from a free-flowing arterial line. Platelet counts, D-Dimer levels, plasma fibrinogen concentrations and prothrombin times, expressed as International Normalized Ratios or INR, were measured at the same time. RESULTS: One hundred patients were studied. Fifty-seven infants had elevated levels of TAT (> or = 4 micrograms/l) and B beta 1-42 (> or = 4 nmol/l). The sensitivities of platelets < 150 x 10(9)/l, D-Dimer > 500 ng/ml, fibrinogen < 1.5 g/l, and INR > 1.5 were 39%, 30%, 12%, and 11%, respectively. Corresponding specificities were 88%, 91%, 98%, and 95%. CONCLUSIONS: Abnormal coagulation screens in sick newborn infants strongly support a diagnosis of DIC. However, normal screens do not exclude activation of the coagulation and fibrinolytic systems.
Antithrombin III↗
Activated platelets form protected zones of adhesion on fibrinogen and fibronectin-coated surfaces.
Leukocytes form zones of close apposition when they adhere to ligand-coated surfaces. Because plasma proteins are excluded from these contact zones, we have termed them protected zones of adhesion. To determine whether platelets form similar protected zones of adhesion, gel-filtered platelets stimulated with thrombin or ADP were allowed to adhere to fibrinogen- or fibronectin-coated surfaces. The protein-coated surfaces with platelets attached were stained with either fluorochrome-conjugated goat anti-human fibrinogen or anti-human fibronectin antibodies, or with rhodamine-conjugated polyethylene glycol polymers. Fluorescence microscopy revealed that F(ab')2 anti-fibrinogen (100 kD) did not penetrate into the contact zones between stimulated platelets and the underlying fibrinogen-coated surface, while Fab antifibrinogen (50 kD) and 10 kD polyethylene glycol readily penetrated and stained the substrate beneath the platelets. Thrombin- or ADP-stimulated platelets also formed protected zones of adhesion on fibronectin-coated surfaces. F(ab')2 anti-fibronectin and 10 kD polyethylene glycol were excluded from these adhesion zones, indicating that they are much less permeable than those formed by platelets on fibrinogen-coated surfaces. The permeability properties of protected zones of adhesion formed by stimulated platelets on surfaces coated with both fibrinogen and fibronectin were similar to the zones of adhesion formed on fibronectin alone. mAb 7E3, directed against the alpha IIb beta 3 integrin blocked the formation of protected adhesion zones between thrombin-stimulated platelets and fibrinogen or fibronectin coated surfaces. mAb C13 is directed against the alpha 5 beta 1 integrin on platelets. Stimulated platelets treated with this mAb formed protected zones of adhesion on surfaces coated with fibronectin. These protected zones were impermeable to F(ab')2 antifibronectin but were permeable to 10 kD polyethylene glycol. These results show that activated platelets form protected zones of adhesion and that the size of molecules excluded from these zones depends upon the composition of the matrix proteins to which the platelets adhere. They also show that formation of protected zones of adhesion by platelets requires alpha IIb beta 3 integrins while the permeability properties of these zones of adhesion are regulated by both alpha IIb beta 3 and alpha 5 beta 1 integrins.
Blood Platelets↗
New anticoagulant strategies.
The limitations of standard heparin have prompted the development of a variety of newer antithrombotic agents. In fact, a LMWH preparation has recently been approved for clinical use in North America. Of these novel preparations, LMWH, the direct thrombin inhibitors, and inhibitors of GPIIb-IIIa have been used clinically and are in advanced stages of evaluation. Not only is LMWH effective in the prevention of venous thromboembolic disease in high-risk patients, but its more predictable dose response makes it an ideal candidate for the treatment of venous thrombosis. Further studies are needed to determine whether LMWH is superior to standard heparin as adjunctive therapy in patients undergoing coronary thrombolysis or angioplasty. Particularly promising in the setting of arterial thrombosis are hirudin, hirulog, and 7E3. With the encouraging results reported to date, it is likely that these agents will soon find their way into the treatment armamentarium of arterial thrombosis.
Amino Acid Sequence↗
Fibrin clot lysis by thrombolytic agents is impaired in newborns due to a low plasminogen concentration.
Although thrombolytic drugs have been extensively used in adults, there is sparse information on their effectiveness in newborns whose fibrinolytic system differs significantly from adults. The purpose of this study was to determine if low plasma levels of plasminogen in cord plasma limited the therapeutic effectiveness of thrombolytic agents. Urokinase (UK), streptokinase (SK) and tissue plasminogen activator (TPA) were compared for their ability to lyse washed 125I-labelled adult or cord fibrin clots suspended in cord or adult plasma. 125I-labelled fibrin clots were prepared by recalcifying cord or adult plasma spiked with labelled fibrinogen and then placed into cord or adult plasma which contained either saline or differing amounts of a specific thrombolytic agent. After a 60 min incubation, the remaining 125I-fibrin in clots released 125I-fibrin fragments, and concentrations of fibrinogen, alpha 2-antiplasmin, and plasminogen in the bathing plasma were measured and compared to starting values. Cord fibrin clots were more resistant than adult fibrin clots to all thrombolytic drugs tested (p less than 0.001). On average, the cord system retained 27% more 125I-fibrin in clots, and released 32% less 125I-fibrin fragments into plasma. Fibrinogenolysis was also decreased in cord plasmas compared to adult plasmas. The degree of fibrinolysis and fibrinogenolysis in cord plasma increased to adult values when plasminogen concentrations were increased in the bathing plasma. Thus, cord fibrin clots have an impaired response to thrombolytic agents secondary to low levels of plasminogen.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The effect of thrombin inhibitors on tissue plasminogen activator induced thrombolysis in a rat model.
