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

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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 COVID_pos patients along with distinctive immune signatures.

Longitudinal trends in COVID_pos versus COVID_neg (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 COVID_pos and COVID_neg (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 COVID_pos and COVID_neg cohorts, respectively (i.e. # COVID_pos | # COVID_neg). For certain lab tests, some data points are missing because these time windows had fewer than three data points in the COVID_pos cohort.

Figure 2

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

Longitudinal trends in COVID_pos versus COVID_neg (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 COVID_pos and COVID_neg (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 COVID_pos and COVID_neg cohorts, respectively (i.e. # COVID_pos | # COVID_neg). For certain lab tests, some data points are missing because these time windows had fewer than three data points in the COVID_pos cohort.

Figure 3

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

Longitudinal trends of COVID_pos versus COVID_neg (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 COVID_pos and COVID_neg (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 COVID_pos and COVID_neg cohorts, respectively (i.e. # COVID_pos | # COVID_neg). For certain lab tests, some data points are missing because these time windows had fewer than three data points in the COVID_pos cohort.

Figure 4

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Longitudinal trends of lab tests with daily resolution.

Longitudinal trends of COVID_pos versus COVID_neg (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 COVID_pos cohort.

Figure 5

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Association between platelet counts and thrombosis in the COVID_pos cohort.

Box plots of platelet counts, min/max values, and maximum levels of increase/decline at specific time intervals for COVID_pos and COVID_neg cohorts and subgroups of the COVID_pos cohort with and without thrombotic events after SARS-CoV-2 diagnosis. In the subplot (A), we show platelet counts for COVID_pos (red) and COVID_neg (blue) cohorts. In subplots (**B-F**), we show platelet counts for COVID_pos 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 COVID_pos and COVID_neg cohorts. (B) Platelet counts at the time of PCR testing for COVID_pos patients who did and did not subsequently develop thromboses. (C) Maximum platelet counts (considering counts at and after positive PCR test date) for COVID_pos patients who did and did not subsequently develop thromboses. (D) Minimum platelet counts (considering counts at and after positive PCR test date) for COVID_pos patients who did and did not subsequently develop thromboses. (E) Maximum degree of platelet increases after positive PCR test date for COVID_pos patients who did and did not subsequently develop thromboses. (F) Maximum degree of platelet declines after positive PCR test date for COVID_pos 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 COVID_pos, COVID_neg (matched), and COVID_neg cohorts.

The COVID_neg (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 characteristics	COVID_pos	COVID_neg (matched)	COVID_neg
Number of patients	246	2460	13,666
Age in years	60.8	60.9	64.1
Gender:
Male	137 (56%)	1388 (56%)	7129 (52%)
Race:
White	154 (63%)	1540 (63%)	12,241 (90%)
Black	24 (9.8%)	313 (13%)	569 (4.2%)
Asian	18 (7.3%)	207 (8.4%)	274 (2.0%)
American Indian	23 (9.3%)	81 (3.3%)	81 (0.59%)
Other	27 (11%)	319 (13%)	501 (3.7%)
Medication use in the preceding 30 days of PCR testing date:
Anticoagulants	63 (26%)	596 (24%)	5171 (38%)
Antiplatelets	30 (12%)	298 (12%)	2230 (16%)
Medication use in the preceding 1 year of PCR testing date:
Anticoagulants	86 (35%)	819 (33%)	7476 (55%)
Antiplatelets	40 (16%)	419 (17%)	3620 (26%)
Medical history of thrombotic events in 1 year prior to study period:
Deep vein thrombosis	15 (6.1%)	153 (6.2%)	2,110 (15%)
Pulmonary embolism	12 (4.9%)	112 (4.6%)	1258 (9.2%)
Myocardial infarction	11 (4.5%)	142 (5.8%)	1468 (11%)
Venous thromboembolism	4 (1.6%)	44 (1.8%)	615 (4.5%)
Thrombotic stroke	1 (0.41%)	3 (0.12%)	143 (1.0%)
Cerebral venous thrombosis	0	1 (0.04%)	7 (0.05%)
Disseminated intravascular coagulation	0	1 (0.04%)	30 (0.22%)
Any thrombotic event	31 (13%)	308 (13%)	3901 (29%)
Hospitalized in the month prior to PCR testing date	41 (17%)	304 (12%)	1247 (9%)

Table 2

Summary of lab tests significantly different between COVID_pos and propensity score-matched COVID_neg 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 COVID_pos and COVID_neg 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.

