ORIGINAL RESEARCH

https://doi.org/10.5005/jp-journals-10030-1436
Panamerican Journal of Trauma, Critical Care & Emergency Surgery
Volume 12 | Issue 03 | Year 2023

Descriptive Analysis of Thromboembolic Events in COVID-19 Patients in Qatar

Ahmed F Ramzee¹, Ayman El-Menyar², Mohammad Asim³, Hassan Al-Thani⁴, Fakhar Shahid⁵, Areen Fino⁶, Yaser M Ata⁷, Hamzah El Baba⁸, Arun P Nair⁹, Muna S Al Maslamani¹⁰, Ruben Peralta¹¹, Sandro Rizoli¹²

^1,4,12Trauma Surgery Section, Department of Surgery, Hamad Medical Corporation, Doha, Qatar

²Clinical Research, Trauma & Vascular Surgery, Department of Surgery, Hamad Medical Corporation; Department of Clinical Medicine, Weill Cornell Medical College, Doha, Qatar

³Clinical Research, Trauma & Vascular Surgery, Department of Surgery, Hamad Medical Corporation, Doha, Qatar

^5,7,8Department of Surgery, Hamad Medical Corporation, Doha, Qatar

⁶Department of Family Medicine, Hamad Medical Corporation, Doha, Qatar

^9,10Communicable Disease Center (CDC), Department of Infectious Diseases, Hamad Medical Corporation, Doha, Qatar

¹¹Trauma Surgery Section, Hamad Medical Corporation, Doha, Qatar; Department of Surgery, Universidad Nacional Pedro Henriquez Urena, Santo Domingo, Dominican Republic

Corresponding Author: Ayman El-Menyar, Clinical Research, Trauma & Vascular Surgery, Department of Surgery, Hamad Medical Corporation; Department of Clinical Medicine, Weill Cornell Medical College, Doha, Qatar, Phone: +974 44396130, e-mail: aymanco65@yahoo.com

Received: 15 June 2023; Accepted: 02 December 2023; Published on: 30 December 2023

ABSTRACT

Background: Current literature shows an increased risk of thromboembolic events (TEE) with coronavirus disease of 2019 (COVID-19) infection, possibly due to a unique interplay between the virus and the coagulation system.

Materials and methods: A retrospective observational study of all patients with COVID-19 infection in the State of Qatar between February and August 2020 was performed. Analysis of all patients with TEE was carried out to identify other potential inciting factors for TEE.

Results: There were 210 out of 16,903 (1.2%) patients with COVID-19 infection who developed TEE. Myocardial infarction (MI) was the most common event (76.2), with 11% deep vein thrombosis (DVT) and <10% with pulmonary embolism (PE), stroke, and other thrombotic events.

Conclusion: Our study showed a low incidence of TEE compared to current literature. Patients with a previous history of thrombotic events were at a higher risk of developing a second event. Other significant contributing factors may have had a role in the development of TEE in the rest of the group. This questions the current belief that COVID-19 significantly increases the risk of TEE in the healthy population.

How to cite this article: Ramzee FA, El-Menyar A, Asim M, et al. Descriptive Analysis of Thromboembolic Events in COVID-19 Patients in Qatar. Panam J Trauma Crit Care Emerg Surg 2023;12(3):120–130.

Source of support: Nil

Conflict of interest: Dr Sandro Rizoli and Dr Ruben Peralta are associated as the Editorial board members of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of these Editorial board members and their research group.

Keywords: Coronavirus disease of 2019, Epidemic, Infarction, Infection, Qatar, Thromboembolic

INTRODUCTION

The coronavirus disease of 2019 (COVID-19) pandemic by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has disrupted the world since December 2019.¹ COVID-19 disease ranges from asymptomatic to mild respiratory tract infections to pneumonia and even acute respiratory distress syndrome, shock, and multiorgan failure.² Several risk factors are known to increase susceptibility to developing a more severe course of illness, including old age, diabetes, chronic kidney disease, obesity, and chronic cardiovascular disease.³

