Biomedical subjects
Publications and source records attributed to J Kienast.
Advances in interventional cardiology offer new choices for patients with coronary artery disease. Unfortunately, these new procedures are associated with complications, such as femoral artery pseudoaneurysms. Accurate and timely vascular assessments by adult health nurses can detect this problem and result in prompt treatment, sometimes including ultrasound-guided compression.
Septic shock and multiple organ failure may be associated with coagulation activation, disseminated fibrin formation, and consumption of coagulation inhibitors such as antithrombin III. We have evaluated prospectively coagulation measurements in patients with severe chemotherapy-induced neutropenia. This group of patients was chosen because of their high risk of developing severe septic complications, thus allowing serial prospective coagulation testing before and during evolving sepsis or septic shock. Sixty-two patients with febrile infectious events were accrued to the study. Of these, 13 patients progressed to severe sepsis and 13 additional patients to septic shock as defined according to standard diagnostic criteria. At the onset of fever, factor (F) VIIa activity, FVII antigen and antithrombin III (AT III) activity decreased from normal baseline levels and were significantly lower in the group of patients who progressed to septic shock compared with those that developed severe sepsis (medians: 0.3 v 1.4 ng/mL, 21 v 86 U/dL and 45% v 95%; P < .001). The decrease of these measurements in septic shock was accompanied by an increase in prothrombin fragment 1+2 (median: 3.6 v 1.4 nmol/L; P = .05), a marker of thrombin generation. These differences were sustained throughout the septic episode (P < .0001). FVIIa and AT III levels of < 0.8 ng/mL and < 70%, respectively, at onset of fever predicted a lethal outcome with a sensitivity of 100% and 85%, and a specificity of 75% and 85%, respectively. In contrast, FXIIa-alpha antigen levels were not different between groups at onset of fever but increased modestly during the course of septic shock (P = .001). Thus, septic shock in neutropenic patients is associated with increased thrombin generation. Furthermore, both FVIIa and AT III measurements are sensitive markers of an unfavorable prognosis.
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OBJECTIVE: To study comparatively the effects of volume-controlled vs. biphasic positive airway pressure mechanical ventilation on respiratory mechanics and oxygenation in leukopenic patients with severe respiratory failure. DESIGN: Prospective, comparative study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: Leukopenic (<1000 leukocytes/microliter) patients (n=20) after cytoreductive chemotherapy requiring mechanical ventilation for severe respiratory failure (Murray score of > 2.5). INTERVENTION: Patients were assigned in a consecutive, alternating manner to receive either volume-controlled or biphasic positive airway pressure mechanical ventilation, starting within 12 to 24 hrs after endotracheal intubation. MEASUREMENTS AND MAIN RESULTS: Tidal volume, inspiratory flow, peak inspiratory and positive end-expiratory pressures, FIO2, and arterial blood gas analyses were recorded hourly for a study period of 48 hrs. Biphasic positive airway pressure ventilation was associated with a significant reduction in peak inspiratory pressure (mean differences at 24, 36, and 48 hrs: 4.4, 3.4, and 4.2 cm H2O; p = .024, .019, and .013, respectively) and positive end-expiratory pressures (mean differences at 24, 36, and 48 hrs: 1.6, 1.4, and 1.5 cm H20; p = .023, .024, and .023, respectively) at significantly lower FIO2 (mean differences at 12, 24, 36, and 48 hrs; p = .007, .015, .016, and .011, respectively). PaO2/FIO2 ratios and CO2 removal were similar under ventilatory conditions. CONCLUSIONS: Biphasic positive airway pressure ventilation offers the advantage of significantly reduced peak inspiratory and positive end-expiratory pressures at a lower FIO2 and with at least similar oxygenation and CO2 removal as achieved by volume-controlled mechanical ventilation. Our results are in line with previous reports on nonleukopenic patients and suggest that the positive effects of pressure-limited mechanical ventilation are independent of circulating white blood cells. Further studies are mandatory to demonstrate clinical benefit in this critically ill patient population.