Test	Units	Time window	Count COVID_pos	Count COVID_neg	Mean COVID_pos	Mean COVID_neg	Cohen's D	BH-adj M-W p-value
ABGRS pH Arterial	pH	Days 16–30 Post-Dx	18	91	7.45	7.4	0.775	0.02
ABGRS PO₂ Arterial	mm Hg	Days 1–3 Post-Dx	16	204	81.9	129.6	−0.797	3.1E-03
ABGRS PO₂ Arterial	mm Hg	Days 4–6 Post-Dx	25	82	78.1	113.2	−0.712	8.8E-03
ABGRS PO₂ Arterial	mm Hg	Days 7–9 Post-Dx	23	58	77.2	121.9	−0.807	1.0E-03
ABGRS PO₂ Arterial	mm Hg	Days 10–12 Post-Dx	18	37	76.4	104.2	−0.965	2.6E-03
ABGRS PO₂ Arterial	mm Hg	Days 13–15 Post-Dx	15	31	73.1	112.3	−0.964	6.0E-03
Activated Partial Thrombopl Time, P	sec	Days 7–9 Post-Dx	22	66	50.5	36.7	0.727	0.026
Activated Partial Thrombopl Time, P	sec	Days 10–12 Post-Dx	14	54	63.3	39.2	1.085	2.4E-03
Activated Partial Thrombopl Time, P	sec	Days 13–15 Post-Dx	16	48	53.1	37.6	1.065	5.6E-03
Activated Partial Thrombopl Time, P	sec	Days 16–30 Post-Dx	19	149	56.2	37.5	0.884	0.027
Alanine Aminotransferase (ALT), P	U/L	Days 10–12 Post-Dx	27	104	77.3	46	0.512	0.015
Albumin, P	g/dL	Days 7–9 Post-Dx	42	188	3.06	3.41	−0.54	5.6E-03
Albumin, S/P	g/dL	Clinical presentation	85	812	3.43	3.81	−0.591	4.8E-06
Albumin, S/P	g/dL	Days 1–3 Post-Dx	77	525	3.26	3.6	−0.541	3.8E-05
Albumin, S/P	g/dL	Days 10–12 Post-Dx	61	254	3.35	3.66	−0.47	2.6E-03
Alkaline Phosphatase, P	U/L	Days 4–6 Post-Dx	42	139	88.8	126.7	−0.395	3.7E-03
Arterial O₂ PP Diff	None	Clinical presentation	21	106	268.1	152.1	0.924	9.7E-03
Arterial O₂ PP Diff	None	Days 1–3 Post-Dx	22	112	225.9	147.4	0.639	0.017
Arterial O₂ PP Diff	None	Days 4–6 Post-Dx	17	49	271.4	155	0.891	4.8E-03
Aspartate Aminotransferase (AST), P	U/L	Days 10–12 Post-Dx	27	107	67.6	44.7	0.404	3.6E-04
Basophils Absolute	×10(9)/L	Clinical presentation	133	1400	0.0251	0.0379	−0.412	5.8E-06
Bicarbonate [MMOL/L] in Arterial Blood	mmol/L	Days 16–30 Post-Dx	18	91	28.6	24.3	0.857	7.6E-03
Bicarbonate in Arterial Blood	mmol/L	Days 1–3 Post-Dx	26	193	23.2	21.4	0.513	0.027
BUN, P	mg/dL	Days 16–30 Post-Dx	49	562	31.4	21.9	0.555	3.9E-03
C-reactive Protein Quantative, S	mg/L	Clinical presentation	85	666	100.2	68.2	0.375	6.8E-05
Calcium, Ionized, B	mg/dL	Clinical presentation	14	201	4.36	4.77	−0.67	0.015
Calcium, Ionized, B	mg/dL	Days 1–3 Post-Dx	18	270	4.42	4.73	−0.783	8.5E-04
Calcium, Total, P	mg/dL	Clinical presentation	89	1144	8.71	9.05	−0.468	5.5E-06
Calcium, Total, P	mg/dL	Days 1–3 Post-Dx	77	910	8.52	8.81	−0.459	3.2E-04
Calcium, Total, P	mg/dL	Days 7–9 Post-Dx	71	353	8.61	8.93	−0.457	1.8E-03