COVID-19 is predominantly a disease of the respiratory system; however, it has the potential to become a multisystem disorder.⁴ A large number of studies have shown an increased risk of thromboembolic events (TEE) in patients with severe COVID-19 disease, with several recommendations being made on subduing this supposed hypercoagulable state.⁵–⁷ The coagulation derangement in patients with COVID-19 has been linked to the hyperinflammatory response, cytokine storm, and increased platelet activation induced by SARS-CoV-2 viral particles that gain entry into the circulatory system via endothelial angiotensin-converting enzyme 2 receptors, mainly in the lungs.⁷^,⁸

The pathology of coagulation defects is poorly understood and has been labeled as COVID-19-associated coagulopathy (CAC) owing to differences in other critical illness coagulopathies.⁵–⁹ This has prompted recommendations for prophylactic anticoagulation, regardless of thromboembolism risk assessment in severe cases of COVID-19.¹⁰ The National Institute of Health (NIH) recommends the same routine thromboprophylaxis for non-COVID-19 to be applied to COVID-19 patients.¹¹

Most existing literature does not provide detailed background information on patients’ baseline characteristics as well as management interventions during hospitalization for COVID-19 disease, which may have implications for the development of TEE.

In the State of Qatar, COVID-19 response and management are provided by a single centralized healthcare system that sets standards and protocols for all hospitals. During the first wave of COVID-19 (2019–2020), all symptomatic patients were admitted to hospitals managed by the central health system. Asymptomatic patients were placed in quarantine facilities under the purview of the same corporation. This ensured that all patients with COVID-19 infection in the country were monitored and cared for by a single body and according to the same standard of care that was applied to all patients. Given these findings, we set out to study the incidence and describe the characteristics of patients with COVID-19 who developed TEE in Qatar.

MATERIALS AND METHODS

This was a retrospective observational study of all consecutive adult patients (≥18 years of age) admitted to the treatment and quarantine centers with COVID-19 infection and who developed thromboembolic complications during the hospital course between February and August 2020. In Qatar, the COVID-19 pandemic management is coordinated by the Hamad Medical Corporation (HMC), which is under the purview of the Ministry of Public Health. Four main hospitals were designated as COVID-19 treatment facilities (Hazm Mebaireek General Hospital, Communicable Disease Center, Mesaieed Hospital, and Ras Laffan Hospital). All quarantine centers were managed under the Communicable Disease Center, which has a centralized database from where the data were retrieved. The study included all COVID-19-positive TEE patients admitted to a regular ward or intensive care unit (ICU). Patients initially admitted for non-COVID-19 conditions and tested positive for COVID-19 infection were transferred to the designated COVID-19 facilities and were also included in our analysis. COVID-19 infections were confirmed by reverse transcription polymerase chain reaction test on a nose/throat swab. Patients were categorized as asymptomatic, mild, severe, and critically ill according to the HMC-CDC protocol. Briefly, COVID-19 was considered mild if there was evidence of lower respiratory disease during clinical assessment or imaging and who have an peripheral oxygen saturation (SpO₂) of >94% on room air or at sea level. Severe COVID-19 cases referred to those who had SpO₂ of <94% on room air or at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (partial pressure of oxygen/fraction of inspired oxygen) <300 mm Hg, a respiratory rate >30 breaths/minute, or lung infiltrates >50%. COVID-19-associated pneumonia with respiratory failure, septic shock, and/or multiple organ dysfunction were considered critical cases. A routine thromboprophylaxis protocol was the standard of care for all COVID-19 patients, which is outlined in Figure 1.

Fig. 1: Coronavirus disease of 2019 (COVID-19) thromboprophylaxis protocol in Qatar during the first wave

TEE were retrospectively identified by clinical presentation (recorded in the patient’s charts by physicians and nurses), laboratory, and/or radiologic findings. Myocardial infarction (MI) was diagnosed by clinical symptoms, electrocardiogram changes, and elevated troponin T levels above 10 ng/mL. Pulmonary embolism (PE) was detected by computed tomography (CT) pulmonary angiography ordered to investigate deteriorating respiratory status. Deep vein thromboses (DVT) and arterial thromboses by clinical findings and duplex ultrasonography, while stroke was identified by clinical presentation and CT imaging of the brain.

The medical records of all patients were explored to extract pertinent information related to their baseline characteristics, including comorbidities and interventions and procedures relevant to the development of TEE. All medical visits and admissions for 2 years after the COVID-19 infection were reviewed for major events. Detailed information can be found in the Table S1. Ethical approval for this study was obtained from the Institutional Review Board (MRC-01-20-1047) at the Medical Research Center, HMC, Doha, Qatar.