Because measurements of hemostatic factors might aid the prediction of cardiovascular clinical events, we investigated the long-term prognostic importance of selected hemostatic factors in patients with angina pectoris. At recruitment, 209 patients underwent clinical assessment and coronary angiography, and a range of hemostatic factors were measured. During the follow-up period of 9 years, 58 patients (28%) suffered a cardiac event (acute myocardial infarction or death from cardiac causes). The risk of cardiac events was positively related to baseline measurements of fibrinogen (risk ratio per SD [RR] increase 1.29, 95% confidence interval [CI] 0.99 to 1.68, P=.06) and negatively related to antithrombin III activity measurements (RR 0.75, 95% CI 0.59 to 0.95, P=.02). No other hemostatic factor measured was significantly related to the risk of having a cardiac event. Worsening of angina in the few weeks before and ejection fraction evaluation at the initial angiography were both strongly related to the risk of cardiac events. However, the relationships of fibrinogen and antithrombin III measurements to risk remained almost unchanged after adjusting for worsening of angina and ejection fraction. Fibrinogen and antithrombin III may have an important etiologic role in the prognosis of patients with angina pectoris.
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Variables of the fibrinolytic system were prospectively studied in patients with haematologic malignancies in chemotherapy-induced leukocytopenia at onset and during the course of septicemia to evaluate their prognostic value. This group of patients was chosen because of their high risk of developing severe septic complications, thus allowing serial prospective testing of fibrinolytic variables prior to and during evolving sepsis or septic shock. 62 patients with febrile infectious events were accrued to the study. Of these, 13 patients progressed to severe sepsis and an additional 13 patients to septic shock as defined according to standard diagnostic criteria. At onset of fever, plasminogen activator inhibitor (PAI) activity and PAI-1 antigen levels increased from normal baseline levels and were significantly higher in the group of patients who developed septic shock compared to those with severe sepsis (medians: 10.6 versus 1.3 U/ml, p = 0.0001; 50.0 versus 5.0 ng/ml, p = 0.0002). The increase in PAI activity and antigen in septic shock was accompanied by an increase in tissue-type plasminogen activator antigen and total fibrin(ogen) degradation products and a decrease in alpha(2)-antiplasmin activity (p < 0.006). In contrast, in the group of patients that developed severe sepsis the variables of the fibrinolytic system remained unchanged at onset of fever. These differences between septic shock and severe sepsis were sustained throughout the septic episode for all variables (p < 0.0001). PAI activity of > 5 U/ml at onset of fever predicted a lethal outcome with a sensitivity of 92% and a specificity of 100%. Thus, septic shock in leukocytopenia is associated with significant activation of the fibrinolytic system presumably as a response of the vascular endothelium to inflammatory injury. Furthermore, PAI activity measurements are sensitive markers of an unfavourable prognosis.
On average, plasma fibrinogen concentrations are significantly increased in patients with overt ischaemic heart disease as compared with healthy individuals or patients with normal coronary arteries on angiographic examination. Fibrinogen levels appear to be positively related to the extent and severity of coronary artery disease as assessed by angiography. Prospective studies have demonstrated the prognostic significance of plasma fibrinogen levels, measured during stable phases of the disease, with respect to the incidence of myocardial infarction and cardiovascular mortality. In accordance with the results of prospective population studies, fibrinogen may be considered a cardiovascular risk marker in patients with manifest coronary heart disease. This should be accounted for in future intervention trials.