Calcium, Total, S	mg/dL	Clinical presentation	83	941	8.29	8.91	−0.854	1.9E-13
Calcium, Total, S	mg/dL	Days 1–3 Post-Dx	98	1025	8.28	8.77	−0.717	2.2E-10
Calcium, Total, S	mg/dL	Days 4–6 Post-Dx	87	568	8.4	8.69	−0.435	2.3E-03
Calcium, Total, S	mg/dL	Days 7–9 Post-Dx	82	433	8.49	8.76	−0.384	0.011
Carboxyhemoglobin, ARTERIAL	%	Clinical presentation	34	356	0.507	0.991	−0.71	2.0E-04
Carboxyhemoglobin, Arterial	%	Days 1–3 Post-Dx	44	436	0.535	0.9	−0.711	5.9E-05
Carboxyhemoglobin, Arterial	%	Days 4–6 Post-Dx	58	166	0.678	0.974	−0.544	3.0E-03
Carboxyhemoglobin, Arterial	%	Days 7–9 Post-Dx	45	102	0.704	0.97	−0.472	0.048
Carboxyhemoglobin, Venous	%	Days 1–3 Post-Dx	10	73	0.701	1.16	−0.862	0.02
Carboxyhemoglobin, Venous	%	Days 4–6 Post-Dx	14	47	0.725	1.29	−0.837	3.7E-03
Chloride, P	mmol/L	Days 1–3 Post-Dx	77	906	100.1	101.9	−0.363	7.7E-03
Eosinophils Absolute	×10(9)/L	Pre-diagnosis	28	547	0.0689	0.161	−0.45	1.7E-03
Esosinophils Absolute	×10(9)/L	Days 4–6 Post-Dx	133	559	0.0906	0.172	−0.358	2.4E-06
Fibrinogen, P	mg/dL	Clinical presentation	51	233	528.9	360.7	0.859	8.9E-07
Fibrinogen, P	mg/dL	Days 1–3 Post-Dx	18	319	432.6	297.4	0.836	1.7E-03
Fibrinogen, P	mg/dL	Days 4–6 Post-Dx	26	116	477.8	333.7	0.744	0.014
Glucose, Random, S	mg/dL	Days 13–15 Post-Dx	49	314	150	126.5	0.544	0.013
Hematocrit, B	%	Days 1–3 Post-Dx	158	1582	36.5	33.8	0.433	9.6E-06
Hematocrit, B	%	Days 4–6 Post-Dx	152	851	36	32.1	0.621	2.2E-10
Hematocrit, B	%	Days 7–9 Post-Dx	132	639	35.5	31.8	0.587	5.8E-08
Hematocrit, B	%	Days 10–12 Post-Dx	110	505	35.1	31.8	0.511	1.7E-05
Hemoglobin Arterial	g/dL	Days 1–3 Post-Dx	31	208	12.1	10.8	0.651	0.025
Hemoglobin, B	g/dL	Days 1–3 Post-Dx	158	1682	11.9	11.1	0.358	2.2E-04
Hemoglobin, B	g/dL	Days 4–6 Post-Dx	152	873	11.8	10.4	0.636	1.4E-10
Hemoglobin, B	g/dL	Days 7–9 Post-Dx	132	653	11.6	10.4	0.56	2.0E-07
Hemoglobin, B	g/dL	Days 10–12 Post-Dx	110	516	11.4	10.3	0.49	2.6E-05
Ionized Calcium, Arterial	mg/dL	Days 16–30 Post-Dx	8	36	4.93	4.48	1.561	0.022
Lactate Dehydrogenase, S	U/L	Days 10–12 Post-Dx	21	88	406.2	295.2	0.463	1.4E-03
Lactate, P	mmol/L	Clinical presentation	89	954	1.37	1.93	−0.462	3.1E-06
Lymphocytes Percent	%	Days 13–15 Post-Dx	5	66	33.2	15	1.514	0.048
Lymphs Absolute	×10(9)/L	Days 13–15 Post-Dx	56	349	3.12	1.11	0.44	0.018
Magnesium, Plasma	mg/dL	Days 10–12 Post-Dx	20	87	2.14	1.91	0.772	0.015
Magnesium, S/P	mg/dL	Days 4–6 Post-Dx	47	279	2.22	1.98	0.743	3.0E-03
Magnesium, S/P	mg/dL	Days 7–9 Post-Dx	40	215	2.31	1.97	1.06	4.1E-06
