1. Medicine

Inference from longitudinal laboratory tests characterizes temporal evolution of COVID-19-associated coagulopathy (CAC)

  1. Colin Pawlowski
  2. Tyler Wagner
  3. Arjun Puranik
  4. Karthik Murugadoss
  5. Liam Loscalzo
  6. AJ Venkatakrishnan
  7. Rajiv K Pruthi
  8. Damon E Houghton
  9. John C O'Horo
  10. William G Morice II
  11. Amy W Williams
  12. Gregory J Gores
  13. John Halamka
  14. Andrew D Badley
  15. Elliot S Barnathan
  16. Hideo Makimura
  17. Najat Khan
  18. Venky Soundararajan  Is a corresponding author
  1. nference, inc, United States
  2. Mayo Clinic, United States
  3. Mayo Clinic Laboratories, United States
  4. Mayo Clinic Platform, United States
  5. Janssen pharmaceutical companies of Johnson & Johnson (J&J), United States
https://doi.org/10.7554/eLife.59209
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Cite this article
  1. Colin Pawlowski
  2. Tyler Wagner
  3. Arjun Puranik
  4. Karthik Murugadoss
  5. Liam Loscalzo
  6. AJ Venkatakrishnan
  7. Rajiv K Pruthi
  8. Damon E Houghton
  9. John C O'Horo
  10. William G Morice II
  11. Amy W Williams
  12. Gregory J Gores
  13. John Halamka
  14. Andrew D Badley
  15. Elliot S Barnathan
  16. Hideo Makimura
  17. Najat Khan
  18. Venky Soundararajan
(2020)
Inference from longitudinal laboratory tests characterizes temporal evolution of COVID-19-associated coagulopathy (CAC)
eLife 9:e59209.
https://doi.org/10.7554/eLife.59209
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  3. Download .RIS
6 figures, 9 tables and 1 additional file

Figures

Figure 1
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Longitudinal and temporally resolved analysis highlights positive control lab tests elevated in COVIDpos patients along with distinctive immune signatures.

Longitudinal trends in COVIDpos versus COVIDneg (matched) patients for the following lab tests: (A) SARS-CoV-2 IGG ratio, (B) oxygen saturation in arterial blood, (C) white blood cells, (D) monocytes absolute, and (E) neutrophils, blood. For any window of time during which at least three patients in each cohort had test results, data are shown as mean with standard errors. The normal range for each lab test is shaded in green. Values given horizontally along the top of the plot are Cohen’s D statistics comparing the COVIDpos and COVIDneg (matched) cohorts along with the BH-adjusted Mann-Whitney test p-values. Significant differences (adjusted p-value <0.05) are shown in black, while non-significant values are shown in gray. Values given horizontally along the bottom of the plot are the numbers of patients in the COVIDpos and COVIDneg cohorts, respectively (i.e. # COVIDpos | # COVIDneg). For certain lab tests, some data points are missing because these time windows had fewer than three data points in the COVIDpos cohort.

Figure 2
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Longitudinal trends of COVIDpos patients’ lab tests show distinctive immune, hematologic, and serum chemistry signatures within normal ranges.

Longitudinal trends in COVIDpos versus COVIDneg (matched) patients for the following lab tests: (A) eosinophils absolute, (B) basophils absolute, (C) red blood cell count, (D) mean corpuscular volume, (E) calcium total, plasma, and (F) magnesium total, serum/plasma. For any window of time during which at least three patients in each cohort had test results, data are shown as mean with standard errors. The normal range for each lab test is shaded in green. Values given horizontally along the top of the plot are Cohen’s D statistics comparing the COVIDpos and COVIDneg (matched) cohorts along with the BH-adjusted Mann-Whitney test p-values. Significant differences (adjusted p-value <0.05) are shown in black, while non-significant values are shown in gray. Values given horizontally along the bottom of the plot are the numbers of patients in the COVIDpos and COVIDneg cohorts, respectively (i.e. # COVIDpos | # COVIDneg). For certain lab tests, some data points are missing because these time windows had fewer than three data points in the COVIDpos cohort.

Figure 3
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COVIDpos patients show distinctly opposite temporal trends in fibrinogen and platelet counts starting at the time of diagnosis.

Longitudinal trends of COVIDpos versus COVIDneg (matched) patients for the following lab tests: (A) fibrinogen, plasma, (B) platelets, and (C) other coagulation-related tests including prothrombin time (PT), activated partial thromboplastic time (aPTT), and D-dimers. For any window of time during which at least three patients in each cohort had test results, data are shown as mean with standard errors. The normal range for each lab test is shaded in green. Values given horizontally along the top of the plot are Cohen’s D statistics comparing the COVIDpos and COVIDneg (matched) cohorts along with the BH-adjusted Mann-Whitney test p-values. Significant differences (adjusted p-value <0.05) are shown in black, while non-significant values are shown in gray. Values given horizontally along the bottom of the plot are the numbers of patients in the COVIDpos and COVIDneg cohorts, respectively (i.e. # COVIDpos | # COVIDneg). For certain lab tests, some data points are missing because these time windows had fewer than three data points in the COVIDpos cohort.