BACKGROUND: Increased levels of certain hemostatic factors may play a part in the development of acute coronary syndromes and may be associated with an increased risk of coronary events in patients with angina pectoris. METHODS: We conducted a prospective multicenter study of 3043 patients with angina pectoris who underwent coronary angiography and were followed for two years. Base-line measurements included the concentrations of selected hemostatic factors indicative of a thrombophilic state or endothelial injury. The results were analyzed in relation to the subsequent incidence of myocardial infarction or sudden coronary death. RESULTS: After adjustment for the extent of coronary artery disease and other risk factors, an increased incidence of myocardial infarction or sudden death was associated with higher base-line concentrations of fibrinogen (mean +/- SD, 3.28 +/- 0.74 g per liter in patients who subsequently had coronary events, as compared with 3.00 +/- 0.71 g per liter in those who did not; P = 0.01), von Willebrand factor antigen (138 +/- 49 percent vs. 125 +/- 49 percent, P = 0.05), and tissue plasminogen activator (t-PA) antigen (11.9 +/- 4.7 ng per milliliter vs. 10.0 +/- 4.2 ng per milliliter, P = 0.02). The concentration of C-reactive protein was also directly correlated with the incidence of coronary events (P = 0.05), except when we adjusted for the fibrinogen concentration. In patients with high serum cholesterol levels, the risk of coronary events rose with increasing levels of fibrinogen and C-reactive protein, but the risk remained low even given high serum cholesterol levels in the presence of low fibrinogen concentrations. CONCLUSIONS: In patients with angina pectoris, the levels of fibrinogen, von Willebrand factor antigen, and t-PA antigen are independent predictors of subsequent acute coronary syndromes. In addition, low fibrinogen concentrations characterize patients at low risk for coronary events despite increased serum cholesterol levels. Our data are consistent with a pathogenetic role of impaired fibrinolysis, endothelial-cell injury, and inflammatory activity in the progression of coronary artery disease.
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The potential value of measurements of prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complexes (TAT) and D-dimer for the assessment of antithrombotic efficacy of heparin in acute deep venous thrombosis (DVT) was prospectively investigated. These variables were determined at presentation and subsequently once daily during a course of seven days heparin therapy. Heparin doses were adjusted according to the activated partial thromboplastin time (APTT). Compression ultrasonography was performed at presentation and on day 7 to determine the extent of thrombosis according to a predefined score. Out of a total of 50 patients accrued to the study 44 patients had reduced or unchanged extent of thrombosis, whereas in six patients an extension was documented. Although thrombin generation was significantly inhibited after initiation of heparin therapy as reflected by a decrease in F1 + 2 and TAT levels, these markers were not useful for the detection of patients with DVT extension. In contrast, anti-factor-Xa activities but not APTT measurements were significantly lower in the group of patients with propagation of DVT (median: 0.22 U/ml versus 0.38 U/ml, interquartile range: 0.1-0.33 U/ml versus 0.19-0.55 U/ml; P = 0.001). D-dimer decreased within the first days of heparin therapy but failed to indicate DVT progression. These data suggest that plasma anti-factor-Xa activity correlates better with the antithrombotic efficacy of heparin than APTT measurements and markers of coagulation or fibrinolysis activation.
Increased expression of plasminogen activator inhibitor-1 (PAI-1) has been demonstrated in the human atherosclerotic vessel wall and may contribute to the impaired plasma fibrinolytic capacity in patients at high risk of atherothrombotic events. In addition, the mural PA/plasmin system may have important pathobiologic functions during atherogenesis. We quantitatively analyzed PAs of the tissue type (TPA) and urokinase type (UPA), PAIs, and plasminogen in protein extracts from different layers of human aorta in relation to the presence and severity of atherosclerotic lesions. In comparison with normal control vessels, intimal and neointimal TPA concentrations were reduced in atherosclerotic aortas except in the necrotic core areas of advanced plaques, where TPA was mainly complexed to PAI-1 in extracellular matrix deposits. In the media, TPA antigen was higher in lesional segments and closely associated with smooth muscle cells. UPA antigen was increased in the intima of atherosclerotic lesions and colocalized with tissue-infiltrating macrophages and neointimal smooth muscle cells. By spectrophotometric assay, neither TPA nor UPA activity could be detected in intimal or medial extracts. PAI-1 concentrations increased significantly in the intima of atherosclerotic segments compared with adjacent uninvolved areas or control aortas. The immunohistochemical distribution of PAI-1 was similar to that observed for TPA. A large excess of PAI-1 over PA concentrations, particularly in the intimal layer, characterizes atherosclerotic lesions of the human aorta and suggests that PA action is locally confined and counterbalanced by enhanced PAI expression and accumulation.