Magnesium, S/P	mg/dL	Days 10–12 Post-Dx	36	187	2.26	1.91	1.005	2.9E-06
Magnesium, S/P	mg/dL	Days 13–15 Post-Dx	35	179	2.22	1.89	0.904	1.8E-07
Magnesium, S/P	mg/dL	Days 16–30 Post-Dx	33	317	2.13	1.89	0.906	1.6E-04
Manual Diff Promyelocytes	%	Days 1–3 Post-Dx	6	55	0.25	0	1.402	0.027
Mean Corpuscular Volume	fL	Days 10–12 Post-Dx	110	502	89.5	92	−0.38	8.8E-03
Methemoglobin, ABG	%	Clinical presentation	34	356	0.335	0.571	−0.629	6.0E-03
Methemoglobin, ABG	%	Days 1–3 Post-Dx	44	436	0.425	0.697	−0.463	1.5E-03
Monocytes Absolute	×10(9)/L	Days 1–3 Post-Dx	131	1079	0.447	0.748	−0.502	2.6E-16
Monocytes Absolute	×10(9)/L	Days 4–6 Post-Dx	135	584	0.475	0.715	−0.597	2.2E-10
N-terminal-PRO-Brain Type Natriuretic Peptide, S	pg/mL	Days 4–6 Post-Dx	10	63	415.6	7609.7	−0.525	2.9E-03
Neutrophils, B	×10(9)/L	Clinical presentation	136	1382	5.31	7.12	−0.396	6.3E-06
Neutrophils, B	×10(9)/L	Days 1–3 Post-Dx	130	1141	4.73	6.32	−0.385	5.8E-05
NT-PRO BNP, P	pg/mL	Clinical presentation	25	372	1372.4	5327.9	−0.385	0.046
NT-PRO BNP, P	pg/mL	Days 4–6 Post-Dx	14	20	815.3	4388.8	−0.929	0.02
Nucleated RBC	/100 WBC	Days 13–15 Post-Dx	23	189	1.24	0.447	0.561	1.7E-03
O₂HB	%	Days 1–3 Post-Dx	13	242	88.6	95	−1.37	2.2E-03
O₂HB	%	Days 4–6 Post-Dx	32	90	92.1	93.7	−0.356	0.013
O₂HB	%	Days 7–9 Post-Dx	24	46	91.5	94.5	−0.701	3.3E-04
Osmolality, U	mOsm/kg	Pre-diagnosis	4	80	231.5	478.8	−1.509	0.044
Oxygen Content, Arterial	vol %	Days 4–6 Post-Dx	32	89	16	13.7	0.839	2.4E-03
Oxygen Saturation (%) in Arterial Blood	%	Clinical presentation	27	189	94.2	96.2	−0.52	3.1E-03
Oxygen Saturation (%) in Arterial Blood	%	Days 1–3 Post-Dx	31	216	94.3	97.1	−1.293	8.4E-09
Oxygen Saturation (%) in Arterial Blood	%	Days 4–6 Post-Dx	26	70	94.3	95.7	−0.578	0.014
Oxygen Saturation (%) in Arterial Blood	%	Days 10–12 Post-Dx	18	29	93.4	96.5	−1.254	3.1E-03
Oxygen Saturation (%) in Arterial Blood	%	Days 13–15 Post-Dx	17	28	94.8	96.4	−0.671	0.043
pH Blood Arterial	None	Days 1–3 Post-Dx	26	193	7.42	7.39	0.539	0.035
pH Blood Venous	pH	Days 1–3 Post-Dx	10	82	7.42	7.36	0.963	0.031
pH, POCT, B	None	Clinical presentation	13	202	7.41	7.33	0.708	0.042
Platelets	×10(9)/L	Pre-diagnosis	39	649	184.8	225.9	−0.393	0.024
PO₂	mm Hg	Days 1–3 Post-Dx	8	145	67.2	179.7	−1.301	1.7E-03
PO₂	mm Hg	Days 7–9 Post-Dx	14	16	71.1	121.1	−0.949	0.027
PO₂ Arterial	mm Hg	Days 1–3 Post-Dx	26	193	100.4	150.9	−0.87	8.2E-05
PO₂ Arterial	mm Hg	Days 10–12 Post-Dx	17	25	93.6	134	−0.755	0.019
Potassium, S	mmol/L	Pre-diagnosis	10	398	3.93	4.35	−0.836	0.049
