Prevalence of Thrombotic Complications in ICU-Treated Patients With Coronavirus Disease 2019 Detected With Systematic CT Scanning

Saeed Mirsadraee, MD, PhD, FRCR, FRCPE; Diana A. Gorog, MD, PhD, FRCP; Ciara F. Mahon, BCh, BAO, MSc, MRCP; Bhavin Rawal, MBBS, FRCR; Thomas R. Semple, FRCR; Edward D. Nicol, MD, FRCP, FRCR; Deepa R. J. Arachchillage, MD, MRCP, FRCPath; Anand Devaraj, MD, FRCR; Susanna Price, PhD, FRCP; Sujal R. Desai, MD, FRCR, FRCP; Carole A. Ridge, FFRRCSI; Suveer Singh, MD, PHD; Simon P. G. Padley, MBBS, FRCR

Disclosures

Crit Care Med. 2021;49(5):804-815.

Abstract and Introduction

Abstract

Objectives: Severe coronavirus disease 2019 is associated with an extensive pneumonitis and frequent coagulopathy. We sought the true prevalence of thrombotic complications in critically ill patients with severe coronavirus disease 2019 on the ICU, with or without extracorporeal membrane oxygenation.

Design: We undertook a single-center, retrospective analysis of 72 critically ill patients with coronavirus disease 2019-associated acute respiratory distress syndrome admitted to ICU. CT angiography of the thorax, abdomen, and pelvis were performed at admission as per routine institution protocols, with further imaging as clinically indicated. The prevalence of thrombotic complications and the relationship with coagulation parameters, other biomarkers, and survival were evaluated.

Setting: Coronavirus disease 2019 ICUs at a specialist cardiorespiratory center.

Patients: Seventy-two consecutive patients with coronavirus disease 2019 admitted to ICU during the study period (March 19, 2020, to June 23, 2020).

Interventions: None.

Measurements and Main Results: All but one patient received thromboprophylaxis or therapeutic anticoagulation. Among 72 patients (male:female = 74%; mean age: 52 ± 10; 35 on extracorporeal membrane oxygenation), there were 54 thrombotic complications in 42 patients (58%), comprising 34 pulmonary arterial (47%), 15 peripheral venous (21%), and five (7%) systemic arterial thromboses/end-organ embolic complications. In those with pulmonary arterial thromboses, 93% were identified incidentally on first screening CT with only 7% suspected clinically. Biomarkers of coagulation (e.g., D-dimer, fibrinogen level, and activated partial thromboplastin time) or inflammation (WBC count, C-reactive protein) did not discriminate between patients with or without thrombotic complications. Fifty-one patients (76%) survived to discharge; 17 (24%) patients died. Mortality was significantly greater in patients with detectable thrombus (33% vs 10%; p = 0.022).

Conclusions: There is a high prevalence of thrombotic complications, mainly pulmonary, among coronavirus disease 2019 patients admitted to ICU, despite anticoagulation. Detection of thrombus was usually incidental, not predicted by coagulation or inflammatory biomarkers, and associated with increased risk of death. Systematic CT imaging at admission should be considered in all coronavirus disease 2019 patients requiring ICU.

Introduction

To date, following the first report of coronavirus disease 2019 (COVID-19) in Wuhan in late December 2019, over 60 million people have acquired the disease worldwide. Just over one quarter of symptomatic patients needing hospitalization require intensive care support.^[1]

While patients with severe pulmonary infections and the acute respiratory distress syndrome (ARDS) are at risk of thrombosis,^[2–6] those with COVID-19 appear to be at particularly high risk, despite thromboprophylaxis.^[7] Thrombotic complications in critically ill patients are clinically difficult to detect and may go unrecognized.

Severe COVID-19 pneumonia is characterized by fulminant cytokine release leading to the activation of a coagulation cascade.^[8] A prothrombotic state is a recognized feature of severe COVID-19 infection, manifesting as venous and systemic or pulmonary arterial thrombus; however, the true prevalence of detectable (macrovascular) thrombus and associated complications is unknown.^[9] While typical pathologic features of ARDS are seen in patients with COVID-19,^[1] a recent study reported systemic thrombosis at microvascular level as an additional cause of respiratory failure.^[10]

The prevalence of image-diagnosed thrombosis appears higher in COVID-19 than in comparably ill patients with different etiologies. In a recent study, 22% of COVID-19 ICU patients had pulmonary embolism (without systematic imaging) compared with 7.5% in influenza patients, despite similar severity of respiratory disease.^[11]

The aim of the present study was to evaluate the true prevalence of vascular thrombotic complications in patients with confirmed COVID-19 admitted to ICU for advanced ventilatory support, including those on extracorporeal membrane oxygenation (ECMO), as apparent on systematic CT imaging.