Septic shock is the major cause of treatment-related death in patients with acute myelogenous leukaemia (AML) undergoing intensive chemotherapy. Interleukins (IL)-1 beta, -6, -8, and tumour necrosis factor alpha (TNF-alpha) have been implicated as mediators of septic shock, with circulating leucocytes being considered a major source for their release. However, plasma cytokine levels of leucocytopenic patients with evolving sepsis have not been studied. We have prospectively measured plasma cytokines during chemotherapy-induced leucocytopenia (< 1 x 10(9)/l) in 50 patients with AML. Cytokine levels in patients with severe sepsis (n = 5) or septic shock (n = 8) were compared to those measured in 13 matched patients with uncomplicated febrile infections. In evolving septic shock, IL-6, IL-8 and TNF-alpha peaked within 48 h of fever onset at levels reported for non-leucocytopenic patients and distinctively higher than during uncomplicated febrile episodes (P < 0.05). Peak concentrations measured within 48 h after onset of fever were related to fatal outcome. IL-1 beta was detected in less than 5% of all samples. Cytokine concentrations were unrelated to leucocyte counts and markers of neutrophil or monocyte activation (elastase and neopterin levels, respectively). We conclude that cytokine release associated with evolving septic shock in patients with AML does not depend on circulating leucocytes.
BACKGROUND: As a result of their polypeptidic nature, hirudins could theoretically elicit an immunologic response in humans. METHODS: The present open survey evaluates the allergenic potential of recombinant hirudin CGP 39393 (REVASC) after repeated intravenous or subcutaneous exposures in immunocompetent volunteers with no known previous exposure to hirudins. Clinical signs and symptoms of allergic manifestations and surrogate markers of allergy (i.e. response to skin tests) were collected before and after each administration of CGP 39393. Hirudin-specific immunoglobulin (Ig)G or IgE antibodies were measured. RESULTS: Two hundred and sixty-three healthy volunteers were eligible, of whom 12.2% had a history of allergy and 18.3% had a high level of total IgE. No signs or symptoms of allergy directly attributable to CGP 39393 were reported, either during or immediately after a first challenge. Irritative skin reactions, to either the prick or the intradermal skin test, were observed in eight volunteers 28-56 days after the challenge. Three out of 200 volunteers exposed to a second course of CGP 39393 showed signs and symptoms of an allergic reaction. In all but one subject with a pruritic erythema it was possible to rule out a causative role for CGP 39393 (0.50%, 95% confidence limits [CL] 0.01-2.75). Three other volunteers displayed a suspect or a positive immediate-type skin reaction to the follow-up intradermal skin test without any signs or symptoms of allergy. Another asymptomatic volunteer (0.80%, 95% CL: 0.02-4.41) developed a low [i.e. 1+ on the radio-allergosorbent test (RAST) scale] but measurable titre of hirudin-specific IgE antibodies after the second exposure to CGP 39393. A third exposure in five volunteers was clinically uneventful. A positive reaction to the prick test and to the intradermal skin test was observed in one individual. CONCLUSIONS: Recombinant hirudin CGP 39393 appears to be a weak allergen. Repeated exposures are safe in fully immunocompetent subjects, including those with a history of previous allergies and high levels of total IgE. Type I allergic reactions are rare (i.e. less than 1%) after a second exposure and are limited to the skin. Routine skin tests are not needed to identify patients at risk of developing type I allergic reactions. Hirudin-specific IgE antibodies are rarely seen and then at very low titres.