**Table S1:** Details of individual patients, including major co-risk factors for VTE, VTE prophylaxis, and outcome
S. no.	Gender	Age	Severity of COVID-19	Type of TEE	Anatomic location of TEE	VTE prophylaxis	History of previous VTE	History of cancer	Access lines	Other procedures	Outcome (alive or dead)	Duration of anticoagulation	Follow-up Doppler	Last follow-up + outcome	Comments
1	Male	42	Severe	DVT	CFV, SFV, POPV, and PTV	Heparin 5000 U, twice daily, then enoxaparin 40 mg daily	Yes, at the same site 2 years prior	No	RA line; IJV	None	Alive	Rivaroxaban for 6 months	At 6 months: complete recanalization of CFV + SFV, partial recanalization of POPV + PTV	Alive + asymptomatic at 29 months
2	Male	74	Critical	DVT + arterial thrombus	All deep veins of the upper limb extending to IJV; right RA	Enoxaparin 40 mg daily	No	No	Left IJV central line	None	Death within a month of admission		None	–
3	Female	70	Asymptomatic	Arterial thrombus	Femoral artery	No, presented to the hospital with an ischemic limb	No	No	IJV	Embolectomy + four-compartment fasciotomy	Death		None	–	BMI: 54 ESRD
4	Male	49	Mild	PE	Segmental branches of the right lower lobar artery	Enoxaparin 40 mg daily	No	No	No	None	Alive	Lost to follow-up after 2 months	None	Lost to follow-up after 2 months
5	Male	35	Asymptomatic	PVT	PVT	None	No	HCC with lung mets	Femoral vein	None	Death			–
6	Male	52	Critical	DVT	CFV	Heparin 5000 U twice daily	No	No	ECMO cannulation in the femoral vein	None	Death			–	Critical COVID-19 presented with severe respiratory failure and cardiac arrest; on long-term ECMO but eventually succumbed
7	Male	66	Mild	DVT	Axillary + subclavian	Enoxaparin 40 mg daily	No	No	No		Alive	On rivaroxaban; the patient returned to his home country after 5 months	None	Alive at 5 months	The patient had axillary lymphadenopathy with an abscess on the same side; benign.
8	Female	55	Mild	DVT–2 months after recovery	External iliac, common femoral + superficial femoral.	None	No	Ovarian cancer with metastasis	No	No	Alive	Rivaroxaban ongoing	At 10 months: partial recanalization	Alive at 28 months
9	Male	33	Mild	Abdominal vein thrombus	PVT, splenic, SMV	Enoxaparin 40 mg daily	No	Metastatic gastric cancer	No	No	Death		Death within 1 month of admission	–
10	Female	63	Mild	superficial vein thrombus	GSV	Enoxaparin 30 mg daily	No	Metastatic breast cancer	No	No	Alive	Enoxaparin 6 weeks	Complete resolution in 1 year	Alive at 30 months
11	Male	31	Mild	Hepatic vein thrombosis	Hepatic vein	None	No	No	No	No	Alive	Rivaroxaban ongoing	Cavernous transformation of the portal vein	Alive at 28 months	The patient developed PVT postsleeve gastrectomy prior to COVID-19 infection
12	Male	51	Critical	DVT	SFV, POPV, PTV	Dalteparin 7500 U daily	No	No	IJV	None	Alive		No follow-up after discharge	No follow up
13	Male	65	Critical	DVT	Left IJV	Dalteparin 5000 U daily	No	No	Left IJV line, kinked, nonfunctional	None	Death			–
14	Male	47	Mild	Stroke + DVT	Right MCA,Right common carotid artery,CFV + SFV	Enoxaparin 40 mg daily	No	No	Femoral	None	Alive	Ongoing		Neurological deficit; returned to home country after discharge	Presented to hospital with a stroke