Figure 4
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Longitudinal trends of lab tests with daily resolution.

Longitudinal trends of COVIDpos versus COVIDneg (matched) patients for the following lab tests: (A) platelets; (B) fibrinogen, plasma; (C) prothrombin time, plasma; (D) activated partial thromboplastin time; (E) D-dimer; (F) magnesium, serum/plasma; (G) basophils absolute; (H) neutrophils, blood; (I) alkaline phosphatase, serum. The reference ranges are shown at the top of each plot. For each cohort, average lab values and standard errors are shown for each day with at least three observations. For certain lab tests, some data points are missing because these days had fewer than three data points in the COVIDpos cohort.

Figure 5
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Association between platelet counts and thrombosis in the COVIDpos cohort.

Box plots of platelet counts, min/max values, and maximum levels of increase/decline at specific time intervals for COVIDpos and COVIDneg cohorts and subgroups of the COVIDpos cohort with and without thrombotic events after SARS-CoV-2 diagnosis. In the subplot (A), we show platelet counts for COVIDpos (red) and COVIDneg (blue) cohorts. In subplots (B-F), we show platelet counts for COVIDpos patients who did and did not subsequently develop thromboses (purple and black, respectively). Horizontal dotted gray lines correspond to upper and lower limits of normal platelet counts (150−450 × 109/L), and horizontal red line shows 100 × 109/L. At the top of each plot, Cohen’s D effect size and p-value from the Mann-Whitney statistical test are shown. (A) Platelet counts at the time of PCR testing for COVIDpos and COVIDneg cohorts. (B) Platelet counts at the time of PCR testing for COVIDpos patients who did and did not subsequently develop thromboses. (C) Maximum platelet counts (considering counts at and after positive PCR test date) for COVIDpos patients who did and did not subsequently develop thromboses. (D) Minimum platelet counts (considering counts at and after positive PCR test date) for COVIDpos patients who did and did not subsequently develop thromboses. (E) Maximum degree of platelet increases after positive PCR test date for COVIDpos patients who did and did not subsequently develop thromboses. (F) Maximum degree of platelet declines after positive PCR test date for COVIDpos patients who did and did not subsequently develop thromboses.

Figure 6
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Longitudinal analyses of platelet counts, plasma fibrinogen, and D-dimer levels in individual patients with or without thrombotic disease.

In each plot, shaded regions represent time periods when the patient was taking a specific anticoagulant or antiplatelet medication. Medications taken for prophylaxis are denoted in the legend with (ppx). (A) Patient 124 developed hemorrhagic and thrombotic phenotypes in the context of declining fibrinogen, declining platelets, and increasing D-dimers. This is consistent with a DIC-like coagulopathy. (B) Patient 23 developed clots in the setting of declining fibrinogen and elevated D-dimers but stable platelet counts which increased shortly thereafter. (C) Patient 79 developed clots while showing increases in platelet counts along with plasma fibrinogen and D-dimers. (D) Patient 94 developed clots with relatively stable platelet counts and steadily declining plasma fibrinogen. (E) Patient 13 did not develop clots or bleeding despite a coordinate decrease in platelet counts and fibrinogen which may be mistaken for a DIC-like coagulopathy. (F) Patient 51 did not develop clots despite showing a post-diagnosis decline in plasma fibrinogen similar to several patients in the thrombotic cohort.

Tables

Table 1
Summary of patient characteristics for the overall COVIDpos, COVIDneg (matched), and COVIDneg cohorts.

The COVIDneg (matched) cohort was constructed using 1:10 propensity score matching to balance each of the clinical covariates, including demographics (age, gender, race), medication use (anticoagulant/antiplatelet use in the preceding 30 days/1 year of PCR testing date), medical history of thrombotic events from the past year, and hospitalization status in the month prior to the date of PCR testing.

Patient characteristicsCOVIDposCOVIDneg (matched)COVIDneg
Number of patients246246013,666
Age in years60.860.964.1
Gender:
Male137 (56%)1388 (56%)7129 (52%)
Race:
White154 (63%)1540 (63%)12,241 (90%)
Black24 (9.8%)313 (13%)569 (4.2%)
Asian18 (7.3%)207 (8.4%)274 (2.0%)
American Indian23 (9.3%)81 (3.3%)81 (0.59%)
Other27 (11%)319 (13%)501 (3.7%)
Medication use in the preceding 30 days of PCR testing date:
Anticoagulants63 (26%)596 (24%)5171 (38%)
Antiplatelets30 (12%)298 (12%)2230 (16%)
Medication use in the preceding 1 year of PCR testing date:
Anticoagulants86 (35%)819 (33%)7476 (55%)
Antiplatelets40 (16%)419 (17%)3620 (26%)
Medical history of thrombotic events in 1 year prior to study period:
Deep vein thrombosis15 (6.1%)153 (6.2%)2,110 (15%)
Pulmonary embolism12 (4.9%)112 (4.6%)1258 (9.2%)
Myocardial infarction11 (4.5%)142 (5.8%)1468 (11%)
Venous thromboembolism4 (1.6%)44 (1.8%)615 (4.5%)
Thrombotic stroke1 (0.41%)3 (0.12%)143 (1.0%)
Cerebral venous thrombosis01 (0.04%)7 (0.05%)
Disseminated intravascular coagulation01 (0.04%)30 (0.22%)
Any thrombotic event31 (13%)308 (13%)3901 (29%)
Hospitalized in the month prior to PCR testing date41 (17%)304 (12%)1247 (9%)
Table 2
Summary of lab tests significantly different between COVIDpos and propensity score-matched COVIDneg cohorts during at least one clinical time window.

