Objectives The OVID study will demonstrate whether prophylactic-dose enoxaparin improves survival... more Objectives The OVID study will demonstrate whether prophylactic-dose enoxaparin improves survival and reduces hospitalizations in symptomatic ambulatory patients aged 50 or older diagnosed with COVID-19, a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation. Trial design The OVID study is conducted as a multicentre open-label superiority randomised controlled trial. Participants Inclusion Criteria 1. Signed patient informed consent after being fully informed about the study’s background. 2. Patients aged 50 years or older with a positive test for SARS-CoV2 in the past 5 days and eligible for ambulatory treatment. 3. Presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature >37.5° C. 4. Ability of the patient to travel to the study centre by private transportation, performed either by an accompanying person from the same household or by the patient themselves 5. Ability to ...
Clinical thrombophilia is the consequence of multiple gene and/or environment interactions. Throm... more Clinical thrombophilia is the consequence of multiple gene and/or environment interactions. Thrombophilia screening requires a targeted patient with specific indication, in which a finding would have implications. Carrying out a thrombophilia examination in the physician’s practice is often a cause of uncertainty and concern. The concerns begin in choosing the right patient to be examined, are associated with the time of investigation, with the choice of analysis, the test-material and with the correct interpretation of the results. Difficulties, which can influence the results, can occur with both organization and blood sampling. As common for any analysis, pre-analytical, analytical and post-analytical factors should be considered, as well as the possibility of false positive or false negative results. Finally, recommendation of correct therapeutic and prophylactic measures for the patient and his relatives is an additional focus. In this article we want to provide—on the basis of...
The utility of thrombophilia testing in clinical practice is still a matter of debate because stu... more The utility of thrombophilia testing in clinical practice is still a matter of debate because studies have not shown a benefit in the reduction of recurrent venous thromboembolism (VTE) risk in patients with thrombosis, despite the clearly higher VTE risk for first thrombosis. Screening for thrombophilia is indicated in selected patients. Particularly in selected young patients, especially women of childbearing age, the knowledge of the genetic thrombophilic defect may help in specific situations to decrease the risk of VTE events. Avoidance of modifiable risk factors and/or prophylactic thromboembolic procedures may be evaluated in selected patients. A comprehensive workup including personal and familial history, clinical examination, and laboratory test results including hereditary thrombophilia remains helpful in assessing the cumulative risk and the management of this group of selected patients.
We report the case of a 28-year old woman with extensive red-black colored lesions of the skin on... more We report the case of a 28-year old woman with extensive red-black colored lesions of the skin on the left thigh, which appeared without trauma. The disease arrived during longterm coumarin therapy because of a deep vein thrombosis and an antiphospholipid syndrome. After consideration of the differential diagnoses and due to the typical clinical picture we made the diagnosis of coumarin necrosis. We review the clinical and therapeutic features for this rare complication.
Intraoperative major bleeding is a common complication during surgery and can lead to the transfu... more Intraoperative major bleeding is a common complication during surgery and can lead to the transfusion of blood products and/or procoagulant drugs. This is a therapeutic challenge, and adherence to guidelines is desirable to preserve blood product resources. The intraoperative administration of fibrinogen concentrate, a pro-coagulant drug, in bleeding patients might reduce the use and therefore the risks associated with blood products. In this observational pilot study we determined whether fibrinogen measured by point-of-care thromboelastometry (Rotem®, fibtem-test) would lead to a similar therapeutical decision concerning the administration of fibrinogen concentrate when compared to the standard method (Clauss). Blood samples of 36 patients undergoing major surgery were simultaneously analyzed using both methods. According to the cutoff values of current guidelines based on the standard method, no patient would receive fibrinogen concentrate. In comparison, if point-of-care thrombo...