Successful coronary thrombolysis depends on rapidly restoring blood flow and maintaining patency of the infarct-related artery. Although widely used as an adjunct to lytic therapy, heparin is limited in its ability to produce these effects. Since the limitations of heparin may reflect its inability to inactivate clot-bound thrombin, we developed a rat model of tissue plasminogen activator (t-PA) induced thrombolysis to compare doses of heparin, hirudin, hirulog (a synthetic hirudin-derived peptide), and D-Phe-Pro-ArgCH2Cl (PPACK) that produced a 4-fold prolongation of the baseline activated partial thromboplastin time (APTT) with saline in terms of their ability to accelerate thrombolysis and to prevent reocclusion. A thrombus rich in red cells and fibrin was formed in the distal aorta by applying an external constrictor after denuding the endothelium with a balloon catheter. Thrombolysis was induced with t-PA (1 mg/kg bolus, followed by 1 mg kg-1 h-1 over 30 min) and the rats were then randomized to receive a concomitant 80 min infusion of a thrombin inhibitor or saline. By continuously monitoring blood flow and pre- and post-stenotic blood pressures, the time to clot lysis, and the number of reocclusions were determined. Compared to saline, heparin had no significant effect on these variables.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Chloromethyl Ketones↗
Interactions of thermally denatured fibrinogen on polyethylene with plasma proteins and platelets.
During the investigation of fibrin deposition onto hydrophobic polymers in contact with human blood, a model was developed in which fibrinogen was denatured and irreversibly coated onto a polyethylene surface by heating to 70 degrees C for 10 min. The denatured fibrinogen-polyethylene surface is resistant to fluid wall shear rates of up to 550 s-1 and the fibrinogen does not desorb in the presence of plasma proteins. Compared to uncoated polyethylene, little albumin or fibrinogen adsorbs to heat-denatured fibrinogen. Thrombin binds to the denatured fibrinogen-coated polyethylene with low affinity and also acts on the surface-bound denatured fibrinogen and cleaves fibrinopeptide A (FPA) quantitatively. Washed, 51Cr-labeled platelets do not adhere to the thermally denatured fibrinogen at either low or high shear rates compared to surfaces coated with undenatured fibrinogen (p < 0.01). These observations support the role of the D domain of fibrinogen in platelet adhesion because this is the region that is denatured by heating. In contrast, the E domain of fibrinogen is not altered by heating to 70 degrees C and hence remains susceptible to thrombin and/or plasmin cleavage. The characteristics of this surface are such that it can be used to develop fibrin-coated surfaces for use in studies of thrombus formation on artificial surfaces.
Absorption↗
Lymphedema 30 years after radical mastectomy.
Lymphedema is a common and often distressing consequence of the management of breast cancer. This is the first report of new onset lymphedema 30 yr after radical mastectomy for the management of breast cancer. The patient's swelling began 10 days after commencing daily finger sticks to follow blood sugar, stemming from a recent diagnosis of diabetes mellitus. If proper precautions had been observed, swelling may not have developed. The patient had marked reduction of her edema with appropriate use of graded compression garments and self administered massage therapy, after early recognition and prompt intervention into her problem. This case highlights efforts that need to be made to prevent the development of edema.
Aged↗
Thrombin/antithrombin III complex formation in the neonatal respiratory distress syndrome.
Intravascular and intra-alveolar thrombin generation may exacerbate the pulmonary hypertension and surfactant dysfunction that characterize the neonatal respiratory distress syndrome (RDS). Although low levels of the most important thrombin inhibitor, antithrombin III (AT III), have been reported in infants with RDS, direct evidence of increased intravascular thrombin generation has been lacking. Accordingly, the objective of this study was to determine whether thrombin generation is increased in severe neonatal RDS. Thirty-nine infants of 25 to 29 wk gestation with a clinical and radiologic diagnosis of RDS were enrolled in a prospective cohort study. Plasma levels of thrombin/antithrombin III complexes (TAT) and AT III activity, measured 36 to 72 h after birth, were related to RDS severity. Seventeen infants had severe RDS (mean airway pressure greater than 10 cm H2O or FlO2 greater than 0.8), and 22 had mild or moderate disease. Mean birthweight (1,017 versus 1,054 g) and mean gestational age (27.8 versus 27.4 wk) were similar in both groups. The median TAT level in infants with severe RDS was significantly higher than that in patients with mild or moderate disease (10.7 and 4.0 micrograms/L, respectively; p less than 0.001). In addition, the mean AT III activity in infants with severe RDS was significantly lower than that in less severely affected patients (0.31 and 0.46 U/ml, respectively; p less than 0.01). Considering the entire cohort, plasma TAT levels were inversely correlated with the arterial/alveolar oxygen tension ratio (r = -0.48, p = 0.0022) and the ventilator efficiency index (r = -0.51, p = 0.0011). The elevated TAT levels and reduced AT III activity in infants with severe RDS are consistent with increased thrombin generation and resulting AT III consumption. Therefore, to regulate thrombin activity, these infants may benefit from replacement therapy with AT III concentrate.
Antithrombin III↗