15	Male	45	Mild	DVT	Perforator vein	Enoxaparin 40 mg daily	No	No	None	None	Alive	Rivaroxaban for 6 months	None	No follow-up after 6 months
16	Male	58	Severe	DVT	Subclavian, axillary, and brachial veins; central line-associated pseudoaneurysm with large hematoma	Dalteparin 7500 U daily	No	No	IJV	Thrombin injection at pseudoaneurysm	Alive	Ongoing upon discharge	None	Returned to home country after discharge	Compression neuropathy of brachial plexus due to large hematoma/pseudoaneurysm
17	Female	66	Critical	DVT	IJV	Enoxaparin 120 mg daily	Yes; same site	Gastric cancer	Femoral vein	None	Death			Died within a month due to mixed shock and multiorgan failure	Morbidly obese
18	Male	55	Mild	DVT	PVT+ mesenteric vein	Enoxaparin 100 mg twice daily	No	No	No	None	Alive	Rivaroxaban ongoing		Alive 29 months	Multiple comorbidities: AF, CAD, CVA, renal transplant; presented with abdominal pain; DVT diagnosed on admission
19	Female	30	Mild	DVT	External Iliac + CFV	Enoxaparin 40 mg daily	No	No	IJV,RA	None	Alive	IVC filter + enoxaparin: 1 month	Complete resolution within 3 months	Alive at 30 months
20	Male	30	Critical	DVT	CFV	Enoxaparin 40 mg daily	No	No	IJV,ECMO	None	Alive			Last follow-up: 2 months after discharge
21	Male	58	Critical	DVT	IJV	Enoxaparin 40 mg daily	No	Leukemia	Femoral + IJV	None	Alive	dabigatran, 150 mg		Last follow-up: 28 months postdischarge	Developed AF after COVID-19
22	Male	27	Mild	Superficial vein thrombosis	Cephalic	Enoxaparin 40 mg daily	No	Nu	None	None	Alive	None	None	Last follow-up–4 months postdischarge
23	Male	63	Mild	Large artery thrombosis	Circumferential abdominal aortic aneurysm with thrombus	Enoxaparin 40 mg daily	No	SCC of head and neck	None	None	Died	The patient had a GI bleed	6 months: persistent	Died 6 months later due to complications of cancer
24	Male	31	Mild	DVT	Brachial vein	Enoxaparin 40 mg daily	No	Acute leukemia	No	None	Died	No due to thrombocytopenia		Recovered from COVID-19 but died 4 months later due to complications of cancer
25	Male	86	Critical	DVT + PE	POPV, PTV, SFV, saddle embolus	Enoxaparin 40 mg daily	No	No	No	No	Died	Dabigatran for 6 months	None	Died 7 months after COVID-19 recovery from massive GI bleeding
26	Male	55	Critical	Arterial	Splenic artery embolism	Dalteparin 5000 U daily	History of DVT, PE, and ischemic stroke 3 years prior	No	IJV	No	Died after 3 months in ICU	Ongoing till death	No	multiple preexisting cardiac issues: amyloidosis, PE, AF
27	Male	50	Mild	Arterial	Embolic stroke, splenic artery, bilateral popliteal artery	No, as the presentation to the hospital was with ischemia	No	No	No	Embolectomy	Alive	Dabigatran	No	Presented with ischemic symptoms + AF; the last follow-up 12 months postrecovery
28	Male	65	Critical	DVT	Bilateral IJV	Dalteparin 5000 U daily	No	No	IJV, femoral	None	Died	Ongoing	No
29	Male	85	Severe	DVT	CFV, SFV, POPV, PTV	Dalteparin 7500 U daily	No	No	IJV	IVC filter	Alive	No	Duplex scan 3 months later: complete resolution	Alive at 26 months
30	Male	51	Critical	DVT + PE	CFV, bilateral segmental PE	Enoxaparin 40 mg daily	No	No	ECMO: femoral	None	Alive	Rivaroxaban		No follow-up 1 month after recovery