SummaryImmunoglobulin light chain (AL) amyloidosis is a systemic disease caused by a plasma cell ... more SummaryImmunoglobulin light chain (AL) amyloidosis is a systemic disease caused by a plasma cell clone synthesizing an unstable light chain, which forms amyloid fibrils. Deposition of amyloid fibrils affects primarily kidney, heart, nervous system, spleen, liver, gastrointestinal tract and the skin. Skin bleeding in these patients is called amyloid purpura. Classically, it occurs spontaneously and bilaterally in the periorbital region. Vessel wall fragility and damage by amyloid are the principal causes of periorbital and gastrointestinal bleeding. Additionally, coagulation factor inhibitory circulating paraprotein, hyperfibrinolysis, platelet dysfunction or isolated acquired factor X deficiency may contribute to even more severe, diffuse bleedings.Early diagnosis remains essential for improvsis. Although pictures of amyloid purpura have been often reported in the literature, the clinical diagnosis may be delayed. We report a case of cutaneous manifestation of AL amyloi-dosis diagno...
Objective The collection of lung fluid using a suction catheter (s-Cath) and non-bronchoscopic br... more Objective The collection of lung fluid using a suction catheter (s-Cath) and non-bronchoscopic bronchoalveolar lavage (mini-BAL) are two minimally invasive methods of sampling the distal airspaces in patients with the acute respiratory distress syndrome (ARDS). The objective of this study was to determine the similarity of the lung fluid samples recovered by these methods using proteomic analysis. Methods Distal lung fluid samples were collected from seven mechanically ventilated patients with ARDS using both s-Cath and mini-BAL in each patient and compared using two-dimensional difference gel electrophoresis. Protein spots of interest were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Main Results An average of 2,164 spots was detected in the s-Cath and mini-BAL samples. Of these, 68.4% of the protein spots were similar between the s-Cath and mini-BAL samples, 13.2% were increased in s-Cath compared to mini-BAL, and 18.4% were decrea...
Dear Sir, Long trips, especially air flights, are considered a risk for venous thromboembolism [1... more Dear Sir, Long trips, especially air flights, are considered a risk for venous thromboembolism [1–5]. The frequency of symptomatic thromboembolic events increases with the distance flown, but appears to be low [3]. In a recent study, however, Scurr et al. found symptomless calf vein thrombosis detected by ultrasonography in up to 10% of long-haul travelers [4]. Given the limited sensitivity of the method [6], the true incidence of travel-associated distal thrombi may even be higher. Taken together, these data suggest that subclinical thrombosis may be frequent during air travel but usually resolves once mobility is resumed. Accordingly, symptomatic thromboembolic events would reflect a rare situation where activation of coagulation escapes the natural control systems. The prolonged sitting position during an air trip is associated with venous stasis, decreased blood flow and hemoconcentration, and is widely assumed to be the main causal factor for thrombus formation in this setting. If this assumption is correct, prolonged immobility in a sitting position by itself would be sufficient to activate coagulation. Subclinical activation of coagulation a so-called prethrombotic state [7] can be assessed by sensitive biochemical markers of thrombin generation (prothrombin fragment 1þ 2, F1þ 2), of ongoing fibrin formation (fibrinopeptide A, FPA) and lysis (D-dimer, DD). The aim of this study was to test the hypothesis that prolonged immobility in a sitting position similar to the one occurring during air traveling activates coagulation. Forty healthy subjects of either sex (median age 29.5 years, range 19–58) with a negative personal and family history and no known risk factor for thromboembolism were kept seated for 6 h on normal chairs, with their knees bent; during this period they were allowed to drink, eat, read or watch television. At baseline and after 3 and 6 h of immobilization, blood was collected in CTADPPACK anticoagulant from sitting probands with a clean venepuncture from an antecubital vein under controlled venous stasis for measurement of F1þ 2 (Enzygnost F1þ 2 Behring), FPA (RIA reagents supplied by Imco), and DD (mini-VIDAS, BioMérieux). Hemoglobin concentration and hematocrit were determined as well. In order to control for the circadian variations of the hemostatic system [8], we used the same protocol for blood