RABG Calculated O₂ Hemoglobin	%	Days 1–3 Post-Dx	22	109	93.6	95	−0.464	2.9E-03
RABG Calculated O₂ Hemoglobin	%	Days 4–6 Post-Dx	16	49	93.2	95.3	−0.859	2.3E-03
RABG Calculated O₂ Hemoglobin	%	Days 10–12 Post-Dx	13	22	94	96.3	−1.269	0.038
RABG PF Ratio	None	Days 4–6 Post-Dx	17	49	1.46	2.68	−1.489	6.9E-05
RABG PF Ratio	None	Days 7–9 Post-Dx	13	22	1.75	2.56	−1.006	0.038
RABG PF Ratio	None	Days 10–12 Post-Dx	13	22	1.83	3.22	−1.518	3.9E-03
RBC (Red Blood Cell) Count	×10(12)/L	Clinical presentation	151	1671	4.32	3.99	0.409	2.0E-04
RBC (Red Blood Cell) Count	×10(12)/L	Days 1–3 Post-Dx	158	1562	4.13	3.73	0.524	5.8E-08
RBC (Red Blood Cell) Count	×10(12)/L	Days 4–6 Post-Dx	152	846	4.08	3.55	0.693	3.2E-12
RBC (Red Blood Cell) Count	×10(12)/L	Days 7–9 Post-Dx	132	635	4	3.49	0.656	2.4E-09
RBC (Red Blood Cell) Count	×10(12)/L	Days 10–12 Post-Dx	110	502	3.95	3.48	0.587	6.1E-07
Red Cell Distribution Width CV	%	Days 4–6 Post-Dx	137	722	14.1	15.1	−0.373	3.4E-04
Red Cell Distribution Width CV	%	Days 7–9 Post-Dx	119	552	14.2	15.4	−0.431	9.8E-05
Red Cell Distribution Width CV	%	Days 10–12 Post-Dx	97	429	14.5	15.7	−0.394	1.2E-03
Sodium, P	mmol/L	Clinical presentation	89	1141	135.6	137.3	−0.375	7.3E-03
Sodium, P	mmol/L	Days 1–3 Post-Dx	77	927	136.6	138.1	−0.377	4.7E-03
Sodium, S	mmol/L	Days 10–12 Post-Dx	69	334	140.8	138.3	0.651	2.0E-04
Spont. Breaths/min	None	Days 4–6 Post-Dx	23	67	25	20.2	0.767	0.016
Tacrolimus, B	ng/mL	Days 7–9 Post-Dx	8	81	4.22	8.12	−1.102	8.8E-03
Tacrolimus, B	ng/mL	Days 10–12 Post-Dx	8	79	3.8	9.24	−1.468	2.5E-03
Tacrolimus, B	ng/mL	Days 13–15 Post-Dx	7	71	3.7	8.52	−1.47	7.5E-03
Tacrolimus, B	ng/mL	Days 16–30 Post-Dx	10	110	4.93	7.8	−1.094	0.022
Temperature	None	Clinical presentation	23	136	37	36.7	0.591	0.042
Temperature	None	Days 1–3 Post-Dx	23	189	37	36.4	0.765	4.8E-04
Triglycerides, S/P	mg/dL	Days 4–6 Post-Dx	16	41	326.2	173	1.196	7.3E-03
Triglycerides, S/P	mg/dL	Days 7–9 Post-Dx	17	24	310.6	191.5	0.945	0.016
Triglycerides, S/P	mg/dL	Days 10–12 Post-Dx	17	35	364.5	174.4	1.217	4.0E-03
Triglycerides, S/P	mg/dL	Days 16–30 Post-Dx	10	77	276.1	166.4	0.83	0.024
Troponin T, 5TH GEN, P	ng/L	Days 4–6 Post-Dx	18	54	21.4	245.3	−0.499	7.5E-03
Troponin T, Baseline, 5TH Gen, P	ng/L	Days 7–9 Post-Dx	11	43	15.1	53.7	−0.538	0.037
VBGRS HGB	g/dL	Days 4–6 Post-Dx	36	99	12.3	10.5	0.932	3.6E-04
White Blood Cells	×10(9)/L	Days 1–3 Post-Dx	158	1650	6.67	9.08	−0.439	3.2E-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.