31	Male	74	Mild	Arterial	SFA, POP, TIB-ANT	Dalteparin 5000 U daily	No	No	None	CO₂ angioplasty + anterior tibial artery angioplasty	Died	Ongoing till death	None	Cardiac arrest 3 months later
32	Male	64	Mild	DVT	CFV, POPV	On rivaroxaban	Yes, same site 3 months prior to COVID-19 infection	No	None	None	Alive	Ongoing	At 1 year–partial recanalization	Alive at 28 months postrecovery
33	Male	40	Critical	PE	Left lower segmental	Enoxaparin 40 mg daily	No	No	ECMO, IJV	None	Alive	Rivaroxaban	No	Alive at 4 months postrecovery
34	Male	40	Mild	DVT	Portal vein	Enoxaparin 40 mg daily	No	HCC	IJV	None	Died	Ongoing till death	No	Presented with symptoms of cancer. Died within a month of admission due to cancer-related complications
35	Female	67	Mild	DVT	External iliac, CFV, SFV, POPVe, and PTV	Enoxaparin 40 mg daily	No	Uterine cancer, metastatic	No	None	Died	Enoxaparin 80 mg twice daily		Expired 1-year postrecovery from COVID-19 due to cancer complications
36	Male	61	Severe	DVT	CFV, SFV, POPV, PTV	Enoxaparin 40 mg daily	No	No	No	None	Alive	Rivaroxaban		Alive at 24 months
37	Male	55	Mild	DVT	Portal vein	Enoxaparin 40 mg daily	No	HCC	No	None	Alive	Rivaroxaban for 6 months	None	No follow-up after discharge
38	Male	62	Mild	DVT	Portal vein	Enoxaparin 40 mg daily	No	HCC	No	No	Died			Died within 2 months of hospitalization due to cancer complications
39	Female	28	Mild	DVT	SFJ, SFV, POPV, EIV	The patient was on dabigatran	Preexisting DVT at same site	No	No	None	Alive	Dabigatran ongoing	No improvement in 24 months	Alive at 27 months postrecovery
40	Male	81	Mild	DVT	SFV	The patient presented with DVT	No	No	No	No	Alive	Rivaroxaban–1 year		Alive at 17 months postrecovery; the patient was s/p ex. laparotomy, immobile; presented to hospital with DVT
41	Female	41	Mild	Arterial	Subclavian artery	Enoxaparin 40 mg daily	No	No	No	Embolectomy	Alive	Warfarin	No	Alive at 7 months; history of Takayasu arteritis
42	Female	65	Mild	CVA	Lacunar infarct	No, presented with symptoms	No	No	No	No	Alive	No	No	Alive at 4 months postdischarge
43	Male	58	Severe	DVT	Bilateral IJV	Enoxaparin 40 mg daily	No	Leukemia	Bilateral IJV	No	Alive	Dabigatran	No	Alive at 16 months
44	Male	66	Severe	CVA	Cerebellar	Dalteparin 5000 U daily	No	No	IJV	No	Alive		No	Alive at 28 months
45	Male	52	Mild	CVA	Frontoparietal infarct	Presented to hospital with CVA symptoms	No	No	No	No	Alive		No	Alive at 5 months
46	Male	49	Mild	Arterial	MI + celiac artery	Presented to hospital with symptoms	Previous MI	No	No	Pacemaker	Alive		No	Alive at 10 months
47	Male	47	Critical	Arterial	Femoral	On fondaparinux for AF	No	No	ECMO	None	Alive		Rivaroxaban: 6 months	Alive at 16 months
48	Male	59	Mild	CVA	Right MCA	Presented with stroke symptoms	No	No	No	None	Alive			Alive at 9 months
49	Male	60	Mild	CVA	MCA	Presented with stroke symptoms	No	No	No	No	Alive			Alive at 29 months
50	Male	54	Mild	PE	Left lower segmental	Enoxaparin 40 mg daily	No	No	Right IJV	None	Alive		No	Alive at 6 months postrecovery
51	Male	54	Mild	CVA	MCA	Enoxaparin 60 mg daily	No	No	None	None	Alive		Warfarin	Alive at 29 months
52	Female	55	Mild	DVT+ PE	Left lower lobe; IIV + CFV	Presented with symptoms	No	Metastatic ovarian cancer	None	None	Alive		Tenzaparin 6000 U daily	Alive at 25 months