sampling in a subgroup of 18 volunteers who were allowed to move freely (control group). Statistical probability was assessed with repeated measures ANOVA on ranks followed by pairwise multiple comparison procedures (Student–Newman–Keuls method) for non-normally distributed data. A linear regression was done for correlation between data at baseline and after 6 h. A difference was considered significant when P <0.05. Over the 6 h of sitting position there was no change in the plasma levels of FPA and DD, whereas F1þ 2 levels decreased from a median of 0.49 to 0.40 nmol L 1 (P< 0.0001, Table 1). The F1þ 2 decrease was both relevant in quantitative terms ( 20% of the baseline values) and consistent among the volunteers (being present in 80% of them). For the three markers, there was a significant correlation between the values at baseline and those measured after 6 h (F1þ 2: r1⁄4 0.63, P< 0.0001; FPA: r1⁄4 0.52, P< 0.0007; DD: r1⁄4 0.83, P< 0.0001). Plasma volume did not change over the 6 h as indicated by stable values for hemoglobin and hematocrit. In the control group, values for F1þ 2 significantly decreased in the sitting position but did not change under ambulant conditions (Table 2). Overall, the quality of blood sampling and processing was very high, as reflected by individual values for FPA which were within the normal range in 168/176 samples (96%), were slightly increased in seven samples, and were above 5.5 nmol L 1 (and thus likely to represent a faulty venepuncture) in one sample (0.6%). Using the biochemical markers of thrombin generation and of ongoing fibrin formation and lysis, we were not able to confirm the hypothesis of activation of coagulation in subjects immobilized in a sitting position. While the failed increase in FPA and DD would not by itself definitively reject the study hypothesis (small quantities of fibrin deposited in the lower limbs could have escaped detection due to the effect of dilution of these markers in circulating blood), the significant decrease of F1þ 2 indicates a reduced rate of thrombin generation during sitting. The decrease in F1þ 2 cannot be explained solely by circadian variations and was the consequence of the prolonged immobilization in a sitting position. It is tempting to speculate that the reduction in thrombin generation reflects a protective down-regulation of the hemostatic system to counter the effect of venous stasis. This suggestion, however, has to be tempered by the fact that thrombin has both procoagulant and anticoagulant effects [9], and that the protein C system mediated anticoagulant effect may even be prevalent under…
Recent studies have shown that a low clinical pretest probability may be adequate for excluding h... more Recent studies have shown that a low clinical pretest probability may be adequate for excluding heparin-induced thrombocytopenia. However, for patients with intermediate or high pretest probability, laboratory testing is essential for confirming or refuting the diagnosis. Rapid assessment of anti-PF4/heparin-antibodies may assist clinical decision-making. To evaluate the performance of rapid ID-H/PF4-PaGIA. In particular, we verified reproducibility of results between plasma and serum specimens, between fresh and frozen samples, and between different ID-H/PF4-polymer lots (polystyrene beads coated with heparin/PF4-complexes). The samples studied were 1376 plasma and 914 corresponding serum samples from patients investigated for suspected heparin-induced thrombocytopenia between January 2000 and October 2008. Anti-PF4/heparin-antibodies were assessed by ID-H/PF4-PaGIA, commercially available ELISAs and heparin-induced platelet aggregation test. Among 914 paired plasma/serum samples we noted discordant results (negative vs. low-titre positive) in nine instances (1%; 95%CI, 0.4-1.6%). Overall, agreement between titres assessed in plasma vs. serum was highly significant (Spearman correlation coefficient, 0.975; P &lt; 0.0001). Forty-seven samples tested both fresh and after freezing/thawing showed a good agreement, with one discordant positive/negative result (Spearman correlation coefficient, 0.970; P &lt; 0.0001). Among 1376 plasma samples we noted a strikingly variable incidence of false negative results (none - 82%; 95%CI, 66-98%), depending on the employed ID-H/PF4-polymer lot. Faulty lots can be recognized by titrating commercial positive controls and stored samples of HIT-patients. Laboratories performing the assay should implement stringent internal quality controls in order to recognize potentially faulty ID-H/PF4-polymer lots, thus avoiding false negative results.
