High Plasma Apolipoprotein(a) Concentration and Low Plasmin Tpa Enzymatic Activity in Hospitalized Patients with COVID-19

Abstract Thrombotic and thromboembolic complications in patients diagnosed with coronavirus disease 2019 (COVID-19) are emerging as important sequelae that contribute to mortality, including disseminated intravascular coagulation, pulmonary embolism, deep vein thrombosis, ischemic stroke, and myocardial infraction. Reported incidence of thrombotic and thromboembolic complications in moderate/severe COVID-19 patients is from 21% to 49%, while even higher incidence in non-surviving COVID-19 patients. However, the underlying mechanism between thrombosis and COVID-19 is still unclear. Tissue-type plasminogen activator (tPA) plays an important role on initiating fibrinolysis by converting zymogen plasminogen to plasmin, a serine protease that degrades the fibrin clot, and therefore preventing excessive pathological blood clots. A homologous protein to plasminogen is apolipoprotein(a) [apo(a)], a major component of lipoprotein(a). The apo(a) inhibits fibrinolysis and exacerbates thrombosis through blocking the conversion from Glu-plasminogen to Lys-plasminogen, which has a higher binding affinity to fibrin and is a better substrate to tPA. The population distribution of plasma apo(a) level is positively skewed (most values are clustered around the left tail of the distribution close to zero), and the plasma apo(a) level in most people is less than 300 μg/mL. High plasma concentration of apo(a) (> 300 μg/mL), or genetic variants of LPA, the gene that encodes for apo(a), correlates with thrombotic cardiovascular risk and thromboembolic risk in many population-based clinical or genetic studies. To investigate the potential correlation between infection of SARS-COV-2 and thrombosis, we tested de-identified plasma samples collected from hospitalized patients with or without positivity of SARS-CoV-2 testing results and COVID-19 diagnosis (ICD10CM:U07.1) through the COVD-19 Tissue Bank at the Medical College of Wisconsin. The tPA enzymatic activity was measured by the release of p-nitroaniline chromophore from a plasmin-specific synthetic substrate with exogenous human plasminogen, with the intensity of color proportional to tPA activity. The apo(a) concentration is measured by ELISA capturing total apo(a) antigen. Our results show that the SARS-CoV-2-positive inpatients have higher plasma tPA concentration than the SARS-CoV-2 negative inpatients (6.0 versus 3.0 ng/mL, p<0.05), while plasma tPA enzymatic activity is lower in SARS-CoV-2-positive inpatients than the SARS-CoV-2 negative inpatients (15.2 versus 25.5 ΔA/min/mL/10 4, p<0.0001) (Figure A). The plasma apo(a) concentration is significantly higher in SARS-CoV-2-positive inpatients than in the plasma from SARS-CoV-2-negative inpatients (the median of the two groups are 114.8 versus 34.4 μg/mL, p<0.05) (Figure B). Among the 20 hospitalized patients with COVID-19, 13 survived. The 13 survived patients have one additional plasma sample collected after recovering from COVID-19 (date range between the two blood collections of onset and after recovery is from 19 to 87 days, the mean duration is 42 days). After recovery, 11 out of 13 surviving patients have increased plasma tPA enzymatic activity (the mean value at onset versus recovery is 5.2 versus 7.1 ΔA/min/mL/10 4, p<0.05) (Figure C). Consistently, 11 out of 13 surviving patients have decreased plasma apo(a) concentration compared to the plasma collected during the onset of COVID-19 from the same individuals (the median values of the onset and recovery are 141.1 versus 106.5 μg/mL, p<0.001) (Figure D). In summary, our study shows lower tPA enzymatic activity and higher apo(a) concentration in SARS-CoV-2-positive hospitalized patients compared to SARS-CoV-2-negative hospitalized patients. Among the survived patients, the reduction of apo(a) concentration after recovering from COVID-19 is accordance with the increase of tPA enzymatic activity. Considering the role of apo(a) in inhibiting fibrinolysis through limiting tPA-mediated plasminogen to plasmin conversion, the alteration in apo(a) concentration provide a possible explanation of change of tPA activity in patients with severe COVID-19. Figure 1 Figure 1. Disclosures Baumann Kreuziger: CSL Behring: Consultancy; Quercegen Pharmaceuticals: Consultancy; Vaccine Injury Compensation Program: Consultancy.