AF, atrial fibrillation; BMI, body mass index; CFV, common femoral vein; CVA, cerebrovascular accident; DVT, deep vein thrombosis; EIV, external iliac vein; ESRD, end stage renal disease; GSV, great saphenous vein; HCC, hepatocellular carcinoma; IIV, internal iliac vein; IVC, inferior vena cava; IJV, internal jugular vein; SFV, superficial femoral vein; MCA, middle cerebral artery; MI, myocardial infarction; PE, pulmonary embolism; POPV, popliteal vein; PTV, posterior tibial vein; PVT, portal vein thrombosis; RA, radial artery; SCC, squamous cell carcinoma; SFA, superficial femoral artery; SMV, superior mesenteric vein; TIB-ANT, tibialis anterior

Statistical Analysis

Data were presented using descriptive statistics as proportions, medians (range), or mean (±standard deviation) as appropriate. Data analysis was carried out using the Statistical Package for Social Sciences (SPSS) version 21 (SPSS Inc., Chicago, Illinois, United States of America).

RESULTS

Between February and August 2020, 16,903 patients with COVID-19 infection were identified and treated in the State of Qatar, out of which 210 (1.2%) were diagnosed with thromboembolic complications.

Characteristics of patients with TEE are shown in Table 1. The mean age was 54.1, predominantly male (>80%). A total of 153 out of the 210 patients were of South Asia origin (72%). The mean body mass index was 26.6 kg/m². Approximately one-fifth were smokers (19%). The majority of patients had a history of MI (80.5%). Mortality in the TEE group was 16.2%.

**Table 1:** Clinical characteristics, comorbidities, management, and outcomes of COVID-19 patients who developed thromboembolism (n = 210)
Variables	Value	Variables	Value
Age	54.1 ± 13.4	Treatment
Females	23 (11.0%)	Enoxaparin	186 (88.6%)
Males	187 (89.0%)	Dalteparin	25 (11.9%)
Non-Qatari	191 (91.0%)	Rivaroxaban	11 (5.2%)
Qatari	19 (9.0%)	Dabigatran	5 (2.4%)
BMI	26.6 ± 5.4	Apixaban	2 (1.0%)
Padua prediction score	4.02 ± 1.78	Heparin	127 (60.5%)
Comorbidities		Aspirin	168 (80.0%)
MI	169 (80.5%)	No prophylaxis	32 (15.2%)
Hypertension	135 (64.3%)	Prophylaxis	178 (84.8%)
Diabetes mellitus	127 (60.5%)	Hospital stay (days)	17.1 (0.4–238)
Rheumatological diseases	3 (1.4%)	ICU admission	123 (59.7%)
Congestive heart failure	15 (7.1%)	ICU length of stay (days)	4.5 (0.2–89.7)
Peripheral vascular disease	2 (1.0%)	Mechanical ventilation	58 (69.0%)
Connective tissue disorders	1 (0.5%)	Ventilatory days	1 (1–49)
Peptic ulcer disease	5 (2.4%)	Death	34 (16.2%)
Chronic kidney disease	31 (14.8%)
Lymphoma	1 (0.5%)
Liver disease	2 (1.0%)
Cancer	11 (5.2%)
AIDS	1 (0.5%)
Smokers	40 (19.0%)
Severity of COVID-19
Asymptomatic	0 (0.0%)
Mild	142 (68.3%)
Moderate	32 (15.4%)
Severe	34 (16.3%)

Thromboprophylaxis coverage, according to the protocol, was high (85%).

Figure 2 shows the distribution of thromboembolic complications. The majority had an acute MI (76.2%). About 80.5% of these patients had a previous history of MI. Eleven percent developed DVT, 3.8% had a stroke, and only 1.9% had PE. The remaining 7.1% had other small to medium vessel thromboses. Table 2 shows the breakdown of non-MI-related TEEs.

**Table 2:** Distribution of non-MI thromboembolic event cases (n = 52)
Type of events	Anatomic location	Number of cases
Deep vein thrombosis	Lower limbs	15
	Upper limbs	4
	Portal vein	6
	Hepatic vein	1
	Internal jugular	5
Superficial vein	Cephalic	1
Arterial events	Lower limb	3
	Upper limb	1
	Aortic	1
	Splenic	1
	Celiac	1
Cerebrovascular accident		8
PE		5

Fig. 2: Distribution of TEE in COVID-19 cases; *others included femoral artery ischemia (n = 2), PVT (n = 5), hepatic vein thrombosis (n = 1), internal jugular vein thrombosis (n = 2), cephalic vein thrombosis (n = 1), circumferential mural thrombosis (n = 1), splenic artery embolism (n = 1), and subclavian artery thrombosis (n = 1)