Data from individual patients were averaged over the defined time windows, and the mean values were compared between COVIDpos and COVIDneg patients. The lab test-time window pairs shown are those which met our defined thresholds for statistical significance and substantial effect (BH-adjusted Mann-Whitney p-value <0.05 and Cohen’s D absolute value >0.35). In particular, 130 of the initial 1709 (test, time window) pairs with at least one patient met these thresholds. Rows are sorted alphabetically by test and then time window (from earliest to latest). Coagulation-related tests of particular interest (fibrinogen, platelets, prothrombin time, activated partial thromboplastin time, and D-dimer) are highlighted in gray. Sample sources are denoted as: P = plasma, S = serum, S/P = serum/plasma, B = blood, U = urine.

TestUnitsTime windowCount COVIDposCount COVIDnegMean COVIDposMean COVIDnegCohen's DBH-adj M-W p-value
ABGRS pH ArterialpHDays 16–30 Post-Dx18917.457.40.7750.02
ABGRS PO2 Arterialmm HgDays 1–3 Post-Dx1620481.9129.6−0.7973.1E-03
ABGRS PO2 Arterialmm HgDays 4–6 Post-Dx258278.1113.2−0.7128.8E-03
ABGRS PO2 Arterialmm HgDays 7–9 Post-Dx235877.2121.9−0.8071.0E-03
ABGRS PO2 Arterialmm HgDays 10–12 Post-Dx183776.4104.2−0.9652.6E-03
ABGRS PO2 Arterialmm HgDays 13–15 Post-Dx153173.1112.3−0.9646.0E-03
Activated Partial Thrombopl Time, PsecDays 7–9 Post-Dx226650.536.70.7270.026
Activated Partial Thrombopl Time, PsecDays 10–12 Post-Dx145463.339.21.0852.4E-03
Activated Partial Thrombopl Time, PsecDays 13–15 Post-Dx164853.137.61.0655.6E-03
Activated Partial Thrombopl Time, PsecDays 16–30 Post-Dx1914956.237.50.8840.027
Alanine Aminotransferase (ALT), PU/LDays 10–12 Post-Dx2710477.3460.5120.015
Albumin, Pg/dLDays 7–9 Post-Dx421883.063.41−0.545.6E-03
Albumin, S/Pg/dLClinical presentation858123.433.81−0.5914.8E-06
Albumin, S/Pg/dLDays 1–3 Post-Dx775253.263.6−0.5413.8E-05
Albumin, S/Pg/dLDays 10–12 Post-Dx612543.353.66−0.472.6E-03
Alkaline Phosphatase, PU/LDays 4–6 Post-Dx4213988.8126.7−0.3953.7E-03
Arterial O2 PP DiffNoneClinical presentation21106268.1152.10.9249.7E-03
Arterial O2 PP DiffNoneDays 1–3 Post-Dx22112225.9147.40.6390.017
Arterial O2 PP DiffNoneDays 4–6 Post-Dx1749271.41550.8914.8E-03
Aspartate Aminotransferase (AST), PU/LDays 10–12 Post-Dx2710767.644.70.4043.6E-04
Basophils Absolute×10(9)/LClinical presentation13314000.02510.0379−0.4125.8E-06
Bicarbonate [MMOL/L] in Arterial Bloodmmol/LDays 16–30 Post-Dx189128.624.30.8577.6E-03
Bicarbonate in Arterial Bloodmmol/LDays 1–3 Post-Dx2619323.221.40.5130.027
BUN, Pmg/dLDays 16–30 Post-Dx4956231.421.90.5553.9E-03
C-reactive Protein Quantative, Smg/LClinical presentation85666100.268.20.3756.8E-05
Calcium, Ionized, Bmg/dLClinical presentation142014.364.77−0.670.015
Calcium, Ionized, Bmg/dLDays 1–3 Post-Dx182704.424.73−0.7838.5E-04
Calcium, Total, Pmg/dLClinical presentation8911448.719.05−0.4685.5E-06
Calcium, Total, Pmg/dLDays 1–3 Post-Dx779108.528.81−0.4593.2E-04
Calcium, Total, Pmg/dLDays 7–9 Post-Dx713538.618.93−0.4571.8E-03
Calcium, Total, Smg/dLClinical presentation839418.298.91−0.8541.9E-13
Calcium, Total, Smg/dLDays 1–3 Post-Dx9810258.288.77−0.7172.2E-10
Calcium, Total, Smg/dLDays 4–6 Post-Dx875688.48.69−0.4352.3E-03