Objectives The OVID study will demonstrate whether prophylactic-dose enoxaparin improves survival... more Objectives The OVID study will demonstrate whether prophylactic-dose enoxaparin improves survival and reduces hospitalizations in symptomatic ambulatory patients aged 50 or older diagnosed with COVID-19, a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation. Trial design The OVID study is conducted as a multicentre open-label superiority randomised controlled trial. Participants Inclusion Criteria 1. Signed patient informed consent after being fully informed about the study’s background. 2. Patients aged 50 years or older with a positive test for SARS-CoV2 in the past 5 days and eligible for ambulatory treatment. 3. Presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature >37.5° C. 4. Ability of the patient to travel to the study centre by private transportation, performed either by an accompanying person from the same household or by the patient themselves 5. Ability to ...
Clinical thrombophilia is the consequence of multiple gene and/or environment interactions. Throm... more Clinical thrombophilia is the consequence of multiple gene and/or environment interactions. Thrombophilia screening requires a targeted patient with specific indication, in which a finding would have implications. Carrying out a thrombophilia examination in the physician’s practice is often a cause of uncertainty and concern. The concerns begin in choosing the right patient to be examined, are associated with the time of investigation, with the choice of analysis, the test-material and with the correct interpretation of the results. Difficulties, which can influence the results, can occur with both organization and blood sampling. As common for any analysis, pre-analytical, analytical and post-analytical factors should be considered, as well as the possibility of false positive or false negative results. Finally, recommendation of correct therapeutic and prophylactic measures for the patient and his relatives is an additional focus. In this article we want to provide—on the basis of...
The utility of thrombophilia testing in clinical practice is still a matter of debate because stu... more The utility of thrombophilia testing in clinical practice is still a matter of debate because studies have not shown a benefit in the reduction of recurrent venous thromboembolism (VTE) risk in patients with thrombosis, despite the clearly higher VTE risk for first thrombosis. Screening for thrombophilia is indicated in selected patients. Particularly in selected young patients, especially women of childbearing age, the knowledge of the genetic thrombophilic defect may help in specific situations to decrease the risk of VTE events. Avoidance of modifiable risk factors and/or prophylactic thromboembolic procedures may be evaluated in selected patients. A comprehensive workup including personal and familial history, clinical examination, and laboratory test results including hereditary thrombophilia remains helpful in assessing the cumulative risk and the management of this group of selected patients.
We report the case of a 28-year old woman with extensive red-black colored lesions of the skin on... more We report the case of a 28-year old woman with extensive red-black colored lesions of the skin on the left thigh, which appeared without trauma. The disease arrived during longterm coumarin therapy because of a deep vein thrombosis and an antiphospholipid syndrome. After consideration of the differential diagnoses and due to the typical clinical picture we made the diagnosis of coumarin necrosis. We review the clinical and therapeutic features for this rare complication.
Intraoperative major bleeding is a common complication during surgery and can lead to the transfu... more Intraoperative major bleeding is a common complication during surgery and can lead to the transfusion of blood products and/or procoagulant drugs. This is a therapeutic challenge, and adherence to guidelines is desirable to preserve blood product resources. The intraoperative administration of fibrinogen concentrate, a pro-coagulant drug, in bleeding patients might reduce the use and therefore the risks associated with blood products. In this observational pilot study we determined whether fibrinogen measured by point-of-care thromboelastometry (Rotem®, fibtem-test) would lead to a similar therapeutical decision concerning the administration of fibrinogen concentrate when compared to the standard method (Clauss). Blood samples of 36 patients undergoing major surgery were simultaneously analyzed using both methods. According to the cutoff values of current guidelines based on the standard method, no patient would receive fibrinogen concentrate. In comparison, if point-of-care thrombo...