Test	Units	Perturbation	Original time window	Count COVID_pos	Count COVID_neg	Mean COVID_pos	Mean COVID_neg	Cohen's D	BH-adjusted M-W p-value
Activated Partial Thrombopl Time, P	sec	−1 day	Days 7−9 Post-Dx	26	72	50.1	38	0.57	0.034
Activated Partial Thrombopl Time, P	sec	+1 day	Days 7−9 Post-Dx	17	58	55	37.5	0.81	0.014
Activated Partial Thrombopl Time, P	sec	−1 day	Days 10−12 Post-Dx	16	57	56.9	38.4	0.808	9.10E-03
Activated Partial Thrombopl Time, P	sec	+1 day	Days 10−12 Post-Dx	15	60	56.9	38	1.106	2.60E-03
Activated Partial Thrombopl Time, P	sec	−1 day	Days 13−15 Post-Dx	15	52	55.5	37.8	1.041	0.014
Activated Partial Thrombopl TIME, P	sec	+1 day	Days 13−15 Post-Dx	14	48	51.8	37.1	0.962	0.015
Activated Partial Thrombopl Time, P	sec	−1 day	Days 16−30 Post-Dx	22	156	55.2	37	0.913	5.70E-03
Activated Partial Thrombopl Time, P	sec	+1 day	Days 16−30 Post-Dx	19	139	56	38.2	0.725	3.80E-02
Fibrinogen, P	mg/dL	−1 day	Clinical presentation	25	92	584.9	370.7	1.067	1.20E-04
Fibrinogen, P	mg/dL	+1 day	Clinical presentation	37	292	488.2	326.2	0.885	8.80E-06
Fibrinogen, P	mg/dL	−1 day	Days 1−3 Post-Dx	41	381	494.5	318	1.023	3.90E-07
Fibrinogen, P	mg/dL	+1 day	Days 1−3 Post-Dx	21	244	420.3	312.2	0.616	7.90E-03
Fibrinogen, P	mg/dL	−1 day	Days 4−6 Post-Dx	27	156	432.2	336	0.495	0.045
Fibrinogen, P	mg/dL	+1 day	Days 4−6 Post-Dx	24	105	472.2	333.2	0.712	0.025
Platelets	x10(9)/L	−1 day	Pre-diagnosis	34	575	187.3	225.6	-0.357	0.057
Platelets	x10(9)/L	+1 day	Pre-diagnosis	118	1533	201.3	234.4	-0.328	7.30E-04