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Does apolipoprotein(a) heterogeneity influence lipoprotein(a) effects on fibrinolysis?

Blood ◽

10.1182/blood.v82.2.392.bloodjournal822392 ◽

1993 ◽

Vol 82 (2) ◽

pp. 392-397 ◽

Cited By ~ 1

Author(s):

L Hervio ◽

MJ Chapman ◽

J Thillet ◽

S Loyau ◽

E Angles-Cano

Keyword(s):

High Plasma ◽

Tissue Type ◽

Plasminogen Activation ◽

Lipoprotein A ◽

Apolipoprotein A ◽

Premature Cardiovascular Disease ◽

Type Plasminogen Activator ◽

Relative Affinity ◽

Lysine Residues ◽

Carboxy Terminal

High plasma levels of lipoprotein(a) [Lp(a)] are considered to be an independent risk factor for premature cardiovascular disease and are inversely associated with apolipoprotein(a) [apo(a)] isoform sizes. The contribution of apo(a) polymorphism to the inhibition of fibrinolysis, a mechanism that may favor thrombus development, was therefore evaluated by measuring the ability of Lp(a) particles of distinct apo(a) isoform content to compete with plasminogen for fibrin binding during plasminogen activation by fibrin-bound tissue-type plasminogen activator. The rate of plasmin generation was most efficiently inhibited by an isoform with a molecular weight (M(r)) of approximately 540 Kd. An isoform with M(r) approximately 590 Kd produced a less pronounced effect, whereas the isoform with M(r) approximately 610 Kd failed to inhibit plasminogen activation. These effects were directly proportional to the amount of Lp(a) bound to the carboxy-terminal lysine residues of degraded fibrin. The relative affinity of the binding (kd range, 16 to 180 nmol/L) reflected the ability of individual Lp(a) isoforms to inhibit the binding of plasminogen (kd, 600 nmol/L). The question of the influence of kringle sequence variability on the binding to fibrin was not addressed by the present work. These data suggest that apo(a) isoform types with high affinity for fibrin may influence the ability of Lp(a) to interfere with fibrinolysis and contribute thereby to the association of elevated levels of Lp(a) with atherosclerotic and thrombotic risks.

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Does apolipoprotein(a) heterogeneity influence lipoprotein(a) effects on fibrinolysis?

Blood ◽

10.1182/blood.v82.2.392.392 ◽

1993 ◽

Vol 82 (2) ◽

pp. 392-397 ◽

Cited By ~ 65

Author(s):

L Hervio ◽

MJ Chapman ◽

J Thillet ◽

S Loyau ◽

E Angles-Cano

Keyword(s):

High Plasma ◽

Tissue Type ◽

Plasminogen Activation ◽

Lipoprotein A ◽

Apolipoprotein A ◽

Premature Cardiovascular Disease ◽

Type Plasminogen Activator ◽

Relative Affinity ◽

Lysine Residues ◽

Carboxy Terminal

Abstract High plasma levels of lipoprotein(a) [Lp(a)] are considered to be an independent risk factor for premature cardiovascular disease and are inversely associated with apolipoprotein(a) [apo(a)] isoform sizes. The contribution of apo(a) polymorphism to the inhibition of fibrinolysis, a mechanism that may favor thrombus development, was therefore evaluated by measuring the ability of Lp(a) particles of distinct apo(a) isoform content to compete with plasminogen for fibrin binding during plasminogen activation by fibrin-bound tissue-type plasminogen activator. The rate of plasmin generation was most efficiently inhibited by an isoform with a molecular weight (M(r)) of approximately 540 Kd. An isoform with M(r) approximately 590 Kd produced a less pronounced effect, whereas the isoform with M(r) approximately 610 Kd failed to inhibit plasminogen activation. These effects were directly proportional to the amount of Lp(a) bound to the carboxy-terminal lysine residues of degraded fibrin. The relative affinity of the binding (kd range, 16 to 180 nmol/L) reflected the ability of individual Lp(a) isoforms to inhibit the binding of plasminogen (kd, 600 nmol/L). The question of the influence of kringle sequence variability on the binding to fibrin was not addressed by the present work. These data suggest that apo(a) isoform types with high affinity for fibrin may influence the ability of Lp(a) to interfere with fibrinolysis and contribute thereby to the association of elevated levels of Lp(a) with atherosclerotic and thrombotic risks.