Calcium, Total, Smg/dLDays 7–9 Post-Dx824338.498.76−0.3840.011
Carboxyhemoglobin, ARTERIAL%Clinical presentation343560.5070.991−0.712.0E-04
Carboxyhemoglobin, Arterial%Days 1–3 Post-Dx444360.5350.9−0.7115.9E-05
Carboxyhemoglobin, Arterial%Days 4–6 Post-Dx581660.6780.974−0.5443.0E-03
Carboxyhemoglobin, Arterial%Days 7–9 Post-Dx451020.7040.97−0.4720.048
Carboxyhemoglobin, Venous%Days 1–3 Post-Dx10730.7011.16−0.8620.02
Carboxyhemoglobin, Venous%Days 4–6 Post-Dx14470.7251.29−0.8373.7E-03
Chloride, Pmmol/LDays 1–3 Post-Dx77906100.1101.9−0.3637.7E-03
Eosinophils Absolute×10(9)/LPre-diagnosis285470.06890.161−0.451.7E-03
Esosinophils Absolute×10(9)/LDays 4–6 Post-Dx1335590.09060.172−0.3582.4E-06
Fibrinogen, Pmg/dLClinical presentation51233528.9360.70.8598.9E-07
Fibrinogen, Pmg/dLDays 1–3 Post-Dx18319432.6297.40.8361.7E-03
Fibrinogen, Pmg/dLDays 4–6 Post-Dx26116477.8333.70.7440.014
Glucose, Random, Smg/dLDays 13–15 Post-Dx49314150126.50.5440.013
Hematocrit, B%Days 1–3 Post-Dx158158236.533.80.4339.6E-06
Hematocrit, B%Days 4–6 Post-Dx1528513632.10.6212.2E-10
Hematocrit, B%Days 7–9 Post-Dx13263935.531.80.5875.8E-08
Hematocrit, B%Days 10–12 Post-Dx11050535.131.80.5111.7E-05
Hemoglobin Arterialg/dLDays 1–3 Post-Dx3120812.110.80.6510.025
Hemoglobin, Bg/dLDays 1–3 Post-Dx158168211.911.10.3582.2E-04
Hemoglobin, Bg/dLDays 4–6 Post-Dx15287311.810.40.6361.4E-10
Hemoglobin, Bg/dLDays 7–9 Post-Dx13265311.610.40.562.0E-07
Hemoglobin, Bg/dLDays 10–12 Post-Dx11051611.410.30.492.6E-05
Ionized Calcium, Arterialmg/dLDays 16–30 Post-Dx8364.934.481.5610.022
Lactate Dehydrogenase, SU/LDays 10–12 Post-Dx2188406.2295.20.4631.4E-03
Lactate, Pmmol/LClinical presentation899541.371.93−0.4623.1E-06
Lymphocytes Percent%Days 13–15 Post-Dx56633.2151.5140.048
Lymphs Absolute×10(9)/LDays 13–15 Post-Dx563493.121.110.440.018
Magnesium, Plasmamg/dLDays 10–12 Post-Dx20872.141.910.7720.015
Magnesium, S/Pmg/dLDays 4–6 Post-Dx472792.221.980.7433.0E-03
Magnesium, S/Pmg/dLDays 7–9 Post-Dx402152.311.971.064.1E-06
Magnesium, S/Pmg/dLDays 10–12 Post-Dx361872.261.911.0052.9E-06
Magnesium, S/Pmg/dLDays 13–15 Post-Dx351792.221.890.9041.8E-07
Magnesium, S/Pmg/dLDays 16–30 Post-Dx333172.131.890.9061.6E-04
Manual Diff Promyelocytes%Days 1–3 Post-Dx6550.2501.4020.027
Mean Corpuscular VolumefLDays 10–12 Post-Dx11050289.592−0.388.8E-03
Methemoglobin, ABG%Clinical presentation343560.3350.571−0.6296.0E-03
Methemoglobin, ABG%Days 1–3 Post-Dx444360.4250.697−0.4631.5E-03
Monocytes Absolute×10(9)/LDays 1–3 Post-Dx13110790.4470.748−0.5022.6E-16
Monocytes Absolute×10(9)/LDays 4–6 Post-Dx1355840.4750.715−0.5972.2E-10
N-terminal-PRO-Brain Type Natriuretic Peptide, Spg/mLDays 4–6 Post-Dx1063415.67609.7−0.5252.9E-03
Neutrophils, B×10(9)/LClinical presentation13613825.317.12−0.3966.3E-06
Neutrophils, B×10(9)/LDays 1–3 Post-Dx13011414.736.32−0.3855.8E-05
NT-PRO BNP, Ppg/mLClinical presentation253721372.45327.9−0.3850.046
NT-PRO BNP, Ppg/mLDays 4–6 Post-Dx1420815.34388.8−0.9290.02
Nucleated RBC/100 WBCDays 13–15 Post-Dx231891.240.4470.5611.7E-03
O2 HB%Days 1–3 Post-Dx1324288.695−1.372.2E-03
O2 HB%Days 4–6 Post-Dx329092.193.7−0.3560.013
O2 HB%Days 7–9 Post-Dx244691.594.5−0.7013.3E-04
Osmolality, UmOsm/kgPre-diagnosis480231.5478.8−1.5090.044