Table 4

Prevalence of thrombotic phenotypes after the clinical presentation in COVID_pos 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 phenotype	Cohort 1: COVID_pos with longitudinal data	Cohort 2: COVID_pos without longitudinal data	Cohort 3: Complete COVID_pos cohort
Deep vein thrombosis	47 (19%)	6 (0.30%)	53 (2.4%)
Pulmonary embolism	22 (8.9%)	9 (0.45%)	31 (1.4%)
Myocardial infarction	10 (4.1%)	8 (0.40%)	18 (0.81%)
Venous thromboembolism	7 (2.8%)	0	7 (0.31%)
Thrombotic stroke	2 (0.81%)	2 (0.10%]	4 (0.18%)
Cerebral venous thrombosis	0	0	0
Disseminated intravascular coagulation	5 (2.0%)	0	5 (0.22%)
Total unique patients with clot	76 (31%)	25 (1.3%)	101 (4.5%)
Total patients	246	1986	2232

Table 5

Enrichment of thrombotic phenotypes among COVID_pos 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 data	Patient does NOT have longitudinal data	Total
Thrombosis	76	25	101
No thrombosis	170	1961	2131
Total	246	1986	2232

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 phenotype	TP	TN	FP	FN	Recall	Precision	Accuracy
Deep vein thrombosis	136	178	24	3	98%	85%	92%
Pulmonary embolism	164	78	7	6	96%	96%	95%
Myocardial infarction	212	65	3	3	99%	99%	98%
Venous thromboembolism	3	97	7	0	100%	30%	93%
Thrombotic stroke	5	0	0	0	100%	100%	100%
Cerebral venous thrombosis	1	0	0	0	100%	100%	100%
Disseminated intravascular coagulation	4	4	0	0	100%	100%	100%
Overall	525	422	41	12	97.8%	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
	COVID_pos	COVID_neg
Total number of patients	2232	72,354
Gender:
Male	1153 (52%)	31,613 (44%)
Female	1074 (48%)	40,714 (56%)
Race:
White	1115 (50%)	62,605 (87%)
Black	420 (19%)	2792 (3.9%)
Asian	151 (6.8%)	1719 (2.4%)
American Indian	29 (1.3%)	302 (0.42%)
Other	517 (23%)	4936 (6.8%)
(B) Demographics of patients with PCR testing data and longitudinal testing data
Test	Units	Perturbation	Original time window	Count COVID_pos	Count COVID_neg	Mean COVID_pos	Mean COVID_neg	Cohen's D	BH-adjusted M-W p-value
Activated Partial Thrombopl Time, P	sec	−1 day	Days 7–9 Post-Dx	26	72	50.1	38	0.57	0.034
Activated Partial Thrombopl Time, P	sec	+1 day	Days 7–9 Post-Dx	17	58	55	37.5	0.81	0.014
Activated Partial Thrombopl Time, P	sec	−1 day	Days 10–12 Post-Dx	16	57	56.9	38.4	0.808	9.10E-03
Activated Partial Thrombopl Time, P	sec	+1 day	Days 10–12 Post-Dx	15	60	56.9	38	1.106	2.60E-03
Activated Partial Thrombopl Time, P	sec	−1 day	Days 13–15 Post-Dx	15	52	55.5	37.8	1.041	0.014
Activated Partial Thrombopl Time, P	sec	+1 day	Days 13–15 Post-Dx	14	48	51.8	37.1	0.962	0.015
Activated Partial Thrombopl Time, P	sec	−1 day	Days 16–30 Post-Dx	22	156	55.2	37	0.913	5.70E-03
Activated Partial Thrombopl Time, P	sec	+1 day	Days 16–30 Post-Dx	19	139	56	38.2	0.725	3.80E-02
Fibrinogen, P	mg/dL	−1 day	Clinical presentation	25	92	584.9	370.7	1.067	1.20E-04
Fibrinogen, P	mg/dL	+1 day	Clinical presentation	37	292	488.2	326.2	0.885	8.80E-06
Fibrinogen, P	mg/dL	−1 day	Days 1–3 Post-Dx	41	381	494.5	318	1.023	3.90E-07
Fibrinogen, P	mg/dL	+1 day	Days 1–3 Post-Dx	21	244	420.3	312.2	0.616	7.90E-03
Fibrinogen, P	mg/dL	−1 day	Days 4–6 Post-Dx	27	156	432.2	336	0.495	0.045
Fibrinogen, P	mg/dL	+1 day	Days 4–6 Post-Dx	24	105	472.2	333.2	0.712	0.025
Platelets	×10(9)/L	−1 day	Pre-diagnosis	34	575	187.3	225.6	−0.357	0.057
Platelets	×10(9)/L	+1 day	Pre-diagnosis	118	1533	201.3	234.4	−0.328	7.30E-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).