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The Ten Point Clock Test: A Quick Screen and Grading Method for Cognitive Impairment in Medical and Surgical Patients

The International Journal of Psychiatry in Medicine ◽

10.2190/5a0f-936p-vg8n-0f5r ◽

1994 ◽

Vol 24 (3) ◽

pp. 229-244 ◽

Cited By ~ 144

Author(s):

Peter J. Manos ◽

Rae Wu

Keyword(s):

Cognitive Impairment ◽

Cognitive Deficits ◽

Neuropsychological Tests ◽

Medical Center ◽

Neuropsychological Test ◽

Hospitalized Patients ◽

Surgical Patients ◽

Tertiary Referral Center ◽

The Mean ◽

State Examination

Objective: The objective of this study was to evaluate the clinical utility of the ten point clock test in screening for and grading cognitive deficits in medical and surgical patients. Method: The setting was the hospital and clinics of Virginia Mason Medical Center, a tertiary referral center. Consecutive samples of hospitalized patients, and clinic outpatients—with and without a dementia—were administered the ten point clock test as well as a number of other neuropsychological tests and measures of cognitive impairment. Results: Clock scores correlated with neuropsychological test scores and with the mini-mental state examination. They were stable from rater to rater, and from day to day in stable patients. The mean clock score of elderly outpatient controls was 8.5, significantly different from the mean of 5.5 scored by patients with a dementia. A cut off score of seven identified 76 percent of outpatients with dementia and 78 percent of elderly controls. Clock scores correlated well with nurses' ratings of their inpatients' cognitive deficits (Spearman's rs = −0.61). The test was easy to administer, even to hospitalized patients. Conclusions: The ten point clock test is reliable, valid, and useful as a quick screen and grading method for cognitive deficits in medical and surgical patients.

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Evidence for increased synthesis of lipoprotein(a) in the nephrotic syndrome.

Journal of the American Society of Nephrology ◽

10.1681/asn.v981474 ◽

1998 ◽

Vol 9 (8) ◽

pp. 1474-1481

Author(s):

M G De Sain-Van Der Velden ◽

D J Reijngoud ◽

G A Kaysen ◽

M M Gadellaa ◽

H Voorbij ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Synthesis Rate ◽

Fractional Synthesis Rate ◽

Lipoprotein A ◽

Control Subjects ◽

Apolipoprotein A ◽

Catabolic Rate ◽

Fractional Synthesis ◽

The Mean

In patients with the nephrotic syndrome, markedly increased levels of lipoprotein(a) (Lp(a)) concentration have been frequently reported, and it has been suggested that this may contribute to the increased cardiovascular risk in these patients. The mechanism, however, is not clear. In the present study, in vivo fractional synthesis rate of Lp(a) was measured using incorporation of the stable isotope 13C valine. Under steady-state conditions, fractional synthesis rate equals fractional catabolic rate (FCR). FCR of Lp(a) was estimated in five patients with the nephrotic syndrome and compared with five control subjects. The mean plasma Lp(a) concentration in the patients (1749+/-612 mg/L) was higher than in control subjects (553+/-96 mg/L). Two patients were heterozygous for apolipoprotein(a) (range, 19 to 30 kringle IV domains), whereas all control subjects were each homozygous with regard to apolipoprotein(a) phenotype (range, 18 to 28 kringle IV domains). The FCR of Lp(a) was comparable between control subjects (0.072+/-0.032 pools/d) and patients (0.064+/-0.029 pools/d) despite the wide variance in plasma concentration. This suggests that differences in Lp(a) levels are caused by differences in synthesis rate. Indeed, the absolute synthetic rate of Lp(a) correlated directly with plasma Lp(a) concentration (P < 0.0001) in all subjects. The present results demonstrate that increased synthesis, rather than decreased catabolism, causes elevated plasma Lp(a) concentrations in the nephrotic syndrome.