SummaryImmunoglobulin light chain (AL) amyloidosis is a systemic disease caused by a plasma cell ... more SummaryImmunoglobulin light chain (AL) amyloidosis is a systemic disease caused by a plasma cell clone synthesizing an unstable light chain, which forms amyloid fibrils. Deposition of amyloid fibrils affects primarily kidney, heart, nervous system, spleen, liver, gastrointestinal tract and the skin. Skin bleeding in these patients is called amyloid purpura. Classically, it occurs spontaneously and bilaterally in the periorbital region. Vessel wall fragility and damage by amyloid are the principal causes of periorbital and gastrointestinal bleeding. Additionally, coagulation factor inhibitory circulating paraprotein, hyperfibrinolysis, platelet dysfunction or isolated acquired factor X deficiency may contribute to even more severe, diffuse bleedings.Early diagnosis remains essential for improvsis. Although pictures of amyloid purpura have been often reported in the literature, the clinical diagnosis may be delayed. We report a case of cutaneous manifestation of AL amyloi-dosis diagno...
Objective The collection of lung fluid using a suction catheter (s-Cath) and non-bronchoscopic br... more Objective The collection of lung fluid using a suction catheter (s-Cath) and non-bronchoscopic bronchoalveolar lavage (mini-BAL) are two minimally invasive methods of sampling the distal airspaces in patients with the acute respiratory distress syndrome (ARDS). The objective of this study was to determine the similarity of the lung fluid samples recovered by these methods using proteomic analysis. Methods Distal lung fluid samples were collected from seven mechanically ventilated patients with ARDS using both s-Cath and mini-BAL in each patient and compared using two-dimensional difference gel electrophoresis. Protein spots of interest were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Main Results An average of 2,164 spots was detected in the s-Cath and mini-BAL samples. Of these, 68.4% of the protein spots were similar between the s-Cath and mini-BAL samples, 13.2% were increased in s-Cath compared to mini-BAL, and 18.4% were decrea...
Dear Sir, Long trips, especially air flights, are considered a risk for venous thromboembolism [1... more Dear Sir, Long trips, especially air flights, are considered a risk for venous thromboembolism [1–5]. The frequency of symptomatic thromboembolic events increases with the distance flown, but appears to be low [3]. In a recent study, however, Scurr et al. found symptomless calf vein thrombosis detected by ultrasonography in up to 10% of long-haul travelers [4]. Given the limited sensitivity of the method [6], the true incidence of travel-associated distal thrombi may even be higher. Taken together, these data suggest that subclinical thrombosis may be frequent during air travel but usually resolves once mobility is resumed. Accordingly, symptomatic thromboembolic events would reflect a rare situation where activation of coagulation escapes the natural control systems. The prolonged sitting position during an air trip is associated with venous stasis, decreased blood flow and hemoconcentration, and is widely assumed to be the main causal factor for thrombus formation in this setting. If this assumption is correct, prolonged immobility in a sitting position by itself would be sufficient to activate coagulation. Subclinical activation of coagulation a so-called prethrombotic state [7] can be assessed by sensitive biochemical markers of thrombin generation (prothrombin fragment 1þ 2, F1þ 2), of ongoing fibrin formation (fibrinopeptide A, FPA) and lysis (D-dimer, DD). The aim of this study was to test the hypothesis that prolonged immobility in a sitting position similar to the one occurring during air traveling activates coagulation. Forty healthy subjects of either sex (median age 29.5 years, range 19–58) with a negative personal and family history and no known risk factor for thromboembolism were kept seated for 6 h on normal chairs, with their knees bent; during this period they were allowed to drink, eat, read or watch television. At baseline and after 3 and 6 h of immobilization, blood was collected in CTADPPACK anticoagulant from sitting probands with a clean venepuncture from an antecubital vein under controlled venous stasis for measurement of F1þ 2 (Enzygnost F1þ 2 Behring), FPA (RIA reagents supplied by Imco), and DD (mini-VIDAS, BioMérieux). Hemoglobin concentration and hematocrit were determined as well. In order to control for the circadian variations of the hemostatic system [8], we used the same protocol for blood sampling in a subgroup of 