Considering that the cohort of patients with MI was in a high-risk category for such an event independent of the COVID-19 infection—over 80% had had a previous MI, we attempted to identify non-COVID-19 TEE risk factors in the remaining patients. A total of 52 patients had non-MI TEE and were further analyzed. Of them, 33 patients (63.5%) had other non-COVID-19-related risk factors for TEE. A total of 14 patients were being treated for an active malignancy at the time of the COVID-19 infection. Of these patients, four patients with advanced hepatocellular carcinoma had portal vein thrombosis (PVT). Another five patients had a prior history of significant TEE, and 12 patients had DVT at the site of large bore central access lines, including five patients with femoral vein thrombosis linked to extracorporeal membrane oxygenation (ECMO) catheters. One patient suffered an iatrogenic injury during central line insertion, resulting in a large pseudoaneurysm of the subclavian and axillary veins. Lastly, one patient had axillary and subclavian vein thrombosis secondary to a large abscess in the axilla.

A total of 40 of the 52 patients received thromboprophylaxis doses of anticoagulants during their hospital stay. Nine of the remaining 13 patients were given full anticoagulant doses from admission as part of the TEE management. A total of 16 patients (30%) died, eight of cancer complications. None of the deaths were attributed to any of the TEE.

DISCUSSION

Given that the COVID-19 pandemic in Qatar was wholly managed by a centralized healthcare system under the Ministry of Public Health with uniform standards and protocols applied to all patients, it allowed us to obtain data on all patients with clinically significant TEE and COVID-19 identified in the country. Current evidence points to a high but variable incidence of TEE associated with COVID-19 disease, ranging from 3 to 85%.⁵^,⁶ We identified a remarkably low incidence of 1.2% TEE in our patient population. A study from the Netherlands reported an incidence of 49% of thrombotic complications in 184 COVID-19 patients admitted to the ICU despite prophylactic anticoagulation.⁵ Reports from France identified a high prevalence of thromboembolic complications (20%) in COVID-19 patients admitted to the ICU. Nearly twice that of patients admitted a year before the pandemic.⁷ A possible explanation for this notable difference in our population could be due to adherence to a single, strict chemical thromboprophylaxis protocol with dose adjusted according to D-dimer levels measured daily at all institutions within the country with the same standardized critical care and COVID-19 management protocols applied to all patients. In a study from China of 81 ICU patients not receiving routine thromboprophylaxis, the incidence of venous thromboembolism (VTE) was 25%.¹² Another possibility for this difference could be due to the fact that routine TEE screening tests were not performed, and all investigations for TEE were performed only after clinical suspicion arose; therefore, clinically silent TEE may have been missed. Centers that had routine mandatory TEE screening, particularly in ICU patients, were found to have higher incidences of TEE.⁶

COVID-19 may result in a complex interplay between the immune and coagulation systems, resulting in a prothrombotic state.¹³ Multiple mechanisms have been described regarding the process of the development of thrombotic microangiopathy and the development of TEE.⁴^,¹⁴^,¹⁵ Direct endothelial injury followed by a hyperinflammatory response may have a role in the development of a unique coagulopathic effect which is distinct from other coagulopathies such as disseminated intravascular coagulation and sepsis-induced coagulopathy (SIC) and has been termed CAC.⁴^,⁹ Direct viral injury to the endothelium leads to the release of plasminogen activator, which is probably responsible for the high D-dimer levels noted in multiple studies, along with large von Willebrand factor (vWF) multimers.⁴ The surge in vWF exceeds the capacity of its cleavage regulators, ADAMTS13 (a disintegrin metalloproteinase), leading to a positive balance of vWF, which contributes to the large increase in microvascular platelet thrombi deposition. The hyperinflammatory response is mediated by an exaggerated complement activation, which results in increased cytokine production (cytokine storm).¹⁴^,¹⁵ An increase in pro-inflammatory cytokines, especially interleukin 6, stimulates tissue factor release by mononuclear cells, resulting in thrombin generation, which compounds the systemic coagulopathic process.⁴ This has been shown in autopsy studies, which revealed lung injury to involve not only the interstitium as previously thought but the endothelium as well.¹⁶^,¹⁷ These studies demonstrated diffuse alveolar damage as a predominant pattern of lung injury, but more importantly, the majority of specimens showed the presence of platelet–fibrin thrombi, which supports the notion that SARS-CoV-2 promotes a thrombogenic response by direct and cytokine-mediated endothelial injury and platelet and fibrin complex deposition.¹⁵–¹⁸ Despite the multiple theories present, no conclusive evidence links the COVID-19 infection as being solely responsible for an increased thromboembolic risk. Most studies to date fail to comment on other potential confounding factors that may compound the risk of thrombosis. In our cohort, nearly two-thirds of the patients had coexisting disease or iatrogenic factors that could have a role in the TEE.