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A Large Cohort Study of SARS-CoV-2 Detection in Saliva: A Non-Invasive Alternative Diagnostic Test for Patients with Bleeding Disorders

Viruses ◽

10.3390/v13122361 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2361

Author(s):

Josiane Iole França Lopes ◽

Carlos Alexandre da Costa Silva ◽

Rodrigo Guimarães Cunha ◽

Alexandra Martins Soares ◽

Maria Esther Duarte Lopes ◽

...

Keyword(s):

Healthcare Workers ◽

Hospitalized Patients ◽

Bleeding Disorders ◽

Hematological Diseases ◽

Non Invasive ◽

Qrt Pcr ◽

Large Cohort Study ◽

The Mean ◽

Sensitivity Specificity ◽

Higher Sensitivity

Diagnosis of SARS-CoV-2 infections is mostly based on the nasopharyngeal swabs (NPS). However, this collection is invasive and uncomfortable, especially for children and patients with coagulopathies, whose NPS collection often causes bleeding. Thus, the aim of this study was to evaluate the usefulness and accuracy of saliva for the diagnosis of COVID-19 in patients presenting bleeding disorders. Samples of NPS, oropharyngeal swabs (OPS), and saliva were collected simultaneously from 1159 hospitalized patients with hematological diseases and from 524 healthcare workers, both symptomatic and asymptomatic for SARS-CoV-2. All samples were evaluated for SARS-CoV-2 by qRT-PCR. SARS-CoV-2 was detected in NPS, OPS and saliva from 16.9%, 14.4% and 15.6% individuals, respectively. Tests in saliva showed sensitivity, specificity, and overall agreement of 73.3%, 96.9% and 92.7% (=0.74), respectively. Salivary tests had good accuracy (AUC = 0.7) for discriminating negative and positive qRT-PCR for SARS-CoV-2. Higher sensitivity was observed in symptomatic than in non-symptomatic patients, as well as in healthy subjects than in patients with hematological disease, in both OPS and saliva. The mean viral load in NPS was significantly higher than in OPS and in saliva samples (p < 0.001). Saliva is a good diagnostic tool to detect SARS-CoV-2, especially among patients symptomatic for COVID-19, and is a valuable specimen for mass screening of hospitalized patients with hematological diseases, especially for those that with bleeding disorders.

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Abstract 17113: Secondary Infections Are Common in Patients Hospitalized for COVID-19 and Are Associated With Severe Outcomes

Circulation ◽

10.1161/circ.142.suppl_3.17113 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Elizabeth R Anderson ◽

Tariq Azam ◽

Husam Shadid ◽

Michael Pan ◽

Hanna Berlin ◽

...

Keyword(s):

Prospective Observational Study ◽

Viral Infections ◽

Clinical Laboratory ◽

Secondary Infection ◽

Kidney Injury ◽

Outcome Data ◽

Hospitalized Patients ◽

Secondary Infections ◽

Life Threatening ◽

The Mean

Background: Secondary infections occur in 10-15% of critically ill sepsis patients. Anecdotal reports suggest secondary infections are common in coronavirus disease 2019 (COVID-19), however data are lacking. We examine the rate of secondary infections in hospitalized patients with COVID-19 and its impact on the cytokine surge and in-hospital outcomes. Methods: The Michigan Medicine Covid-19 Cohort (M2C2) is an ongoing prospective observational study in which detailed clinical, laboratory and outcome data were collected from chart review of consecutive adult patients hospitalized for COVID-19. Patients who were positive for SARS-CoV-2 infection but without respiratory symptoms were not included in this cohort. We define secondary infections as physician-diagnosed and treated bacterial or viral infections secondary to SARS-CoV-2. Results: Of 553 COVID-19 patients hospitalized at Michigan Medicine, 191 (34.5%) developed a secondary infection during hospitalization. The mean age of patients with a secondary infection was 60 years, 61.3% were male compared to 58.8 years, 53.5% male in patients with no secondary infection. Bacterial pneumonia, including ventilator-associated pneumonia, was the most prevalent secondary infection among hospitalized patients (78.5%). Other secondary infections included urosepsis (14.1%), bacteremia (16.8%), and 17.3% of patients developed other types of infections such as shingles and clostridium difficile. 25.8% of patients without secondary infections received antibiotics during their admission compared to 47.1% of patients with secondary infections. Multiple secondary infections (>1) occurred in 43 (8.2%) of patients. Patients with secondary infections were more likely to develop acute kidney injury (78.0% vs. 38.3%, p<0.0001), acute respiratory distress syndrome (78.0% vs. 22.3%, p<0.0001), and death (26.2% vs. 10.2%, p<0.0001) during their hospitalization compared to patients without secondary infections. Conclusions: Secondary infections are common in hospitalized patients with COVID-19 and are associated with life-threatening complications and high mortality. This study suggests that secondary infection prevention may be especially important in COVID-19 patients.