Oxygen Content, Arterialvol %Days 4–6 Post-Dx32891613.70.8392.4E-03
Oxygen Saturation (%) in Arterial Blood%Clinical presentation2718994.296.2−0.523.1E-03
Oxygen Saturation (%) in Arterial Blood%Days 1–3 Post-Dx3121694.397.1−1.2938.4E-09
Oxygen Saturation (%) in Arterial Blood%Days 4–6 Post-Dx267094.395.7−0.5780.014
Oxygen Saturation (%) in Arterial Blood%Days 10–12 Post-Dx182993.496.5−1.2543.1E-03
Oxygen Saturation (%) in Arterial Blood%Days 13–15 Post-Dx172894.896.4−0.6710.043
pH Blood ArterialNoneDays 1–3 Post-Dx261937.427.390.5390.035
pH Blood VenouspHDays 1–3 Post-Dx10827.427.360.9630.031
pH, POCT, BNoneClinical presentation132027.417.330.7080.042
Platelets×10(9)/LPre-diagnosis39649184.8225.9−0.3930.024
PO2mm HgDays 1–3 Post-Dx814567.2179.7−1.3011.7E-03
PO2mm HgDays 7–9 Post-Dx141671.1121.1−0.9490.027
PO2 Arterialmm HgDays 1–3 Post-Dx26193100.4150.9−0.878.2E-05
PO2 Arterialmm HgDays 10–12 Post-Dx172593.6134−0.7550.019
Potassium, Smmol/LPre-diagnosis103983.934.35−0.8360.049
RABG Calculated O2 Hemoglobin%Days 1–3 Post-Dx2210993.695−0.4642.9E-03
RABG Calculated O2 Hemoglobin%Days 4–6 Post-Dx164993.295.3−0.8592.3E-03
RABG Calculated O2 Hemoglobin%Days 10–12 Post-Dx13229496.3−1.2690.038
RABG PF RatioNoneDays 4–6 Post-Dx17491.462.68−1.4896.9E-05
RABG PF RatioNoneDays 7–9 Post-Dx13221.752.56−1.0060.038
RABG PF RatioNoneDays 10–12 Post-Dx13221.833.22−1.5183.9E-03
RBC (Red Blood Cell) Count×10(12)/LClinical presentation15116714.323.990.4092.0E-04
RBC (Red Blood Cell) Count×10(12)/LDays 1–3 Post-Dx15815624.133.730.5245.8E-08
RBC (Red Blood Cell) Count×10(12)/LDays 4–6 Post-Dx1528464.083.550.6933.2E-12
RBC (Red Blood Cell) Count×10(12)/LDays 7–9 Post-Dx13263543.490.6562.4E-09
RBC (Red Blood Cell) Count×10(12)/LDays 10–12 Post-Dx1105023.953.480.5876.1E-07
Red Cell Distribution Width CV%Days 4–6 Post-Dx13772214.115.1−0.3733.4E-04
Red Cell Distribution Width CV%Days 7–9 Post-Dx11955214.215.4−0.4319.8E-05
Red Cell Distribution Width CV%Days 10–12 Post-Dx9742914.515.7−0.3941.2E-03
Sodium, Pmmol/LClinical presentation891141135.6137.3−0.3757.3E-03
Sodium, Pmmol/LDays 1–3 Post-Dx77927136.6138.1−0.3774.7E-03
Sodium, Smmol/LDays 10–12 Post-Dx69334140.8138.30.6512.0E-04
Spont. Breaths/minNoneDays 4–6 Post-Dx23672520.20.7670.016
Tacrolimus, Bng/mLDays 7–9 Post-Dx8814.228.12−1.1028.8E-03
Tacrolimus, Bng/mLDays 10–12 Post-Dx8793.89.24−1.4682.5E-03
Tacrolimus, Bng/mLDays 13–15 Post-Dx7713.78.52−1.477.5E-03
Tacrolimus, Bng/mLDays 16–30 Post-Dx101104.937.8−1.0940.022
TemperatureNoneClinical presentation231363736.70.5910.042
TemperatureNoneDays 1–3 Post-Dx231893736.40.7654.8E-04
Triglycerides, S/Pmg/dLDays 4–6 Post-Dx1641326.21731.1967.3E-03
Triglycerides, S/Pmg/dLDays 7–9 Post-Dx1724310.6191.50.9450.016
Triglycerides, S/Pmg/dLDays 10–12 Post-Dx1735364.5174.41.2174.0E-03
Triglycerides, S/Pmg/dLDays 16–30 Post-Dx1077276.1166.40.830.024
Troponin T, 5TH GEN, Png/LDays 4–6 Post-Dx185421.4245.3−0.4997.5E-03
Troponin T, Baseline, 5TH Gen, Png/LDays 7–9 Post-Dx114315.153.7−0.5380.037
VBGRS HGBg/dLDays 4–6 Post-Dx369912.310.50.9323.6E-04
White Blood Cells×10(9)/LDays 1–3 Post-Dx15816506.679.08−0.4393.2E-12
Table 3
Sensitivity analysis of clinical time intervals for significant coagulation-related lab test trends.