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Next Section

Table 1. Patient Characteristics: Demographics and Medical According to the Presence or Absence of the Primary Composite Endpoint
Clinical Characteristics	All Patients (n = 72)	No Thromboembolic Event	Thromboembolic Event				p ^a
		(n = 30; 42%)	Patients with at least one event (n = 42; 58%)	Venous (n = 15; 21%)	Pulmonary (n = 34; 47%)	Arterial (n = 5; 7%)
Mean age, yr (SD; range)	52 (10; 29–72)	51 (11; 32–79)	52 (10; 29–72)	52 (9; 33–65)	52 (10; 29–72)	48 (6; 39–53)	0.515
Gender, n (%)
Male	53 (74)	25 (83)	28 (67)	9 (60)	22 (65)	4 (80)	0.094
Ethnicity, n (%)
Caucasian	33 (46)	16 (53)	17 (41)	6 (40)	12 (35)	2 (40)	0.253
Asian	32 (44)	10 (33)	22 (52)	8 (53)	19 (56)	2 (40)
African or Caribbean	7 (10)	4 (13)	3 (7)	1 (6)	3 (9)	1 (20)
Comorbidities, n (%)
Diabetes	19 (26)	6 (20)	13 (31)	4 (27)	12 (35)	2 (40)	0.222
Hypertension	26 (36)	9 (30)	17 (40)	6 (35)	13 (37)	2 (40)	0.458
Prior coronary or peripheral artery disease	1 (< 1)	0	0	0	1 (< 1)	0	0.583
Prior stroke	1 (< 1)	0	0	0	1 (< 1)	0	0.583
Smoking history	6 (8)	3 (10)	3 (7)	1 (6)	3 (9)	0	0.491
Mean body mass index (SD; range)	31 (7; 21–64)	32 (8; 21–64)	30 (6; 22–45)	31 (7; 23–44)	31 (6; 22–45)	30 (5; 23–38)	0.614
< 30, n (%)	37 (51)	15 (50)	22 (52)	7 (47)	18 (53)	3 (60)
30–40, n (%)	26 (36)	10 (33)	16 (38);	5 (33)	13 (38)	2 (40)
> 40, n (%)	9 (13)	5 (17)	4 (10)	3 (20)	3 (9)	0
Patients on ECMO, n (%)	35 (49)	13 (37)	22 (63)	6 (17)	18 (51)	4 (11)	0.695
Patients not on ECMO, n (%)	37 (51)	17 (46)	20 (54)	9 (24)	16 (43)	1 (3)
Antiplatelet therapy, n (%)	12 (17)	6 (20)	6 (14)	4 (27)	3 (9)	0 (0)	0.808

ECMO = extracorporeal membrane oxygenation.
^a p value compares patients with and without thrombotic events.