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A model for the effect of bias for cholesterol on the population at risk.

Clinical Chemistry ◽

10.1093/clinchem/34.11.2256 ◽

1988 ◽

Vol 34 (11) ◽

pp. 2256-2259 ◽

Cited By ~ 5

Author(s):

M H Kroll ◽

M Ruddel ◽

R J Elin

Keyword(s):

At Risk ◽

Standard Deviation ◽

Reference Values ◽

Gaussian Distribution ◽

Population Distribution ◽

Reference Value ◽

Mean Value ◽

The Body ◽

Methodological Bias ◽

The Mean

Abstract The location of the Reference Value for an analyte within the population distribution affects the magnitude of error due to methodological bias. Using the gaussian distribution, we evaluated the effects of systematic and proportional biases of the method (positive and negative), mean value, and standard deviation on the magnitude of error. We chose four Reference Values for cholesterol as a model. For a population with a mean of 2.0 and SD of 0.36 g of cholesterol per liter, a 3% positive proportional bias causes sixfold more error at the 50th percentile than at the 97.5th. In general, the error for a given bias (proportional or systematic) is greater for a Reference Value within the body than at the tails of the distribution. Further, the magnitude of the error varies as a function of the mean and standard deviation of the population.

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An index framework founded on the future profit potential of female beef cattle to aid the identification of candidates for culling

Journal of Animal Science ◽

10.1093/jas/skaa334 ◽

2020 ◽

Vol 98 (11) ◽

Author(s):

Fíona L Dunne ◽

Donagh P Berry ◽

Margaret M Kelleher ◽

Ross D Evans ◽

Siobhan W Walsh ◽

...

Keyword(s):

Beef Cattle ◽

Population Distribution ◽

Beef Cows ◽

Calving Interval ◽

Transition Matrices ◽

Individual Female ◽

The Mean ◽

Carcass Performance ◽

Expected Longevity ◽

Profit Potential

Abstract Meticulous culling decisions, coupled with careful breeding decisions, are fundamental to shifting a population distribution in the favorable direction and improving profit per cow. Nevertheless, there is a paucity of easy-to-use dynamic tools to aid in culling decisions in beef cattle. The motivation for the present study was to develop a monetary-based culling tool, here referred to as the Beef Female’s Profit Potential (BFPP), to identify females for culling. The BFPP reflects the expected lifetime profitability of an individual female in a herd for the expected remainder of her lifetime; this profit included that of the beef female herself as well as her progeny. The BFPP index framework was composed of 4 subindexes reflecting the value of an animal: (1) as a nulliparae (this was voided if the cow had already calved), (2) for the remainder of her current parity, (3) summed across each of her expected remaining parities, and (4) when she is retained within the herd and not voluntarily culled. Each subindex was comprised of different components reflecting both genetic and non-genetic effects associated with each female. Transition matrices predicting the expected longevity of each female and their expected month of calving were also utilized in calculating the expected remaining lifetime profitability of each female. The BFPP index was validated on 21,102 beef cows as well as their harvested progeny from 875 herds by stratifying the cows, within herd, into 4 strata based on their BFPP. The mean of the within-herd correlation between the BFPP and the Irish national replacement (i.e., breeding) index was, on average, 0.45 indicating the shortcomings of the breeding index as a culling tool. Cows within the top BFPP stratum had a genetic expectation of accruing almost an additional €36 profit per calving, relative to cows within the worst stratum; when validated on the cow’s own calving interval and survival performance as well as their progeny’s carcass performance, the actual phenotypic value was estimated to be an additional €32 profit per calving. A proportion of this additional profit was due to the harvested progeny of the high BFPP cows having, on average, heavier, more conformed carcasses with less fat cover relative to their poor BFPP contemporaries. This BFPP framework is a useful and easy-to-use tool to aid in producer decision making on the choice of females to voluntarily cull but also on which replacement heifers to graduate into the mature herd.