	COVID_pos	COVID_neg
Total number of patients	2232	72,354
Number of patients with 1+ lab test	566 (25%)	35,188 (49%)
Number patents with 1+ test from day −30 to day −1	299 (13%)	23,116 (32%)
Number patents with 1+ test from day 0 to day 30	452 (20%)	28,666 (40%)
Number of patients with 3+ lab tests of the same type	246 (11%)	13,666 (19%)
Total number of lab tests	98,753	32,40,491
Number of lab tests from day −30 to day −1	12,120	10,33,762
Number of lab tests from day 0 to day 30	86,633	22,06,729
ACTIVATED PTT
Number of lab tests	362	6042
Number of patients with 1+ lab test	93 (4.0%)	3544 (4.9%)
Number of patients with 3+ lab tests	20 (0.86%)	406 (0.56%)
D-DIMER, P
Number of lab tests	911	2846
Number of patients with 1+ lab test	247 (11%)	2395 (3.3%)
Number of patients with 3+ lab tests	99 (4.4%)	56 (0.077%)
FIBRINOGEN, P
Number of lab tests	278	3,017
Number of patients with 1+ lab test	84 (3.8%)	1217 (1.7%)
Number of patients with 3+ lab tests	18 (0.81%)	273 (0.38%)
PLATELETS
Number of lab tests	2646	1,08,722
Number of patients with 1+ lab test	500 (22%)	30,732 (42%)
Number of patients with 3+ lab tests	231 (10%)	11544 (16%)
PROTHROMBIN TIME, P
Number of lab tests	711	28,007
Number of patients with 1+ lab test	197 (8.8%)	10,446 (14%)
Number of patients with 3+ lab tests	46 (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).

	COVID_pos	COVID_neg
Total number of patients	246	13,666
Number patents with 1+ test from day −30 to day −1	150 (61%)	11,567 (85%)
Number patents with 1+ test from day 0 to day 30	240 (98%)	13,501 (99%)
Total number of lab tests	89,587	2,634,070
Number of lab tests from day −30 to day −1	8698	763,808
Number of lab tests from day 0 to day 30	80,889	1,870,262
ACTIVATED PTT
Number of lab tests	355	5186
Number of patients with 1+ lab test	86 (35%)	2722 (20%)
Number of patients with 3+ lab tests	20 (8.1%)	406 (3.0%)
D-DIMER, P
Number of lab tests	855	1720
Number of patients with 1+ lab test	197 (80%)	1293 (9.5%)
Number of patients with 3+ lab tests	99 (40%)	56 (0.41%)
FIBRINOGEN, P
Number of lab tests	275	2965
Number of patients with 1+ lab test	81 (33%)	1168 (8.5%)
Number of patients with 3+ lab tests	18 (7.3%)	273 (2%)
PLATELETS
Number of lab tests	2343	87,517
Number of patients with 1+ lab test	245 (100%)	13,399 (98%)
Number of patients with 3+ lab tests	231 (94%)	11,544 (84%)
PROTHROMBIN TIME, P
Number of lab tests	676	24,489
Number of patients with 1+ lab test	165 (67%)	7209 (53%)
Number of patients with 3+ lab tests	46 (19%)	2502 (18%)

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Colin Pawlowski
Tyler Wagner
Arjun Puranik
Karthik Murugadoss
Liam Loscalzo
AJ Venkatakrishnan
Rajiv K Pruthi
Damon E Houghton
John C O'Horo
William G Morice II
Amy W Williams
Gregory J Gores
John Halamka
Andrew D Badley
Elliot S Barnathan
Hideo Makimura
Najat Khan
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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Longitudinal and temporally resolved analysis highlights positive control lab tests elevated in COVIDpos patients along with distinctive immune signatures.

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

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

Longitudinal trends of lab tests with daily resolution.

Association between platelet counts and thrombosis in the COVIDpos cohort.

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

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

Summary of lab tests significantly different between COVIDpos and propensity score-matched COVIDneg cohorts during at least one clinical time window.

Sensitivity analysis of clinical time intervals for significant coagulation-related lab test trends.

Prevalence of thrombotic phenotypes after the clinical presentation in COVIDpos patients with and without available longitudinal lab testing data.

Enrichment of thrombotic phenotypes among COVIDpos patients with longitudinal lab testing data.

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

General characteristics of patients with SARS-CoV-2 PCR testing.

Lab test data availability in patients with SARS-CoV-2 PCR testing.

Lab test data availability in patients with SARS-CoV-2 PCR testing and longitudinal lab data.

Transparent reporting form

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

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

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

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

Association between platelet counts and thrombosis in the COVID_pos cohort.

Summary of patient characteristics for the overall COVID_pos, COVID_neg (matched), and COVID_neg cohorts.

Summary of lab tests significantly different between COVID_pos and propensity score-matched COVID_neg cohorts during at least one clinical time window.

Prevalence of thrombotic phenotypes after the clinical presentation in COVID_pos patients with and without available longitudinal lab testing data.

Enrichment of thrombotic phenotypes among COVID_pos patients with longitudinal lab testing data.