Results from sensitivity analysis perturbing the time intervals for the significant (coagulation-related lab test, time interval) pairs (i.e. highlighted rows of Table 2). Perturbed results that met both of the significance thresholds (BH-adjusted Mann-Whitney p-value <0.05 and Cohen’s D absolute value >0.35) are highlighted in light green, and perturbed results that only met one of the thresholds for either effect size or statistical significance are highlighted in yellow.

TestUnitsPerturbationOriginal time windowCount COVIDposCount COVIDnegMean COVIDposMean COVIDnegCohen's DBH-adjusted
M-W p-value
Activated Partial Thrombopl Time, Psec−1 dayDays 7−9 Post-Dx267250.1380.570.034
Activated Partial Thrombopl Time, Psec+1 dayDays 7−9 Post-Dx17585537.50.810.014
Activated Partial Thrombopl Time, Psec−1 dayDays 10−12 Post-Dx165756.938.40.8089.10E-03
Activated Partial Thrombopl Time, Psec+1 dayDays 10−12 Post-Dx156056.9381.1062.60E-03
Activated Partial Thrombopl Time, Psec−1 dayDays 13−15 Post-Dx155255.537.81.0410.014
Activated Partial Thrombopl TIME, Psec+1 dayDays 13−15 Post-Dx144851.837.10.9620.015
Activated Partial Thrombopl Time, Psec−1 dayDays 16−30 Post-Dx2215655.2370.9135.70E-03
Activated Partial Thrombopl Time, Psec+1 dayDays 16−30 Post-Dx191395638.20.7253.80E-02
Fibrinogen, Pmg/dL−1 dayClinical presentation2592584.9370.71.0671.20E-04
Fibrinogen, Pmg/dL+1 dayClinical presentation37292488.2326.20.8858.80E-06
Fibrinogen, Pmg/dL−1 dayDays 1−3 Post-Dx41381494.53181.0233.90E-07
Fibrinogen, Pmg/dL+1 dayDays 1−3 Post-Dx21244420.3312.20.6167.90E-03
Fibrinogen, Pmg/dL−1 dayDays 4−6 Post-Dx27156432.23360.4950.045
Fibrinogen, Pmg/dL+1 dayDays 4−6 Post-Dx24105472.2333.20.7120.025
Plateletsx10(9)/L−1 dayPre-diagnosis34575187.3225.6-0.3570.057
Plateletsx10(9)/L+1 dayPre-diagnosis1181533201.3234.4-0.3287.30E-04
Table 4
Prevalence of thrombotic phenotypes after the clinical presentation in COVIDpos patients with and without available longitudinal lab testing data.

For each clotting phenotype listed, a BERT-based neural network was used to extract diagnostic sentiment from individual EHR patient notes in which the phenotype (or a synonym thereof) was present. This automated curation was applied to clinical notes for each patient from day = −1 (clinical presentation) to day = 30 (end of the study period) relative to the PCR testing date. In this table, we show the absolute number of patients with each phenotype along with the percentage of patients in each cohort with the given specific thrombotic phenotype in parentheses.

Clotting phenotypeCohort 1: COVIDpos with longitudinal dataCohort 2: COVIDpos without longitudinal dataCohort 3: Complete COVIDpos cohort
Deep vein thrombosis47 (19%)6 (0.30%)53 (2.4%)
Pulmonary embolism22 (8.9%)9 (0.45%)31 (1.4%)
Myocardial infarction10 (4.1%)8 (0.40%)18 (0.81%)
Venous thromboembolism7 (2.8%)07 (0.31%)
Thrombotic stroke2 (0.81%)2 (0.10%]4 (0.18%)
Cerebral venous thrombosis000
Disseminated intravascular coagulation5 (2.0%)05 (0.22%)
Total unique patients with clot76 (31%)25 (1.3%)101 (4.5%)
Total patients24619862232
Table 5
Enrichment of thrombotic phenotypes among COVIDpos patients with longitudinal lab testing data.