Table 2. Laboratory Results of the Study Cohort According to the Presence or Absence of the Primary Composite Endpoint
Laboratory Result	All Patients (n = 72)	No Thromboembolic Event	Thromboembolic Event				p ^a
Test (normal range)	Mean (SD; range)	(n = 27; 37.5%)	Patients with at least one event (n = 45; 62.5%)	Venous (n = 17; 24%)	Pulmonary (n = 35; 49%)	Arterial (n = 5; 7%)
Hemoglobulin (115–151 g/L)	107 (20; 72–157)	111 (18; 85–149)	105 (21; 72–157)	106 (18; 72–128)	105 (22; 72–157)	102 (23; 74–136)	0.213
Platelet (147–397 × 10^9/L)	270 (100; 69–522)	284 (108; 85–522)	261 (94; 69–473)	297 (82; 128–402)	245 (94; 69–473)	219 (57; 167–306)	0.508
WBC count (5.1–11.4 × 10^9/L)	11.5 (4.9; 2.6–24)	12 (5.6; 2.6–24)	10.9 (4.2; 4.4–21)	12 (4; 6.9–21)	10.7 (4.3; 4.4–21)	7.9 (2.5; 5–11)	0.515
Lymphocyte (1.3–3.7 × 10^9/L)	0.81 (0.51; 0–3.1)	0.82 (0.67; 0–3.1)	0.8 (0.4; 0.2–1.8)	0.72 (0.3; 0.2–1.3)	0.81 (0.4; 0.2–1.8)	0.74 (0.22; 0.5–1.1)	0.289
Ferritin (20–186 μg/L)	1,112 (119; 103–5,646)	1,157 (957; 103–4,044)	1,102 (1,204; 108–5,646)	1,410 (1,582; 108–5,646)	1,070 (1,245;108–5,646)	671 (523; 156–1,482)	0.367
C-reactive protein (0–10 mg/L)	254 (121; 18–642)	248 (112; 18–432)	259 (128; 18–642)	299 (148; 75–642)	256 (111; 26–546)	276 (54; 208–350)	0.995
Creatinine (60–120 μmol/L)	143 (129; 29–611)	150 (139; 30–611)	132 (12; 26–642)	158 (154; 29–556)	137 (121; 30–477)	180 (176; 46–477)	0.743
Urea (2.5–7.8 mmol/L)	11 (7; 2–36)	11 (7; 4–31)	11.5 (8; 1.6–36)	13 (9; 2–36)	11 (7; 2–26)	13 (8; 6–25)	0.834
Albumin (35–50 g/L)	26 (11; 17–105)	27 (15; 18–105)	25 (5; 17–43)	24 (4; 18–32)	25 (6; 17–43)	26 (5; 17–31)	0.722
Alanine aminotransferase (8–40 U/L)	65 (64; 8–353)	72 (81; 8–353)	59 (48; 8–294)	74 (67; 8–294)	58 (53; 8–294)	52 (30; 20–89)	0.909
Alkaline phosphatase (30–130 U/L)	131 (125; 27–1,055)	149 (178; 38–1,055)	118 (63; 27–286)	147 (71; 36–283)	107 (55; 27–286)	116 (62; 57–219)	0.635
Lactate dehydrogenase (266–500 international units/L)	1,053 (494; 96–3,049)	1,078 (468; 96–2,401)	1,035 (518; 333–3,049)	1,024 (343; 342–1,545)	1,048 (554; 333–3,049)	968 (258; 96–3,049)	0.462
d-dimer (0–240 ng/mL)	7,606 (11,743; 148–56,005)	5,160 (6,863; 511–35,547)	9,396 (14,121; 148–56,005)	12,932 (17,399; 451–56,005)	9,762 (14,910; 148–56,005)	6,338 (5,314; 727–13,368)	0.744
Prothrombin time (s) (10.2–13.2)	14 (3; 10–33)	14 (2; 10–22)	14.5 (3.4; 11–33)	14 (1; 11–17)	14 (4; 11–33)	14 (1; 13–15)	0.265
Activated partial thromboplastin time (26–36 s)	38 (14; 16–92)	35 (9; 16–52)	41 (17; 27–92)	41 (17; 26.5–78)	40 (17; 27–92)	34 (4; 27–38)	0.367
Fibrinogen (1.5–4.5 g/L)	6.4 (1.9; 1.4–10.7)	6.5 (1.9; 1.4–10.1)	6.4 (1.9; 2.5–10.7)	6.6 (1.7; 3.8–9.4)	6.3 (1.9; 2.5–10.7)	7.9 (1.8; 6.1–10.3)	0.703
High-sensitivity troponin I (< 11.6 ng/L)	528 (3,420; 3–27,619)	157 (333; 3–1,501)	793 (4,357; 3–27,619)	2,258 (7,625; 4–27,619)	77 (220; 3–1,146)	13 (10; 4–24)	0.131
N-terminal pro B-type natriuretic peptide	197 (264; 9–1,323)	234 (349; 9–1,323)	162 (167; 10–673)	216 (206; 22–673)	153 (172; 10–673)	75 (115; 16–280)	0.652
Creatine kinase (25–171 U/L)	973 (3,211; 30–26,848)	1,416 (4,855; 55–26,848)	657 (968; 30–5,538)	507 (427; 30–1,393)	670 (1,053; 56–5,538)	1,674 (2,183; 257–5,538)	0.728

^a p value compares patients with and without thrombotic events.

Table 3. Categorized Biomarkers of Inflammation and Coagulation
Laboratory Result	All Patients (n = 72), n (%)	No Thromboembolic Event (n = 30; 42%), n (%)	Thromboembolic Event (n = 42; 58%), n (%)	p ^a
Platelet count (10^9/L)				0.537
< 147	11 (15)	4 (13)	7 (17)
147–397 (normal value)	55 (76)	23 (77)	32 (76)
> 397	6 (8)	3 (10)	3 (7)
WBC count (10^9/L)				0.448
< 5.1	3 (4)	1 (3)	2 (5)
5.1–11.4 (normal value)	39 (54)	17 (57)	22 (52)
> 11.4	30 (42)	12 (40)	18 (43)
Lymphocyte count (10^9/L)				0.275
< 1.3	61 (85)	24 (80)	37 (88)
1.3–3.7 (normal value)	11 (15)	6 (20)	5 (12)
> 3.7	0	0	0
Fibrinogen (g/L)				0.693
< 1.5	3 (4)	2 (7)	1 (2)
1.5–4.5 (normal value)	8 (11)	3 (10)	5 (12)
> 4.5	59 (82)	24 (83)	35 (83)
Activated partial thromboplastin time (s)				0.232
< 26	2 (3)	2 (7)	0
26–36 (normal value)	41 (57)	16 (53)	25 (60)
> 36	29 (40)	12 (40)	17 (40)
D-dimer (ng/mL)				0.427
0–240 (normal value)	3 (4)	0	0
241–2,000	18 (25)	9 (30)	9 (23)
2,000–10,000	36 (50)	18 (60)	18 (46)
> 10,000	15 (21)	3 (10)	12 (31)

^a p value compares patients with and without thrombotic events.

Table 4. Relationship Between the Presence of Thromboembolic Events and Secondary Outcome (Clinical Recovery)
Outcome	Positive Thromboembolic Events (n = 42)	Negative Thromboembolic Event (n = 30)	p ^a
Status, n (%)
Discharged	28 (67)	27 (90)	0.022
Died	14 (33)	3 (10)	0.022
Length of hospital stay (d ± sd)	32 ± 18	31 ± 15	0.533
Presentation to final status (d ± sd)	44 ± 21	38 ± 17	0.935