Most of our patients with TEE (76.2%) suffered an MI; however, nearly 81% of them had a previous MI. These findings are similar to those of a large study (86,742 patients) from Sweden reporting a correlation between COVID-19 and MI. The study showed an increased risk of first MI during the 3 days preceding disease onset until 14 days later. The manuscript hypothesized that COVID-19 was an inciting factor for the development of MI.¹⁹ The pathophysiology cannot be fully explained with the existing evidence, except for the stress of acute illness and the potential psychological impact leading to a second event in a vulnerable population.

When considering non-MI-related TEE, the incidence was very low (52 patients). We analyzed the medical records of these patients and noted that the majority (80%) of them had other significant sources that may have put them at an increased risk of developing TEE (Fig. 3). The supplementary table provides a detailed analysis of each patient. About >25% had an active malignancy, with others developing TEE at sites of cannulation. These factors are known risk factors for TEE. Until the completion of this manuscript, the authors were unable to identify studies that investigated other underlying causes for TEE in their patients. This brings into question the actual role of COVID-19 infection in increasing the risk of TEE as opposed to other acute illnesses.

Fig. 3: Proportion of cases with and without co-factors for the development of TEE

Routine chemical thromboprophylaxis for hospitalized patients with COVID-19 is now the standard of care in most centers across the world.¹¹^,¹⁹ A study by Tang et al. reported a significantly lower 28-day mortality in patients receiving heparin thromboprophylaxis. The study included high-risk patients defined as having a SIC score of >4 or D-dimer levels more than six times the normal level.²⁰ Heparin and its related products are anticoagulants but also have anti-inflammatory properties.²¹ Whether such anti-inflammatory properties have a role in TEE prevention is unknown.

Evidence is also conflicting with regard to administering therapeutic (full anticoagulation) or prophylactic doses of anticoagulants in patients with COVID-19. The current NIH guidelines for COVID-19 hospitalized patients recommend prophylactic doses of low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH), as used in non-COVID-19 settings while discouraging full anticoagulation even in high-risk patients.¹¹ There is also insufficient data to recommend routine screening for TEE, regardless of the lab coagulation parameters.¹¹ A randomized controlled trial of 1,191 patients from Brazil compared therapeutic vs prophylactic anticoagulation in COVID-19 patients. Patients were randomly assigned to rivaroxaban, if clinically stable or subcutaneous LMWH/intravenous UFH if unstable and were compared to prophylactic doses of LMWH/UFH. There was no difference in mortality, duration of hospitalization, or duration of supplemental oxygenation. The study, however, reported a significant increase in major bleeding in patients receiving therapeutic doses of anticoagulants (8 vs 2%, p = 0.001).¹⁹

Ethnic disparities in the incidence of TEE in the general population are well known. Higher rates are reported in African Americans, while the lowest are among Asians. Still, no evidence-based recommendations can presently be made regarding thromboprophylaxis in different ethnic groups.²² Most TEE patients in the present study were originally coming from the South Asian region, reflecting the structural distribution of the population in Qatar.

Study Limitations

While the present analysis could be done in the entire population of a country due to the existence of a centralized healthcare system, it is possible that patients admitted to other health facilities may have been missed. However, even considering this possibility, the number of such patients was certainly small. Another limitation is that all TEE investigations were only ordered for patients based on clinical suspicion. While this pragmatic approach may have discarded clinically insignificant TEE, it may also have excluded patients who were not investigated for TEE.

CONCLUSION

The present study analyzed the COVID-19 disease over a 6-month period in 2020 (first wave). In comparison to many recent studies, we found a low prevalence of TEE of 1.2%. Acute MI was the most common TEE, compared to DVT, PE, stroke, and others. Despite the limitations, the present study questions a major contribution of COVID-19 infection in TEE beyond that expected for other similar infections or critical illnesses. The study findings raise attention to patients with major thrombotic risk factors, like cancer or previous thrombotic vent.

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