Contingency table to calculate hypergeometric enrichment significance of thrombosis among patients with longitudinal lab testing data. The 246 patients with longitudinal testing data are those considered in this study, while the 1986 patients who did not have at least three results from one lab test over the defined 60-day window were excluded from this longitudinal analysis.

Patient has longitudinal dataPatient does NOT have longitudinal dataTotal
Thrombosis7625101
No thrombosis17019612131
Total24619862232

  1. Hypergeometric enrichment: p-value <1×10−50.

Table 6
Validation of the BERT model to identify the sentiment of thrombotic phenotypes in clinical notes.

Out-of-sample accuracy results of the BERT model to identify thrombotic phenotypes in 1000 randomly selected sentences from clinical notes which contained at least one mention of a thrombotic phenotype. The columns are (1) Clotting phenotype: thrombotic phenotype identified in the sentence, (2) TP (true positives): count of sentences in which the BERT model correctly identified the sentiment as ‘Yes’, (3) TN (true negatives): count of sentences in which the BERT model correctly identified the sentiment as not ‘Yes’, (4) FP (false positives): count of sentences in which the BERT model incorrectly identified the sentiment as ‘Yes’, (5) FN: (false negatives): count of sentences in which the BERT model incorrectly identified the sentiment as not ‘Yes’, (6) Recall: recall of the BERT model, equal to TP/(TP+FN), (7) Precision: precision of the BERT model, equal to TP/(TP+FP), (8) Accuracy: accuracy of the BERT model, equal to (TP+TN)/(TP+TN+FP+FN).

Clotting phenotypeTPTNFPFNRecallPrecisionAccuracy
Deep vein thrombosis13617824398%85%92%
Pulmonary embolism164787696%96%95%
Myocardial infarction212653399%99%98%
Venous thromboembolism39770100%30%93%
Thrombotic stroke5000100%100%100%
Cerebral venous thrombosis1000100%100%100%
Disseminated intravascular coagulation4400100%100%100%
Overall525422411297.8%92.8%94.7%
Table 7
General characteristics of patients with SARS-CoV-2 PCR testing.

General demographic characteristics of all patients who underwent SARS-CoV-2 PCR testing in the Mayo Clinic EHR database from February 15, 2020 to May 28, 2020. Includes summary characteristics for: (A) all patients with at least one SARS-CoV-2 PCR test, and (B) patients with at least one SARS-CoV-2 PCR test and longitudinal testing data available (i.e. patient received the same lab test on 3 separate days within + / − 30 days of PCR testing date).

(A) Demographics of all patients with PCR testing data
COVIDposCOVIDneg
Total number of patients223272,354
Gender:
Male1153 (52%)31,613 (44%)
Female1074 (48%)40,714 (56%)
Race:
White1115 (50%)62,605 (87%)
Black420 (19%)2792 (3.9%)
Asian151 (6.8%)1719 (2.4%)
American Indian29 (1.3%)302 (0.42%)
Other517 (23%)4936 (6.8%)
(B) Demographics of patients with PCR testing data and longitudinal testing data
TestUnitsPerturbationOriginal time windowCount COVIDposCount COVIDnegMean COVIDposMean COVIDnegCohen's DBH-adjusted M-W p-value
Activated Partial Thrombopl Time, Psec−1 dayDays 7–9 Post-Dx267250.1380.570.034
Activated Partial Thrombopl Time, Psec+1 dayDays 7–9 Post-Dx17585537.50.810.014
Activated Partial Thrombopl Time, Psec−1 dayDays 10–12 Post-Dx165756.938.40.8089.10E-03
Activated Partial Thrombopl Time, Psec+1 dayDays 10–12 Post-Dx156056.9381.1062.60E-03
Activated Partial Thrombopl Time, Psec−1 dayDays 13–15 Post-Dx155255.537.81.0410.014
Activated Partial Thrombopl Time, Psec+1 dayDays 13–15 Post-Dx144851.837.10.9620.015
Activated Partial Thrombopl Time, Psec−1 dayDays 16–30 Post-Dx2215655.2370.9135.70E-03
Activated Partial Thrombopl Time, Psec+1 dayDays 16–30 Post-Dx191395638.20.7253.80E-02
Fibrinogen, Pmg/dL−1 dayClinical presentation2592584.9370.71.0671.20E-04
Fibrinogen, Pmg/dL+1 dayClinical presentation37292488.2326.20.8858.80E-06
Fibrinogen, Pmg/dL−1 dayDays 1–3 Post-Dx41381494.53181.0233.90E-07
Fibrinogen, Pmg/dL+1 dayDays 1–3 Post-Dx21244420.3312.20.6167.90E-03
Fibrinogen, Pmg/dL−1 dayDays 4–6 Post-Dx27156432.23360.4950.045
Fibrinogen, Pmg/dL+1 dayDays 4–6 Post-Dx24105472.2333.20.7120.025
Platelets×10(9)/L−1 dayPre-diagnosis34575187.3225.6−0.3570.057
Platelets×10(9)/L+1 dayPre-diagnosis1181533201.3234.4−0.3287.30E-04
Table 8
Lab test data availability in patients with SARS-CoV-2 PCR testing.