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Relationship Between Cleaved L-Selectin Levels and the Outcome of Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v92.9.3115 ◽

1998 ◽

Vol 92 (9) ◽

pp. 3115-3122 ◽

Cited By ~ 9

Author(s):

M. Extermann ◽

M. Bacchi ◽

N. Monai ◽

M. Fopp ◽

M. Fey ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

High Plasma ◽

Multivariate Statistical ◽

Free Survival ◽

The Mean ◽

American Society ◽

The Relationship ◽

Acute Myeloid

Abstract High plasma levels of the shed form of L-selectin (sL-selectin) are frequently detectable in acute myeloid leukemia (AML). sL-selectin can inhibit blast cell adhesion to vascular endothelium and may thereby influence the phenotype of AML. In this study, we have investigated the relationship between sL-selectin levels and clinical presentation or disease outcome in 100 patients with AML. Fifty-eight patients were found to have sL-selectin levels ≥3.12 μg/mL (≥3 SD above the mean of healthy controls: “increased”). Patients with extramedullary disease such as lymphadenopathies, splenomegaly, hepatomegaly, and/or muco-cutaneous infiltration had significantly increased sL-selectin levels (P < .001). sL-selectin levels were significantly heterogeneous in the French-American-British subtypes (P = .0003). Patients with “normal” sL-selectin levels had higher probability of achieving complete remission (CR) than with “increased” levels: 81% versus 64%, respectively (P = .06). When adjusting for clinically relevant covariates predictive for CR (sex, age, Auer rods), “normal” sL-selectin levels were significantly associated with CR (odds ratio, 3.08; 95% confidence interval [CI], 1.10 to 8.58;P = .03). Moreover, patients with “increased” sL-selectin levels (≥3.12 μg/mL) had shorter event-free survival (EFS) (median 7.3 v 12 months, P = .008) and overall survival (median 1 v 2.05 years, P = .03) than patients with sL-selectin <3.12 μg/mL. Multivariate statistical analysis (adjusted for age and presence of Auer rods) indicated that sL-selectin was an independent prognostic factor for EFS (hazard ratio [HR], 1.96; 95% CI, 1.21 to 3.17, P = .006) and overall survival (HR, 1.80; 95% CI, 1.09 to 2.98; P = .02). Thus, plasma sL-selectin may be a useful prognostic marker in the evaluation of AML at diagnosis. © 1998 by The American Society of Hematology.

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Measuring tissue factor (factor III) activity in plasma.

Clinical Chemistry ◽

10.1093/clinchem/35.9.1897 ◽

1989 ◽

Vol 35 (9) ◽

pp. 1897-1900 ◽

Cited By ~ 27

Author(s):

C Fukuda ◽

K Iijima ◽

K Nakamura

Keyword(s):

Tissue Factor ◽

Disseminated Intravascular Coagulation ◽

Coagulation Factors ◽

High Plasma ◽

Mean Value ◽

Chromogenic Substrate ◽

Intravascular Coagulation ◽

Endogenous Inhibitors ◽

Tissue Thromboplastin ◽

The Mean

Abstract This is a method for measuring tissue factor (TF, Factor III, tissue thromboplastin) activity in plasma by using a chromogenic substrate. As pretreatment, the euglobulin fraction of plasma was prepared by removing endogenous inhibitors and heated at 60 degrees C for 3 min to remove fibrinogen. This allowed us to measure the low TF activity in plasma that could not otherwise be measured. Neither phospholipids nor coagulation factors VII, IX, X, or Xa in the samples interfere. Within-run and day-to-day reproducibility were both good. The mean value obtained by this method for normal persons was 1.02 (SD 0.91) arbitrary units/L. A markedly high plasma TF activity of 20 arb. units/L or more was observed in patients with some types of disseminated intravascular coagulation.

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