18 volunteers who were allowed to move freely (control group). Statistical probability was assessed with repeated measures ANOVA on ranks followed by pairwise multiple comparison procedures (Student–Newman–Keuls method) for non-normally distributed data. A linear regression was done for correlation between data at baseline and after 6 h. A difference was considered significant when P <0.05. Over the 6 h of sitting position there was no change in the plasma levels of FPA and DD, whereas F1þ 2 levels decreased from a median of 0.49 to 0.40 nmol L 1 (P< 0.0001, Table 1). The F1þ 2 decrease was both relevant in quantitative terms ( 20% of the baseline values) and consistent among the volunteers (being present in 80% of them). For the three markers, there was a significant correlation between the values at baseline and those measured after 6 h (F1þ 2: r1⁄4 0.63, P< 0.0001; FPA: r1⁄4 0.52, P< 0.0007; DD: r1⁄4 0.83, P< 0.0001). Plasma volume did not change over the 6 h as indicated by stable values for hemoglobin and hematocrit. In the control group, values for F1þ 2 significantly decreased in the sitting position but did not change under ambulant conditions (Table 2). Overall, the quality of blood sampling and processing was very high, as reflected by individual values for FPA which were within the normal range in 168/176 samples (96%), were slightly increased in seven samples, and were above 5.5 nmol L 1 (and thus likely to represent a faulty venepuncture) in one sample (0.6%). Using the biochemical markers of thrombin generation and of ongoing fibrin formation and lysis, we were not able to confirm the hypothesis of activation of coagulation in subjects immobilized in a sitting position. While the failed increase in FPA and DD would not by itself definitively reject the study hypothesis (small quantities of fibrin deposited in the lower limbs could have escaped detection due to the effect of dilution of these markers in circulating blood), the significant decrease of F1þ 2 indicates a reduced rate of thrombin generation during sitting. The decrease in F1þ 2 cannot be explained solely by circadian variations and was the consequence of the prolonged immobilization in a sitting position. It is tempting to speculate that the reduction in thrombin generation reflects a protective down-regulation of the hemostatic system to counter the effect of venous stasis. This suggestion, however, has to be tempered by the fact that thrombin has both procoagulant and anticoagulant effects [9], and that the protein C system mediated anticoagulant effect may even be prevalent under…
Recent studies have shown that a low clinical pretest probability may be adequate for excluding h... more Recent studies have shown that a low clinical pretest probability may be adequate for excluding heparin-induced thrombocytopenia. However, for patients with intermediate or high pretest probability, laboratory testing is essential for confirming or refuting the diagnosis. Rapid assessment of anti-PF4/heparin-antibodies may assist clinical decision-making. To evaluate the performance of rapid ID-H/PF4-PaGIA. In particular, we verified reproducibility of results between plasma and serum specimens, between fresh and frozen samples, and between different ID-H/PF4-polymer lots (polystyrene beads coated with heparin/PF4-complexes). The samples studied were 1376 plasma and 914 corresponding serum samples from patients investigated for suspected heparin-induced thrombocytopenia between January 2000 and October 2008. Anti-PF4/heparin-antibodies were assessed by ID-H/PF4-PaGIA, commercially available ELISAs and heparin-induced platelet aggregation test. Among 914 paired plasma/serum samples we noted discordant results (negative vs. low-titre positive) in nine instances (1%; 95%CI, 0.4-1.6%). Overall, agreement between titres assessed in plasma vs. serum was highly significant (Spearman correlation coefficient, 0.975; P &lt; 0.0001). Forty-seven samples tested both fresh and after freezing/thawing showed a good agreement, with one discordant positive/negative result (Spearman correlation coefficient, 0.970; P &lt; 0.0001). Among 1376 plasma samples we noted a strikingly variable incidence of false negative results (none - 82%; 95%CI, 66-98%), depending on the employed ID-H/PF4-polymer lot. Faulty lots can be recognized by titrating commercial positive controls and stored samples of HIT-patients. Laboratories performing the assay should implement stringent internal quality controls in order to recognize potentially faulty ID-H/PF4-polymer lots, thus avoiding false negative results.
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