Lab test data availability for all patients who underwent SARS-CoV-2 PCR testing in the Mayo Clinic EHR database from February 15, 2020 to May 28, 2020. Includes counts of lab tests and counts of patients with 1+ and 3+ lab tests both overall and for selected coagulation-related lab tests (activated partial thromboplastin time, D-dimer, fibrinogen, platelets, and prothrombin time).

COVIDposCOVIDneg
Total number of patients223272,354
Number of patients with 1+ lab test566 (25%)35,188 (49%)
Number patents with 1+ test from day −30 to day −1299 (13%)23,116 (32%)
Number patents with 1+ test from day 0 to day 30452 (20%)28,666 (40%)
Number of patients with 3+ lab tests of the same type246 (11%)13,666 (19%)
Total number of lab tests98,75332,40,491
Number of lab tests from day −30 to day −112,12010,33,762
Number of lab tests from day 0 to day 3086,63322,06,729
ACTIVATED PTT
Number of lab tests3626042
Number of patients with 1+ lab test93 (4.0%)3544 (4.9%)
Number of patients with 3+ lab tests20 (0.86%)406 (0.56%)
D-DIMER, P
Number of lab tests9112846
Number of patients with 1+ lab test247 (11%)2395 (3.3%)
Number of patients with 3+ lab tests99 (4.4%)56 (0.077%)
FIBRINOGEN, P
Number of lab tests2783,017
Number of patients with 1+ lab test84 (3.8%)1217 (1.7%)
Number of patients with 3+ lab tests18 (0.81%)273 (0.38%)
PLATELETS
Number of lab tests26461,08,722
Number of patients with 1+ lab test500 (22%)30,732 (42%)
Number of patients with 3+ lab tests231 (10%)11544 (16%)
PROTHROMBIN TIME, P
Number of lab tests71128,007
Number of patients with 1+ lab test197 (8.8%)10,446 (14%)
Number of patients with 3+ lab tests46 (2.1%)2502 (3.5%)
Table 9
Lab test data availability in patients with SARS-CoV-2 PCR testing and longitudinal lab data.

Lab test data availability for all patients who underwent SARS-CoV-2 PCR testing in the Mayo Clinic EHR database from February 15, 2020 to May 28, 2020 with longitudinal testing data available (i.e. patient received the same lab test on three separate days within + / − 30 days of PCR testing date). Includes counts of lab tests and counts of patients with 1+ and 3+ lab tests both overall and for selected coagulation-related lab tests (activated partial thromboplastin time, D-dimer, fibrinogen, platelets, and prothrombin time).

COVIDposCOVIDneg
Total number of patients24613,666
Number patents with 1+ test from day −30 to day −1150 (61%)11,567 (85%)
Number patents with 1+ test from day 0 to day 30240 (98%)13,501 (99%)
Total number of lab tests89,5872,634,070
Number of lab tests from day −30 to day −18698763,808
Number of lab tests from day 0 to day 3080,8891,870,262
ACTIVATED PTT
Number of lab tests3555186
Number of patients with 1+ lab test86 (35%)2722 (20%)
Number of patients with 3+ lab tests20 (8.1%)406 (3.0%)
D-DIMER, P
Number of lab tests8551720
Number of patients with 1+ lab test197 (80%)1293 (9.5%)
Number of patients with 3+ lab tests99 (40%)56 (0.41%)
FIBRINOGEN, P
Number of lab tests2752965
Number of patients with 1+ lab test81 (33%)1168 (8.5%)
Number of patients with 3+ lab tests18 (7.3%)273 (2%)
PLATELETS
Number of lab tests234387,517
Number of patients with 1+ lab test245 (100%)13,399 (98%)
Number of patients with 3+ lab tests231 (94%)11,544 (84%)
PROTHROMBIN TIME, P
Number of lab tests67624,489
Number of patients with 1+ lab test165 (67%)7209 (53%)
Number of patients with 3+ lab tests46 (19%)2502 (18%)

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  1. Colin Pawlowski
  2. Tyler Wagner
  3. Arjun Puranik
  4. Karthik Murugadoss
  5. Liam Loscalzo
  6. AJ Venkatakrishnan
  7. Rajiv K Pruthi
  8. Damon E Houghton
  9. John C O'Horo
  10. William G Morice II
  11. Amy W Williams
  12. Gregory J Gores
  13. John Halamka
  14. Andrew D Badley
  15. Elliot S Barnathan
  16. Hideo Makimura
  17. Najat Khan
  18. Venky Soundararajan
(2020)
Inference from longitudinal laboratory tests characterizes temporal evolution of COVID-19-associated coagulopathy (CAC)
eLife 9:e59209.
https://doi.org/10.7554/eLife.59209