Over the past five years, the results of six prospective randomized trials have set new standards in the primary and secondary prevention of thromboembolism in "nonvalvular" ("nonrheumatic") atrial fibrillation. On the one hand, they have confirmed the increased risk of stroke in these patients amounting to about 5% per year and an annual recurrence rate after a recent transient ischaemic attack or minor stroke of 12%. On the other hand, the results of these trials have unanimously demonstrated a > or = 60% risk reduction with oral anticoagulation at an acceptable risk of major bleeding complications. A reduced intensity of anticoagulant therapy with a target INR of 2.0-3.0 is effective in most of these patients. Both clinical and echocardiographic features allow the identification of subgroups at low or high risk of thromboembolic complications and provide the basis for the individual benefit-to-risk assessment of anticoagulant therapy. Aspirin is currently recommended as a second choice therapy for patients who are poor candidates for oral anticoagulants or who are considered to be at low risk for thromboembolism.
Plasma from healthy individuals, pregnant women and patients on warfarin were distributed to 3 laboratories supporting major cardiovascular surveys (Northwick Park, Muenster and Houston) for assay of factor VII coagulant activity (VIIc) with their own bio-assays. The mean VIIc in 147 samples agreed to within 1% of standard in Northwick Park and Houston, but was 14% of standard lower in Muenster owing to its more potent standard. In samples with an increased VIIc the Northwick Park assay gave a higher result than the other assays owing to its increased responsiveness to activated factor VII (VIIa). Thus when VIIa concentrations were determined directly with a clotting assay which utilises a soluble recombinant tissue factor, the increase in VIIc with increase in VIIa was considerably greater with the Northwick Park assay than the Muenster assay. This feature of the Northwick Park assay was traced to the virtual absence of protein C in its substrate plasma. Factor Va appears rate-limiting for the coagulant expression of VIIa in test plasma. If the thrombotic response to release of tissue factor is determined by the circulating concentration of VIIa, then the Northwick Park factor VII bio-assay may be preferable to other bio-assays currently employed to estimate risk of acute coronary events.
The variability of haemostatic factor measurements in patients presenting with angina pectoris is investigated. In all, 219 middle aged patients (almost all men) provided repeat measurements 2.5 years apart on a battery of haemostatic and haematological tests and other cardiovascular risk factors. Correlations between repeat measurements were lower than might be expected in a healthy population, reflecting a relatively large degree of variability within individuals over time. The highest correlations observed for haemostatic factors were for von Willebrand factor related antigen (r = 0.48) and fibrinogen (r = 0.45). The correlations were generally lower amongst patients who had undergone coronary surgery or angioplasty between the two measurements. We conclude that the underlying relationship of fibrinogen to coronary risk must be much greater than is generally appreciated, since even single measurements are found to be important predictors of risk, despite only moderate stability over time. The very low correlations for beta-thromboglobulin (r = 0.10) and platelet factor 4 (r = 0.03) which were observed in this study casts doubt on their potential usefulness as predictors of long-term cardiovascular risk.
Plasma levels of the prothrombin activation fragment 1 + 2 (F 1 + 2) and of thrombin antithrombin III complexes (TAT) were determined in 225 patients with angina pectoris undergoing coronary angiography. Oral anticoagulant therapy was associated with a marked reduction in mean F1 + 2 (0.63 vs 1.62 nmol/l, p < 0.0001) and TAT levels (1.65 vs 2.23 micrograms/l, p < 0.0001). Omitting patients on oral anticoagulants, TAT values showed a positive association with patients' age (r = 0.18; p = 0.01) and were slightly higher in patients with a history of myocardial infarction than in those without (2.47 vs 2.11 micrograms/l; p = 0.06). Both F1 + 2 and TAT levels were increased in patients with angiographically verified coronary atherosclerosis as compared to patients with angina and angiographically normal coronaries (F1 + 2: 1.76 vs 1.36 nmol/l, TAT: 2.35 vs 2.00 micrograms/l; p-values after adjusting for age, sex and past history of myocardial infarction 0.06 and 0.11 respectively). However, no graded relationship between F1 + 2 or TAT values and severity of atherosclerosis was observed. This study provides suggestive evidence that a procoagulant state exists in patients with angina pectoris and coronary atherosclerosis. Its relevance in predicting coronary ischaemic events needs to be studied prospectively.