Covid-19 associated free hanging clots in acute symptomatic carotid stenosis

Abstract

Background

Thrombotic complications including stroke were previously described following Covid-19. We aim to describe the clinical and radiological characteristics of Covid-19 related with acutely symptomatic carotid stenosis (aSCS).

Method

All patients presenting with an aSCS were prospectively enrolled in an ongoing institutional database. Inclusion criteria for the Covid-19-aSCS group were a combination of both antigen test and a positive reverse-transcriptase (PCR) test for Covid-19 upon admission. Patients with additional potential etiologies for stroke including cardioembolism, carotid dissection or patients with stenosis of <50% on CTA were excluded. A cohort of non-Covid-19 related aSCS patients admitted to the same institution before the pandemic during 2019 served as controls.

Results

Compared to controls (n = 31), Covid-19-aSCS (n = 8), were younger (64.2 ± 10.7 vs 73.5 ± 10, p = 0.027), and less frequently had hypertension (50% vs 90%, p = 0.008) or hyperlipidemia (38% vs 77%, p = 0.029) before admission. Covid-19-aSCS patients had a higher admission NIHSS score (mean 9 ± 7 vs 3 ± 4, p = 0.004) and tended to present more often with stroke (88% vs 55%, p = 0.09) rather than a TIA. Covid-19-aSCS patients had higher rates of free-floating thrombus and clot burden on CTA (88% vs 6.5%, p = 0.002). Covid-19 patients also less often achieved excellent outcomes, with lower percentage of mRS score of 0 after 90-days (13% vs 58%, p = 0.022).

Conclusion

Covid-19- aSCS may occur in a younger and healthier subpopulation. Covid-19- aSCS patients may have higher tendencies for developing complex clots and less often achieve excellent outcomes.

1. Introduction

Thrombotic complications such as acute ischemic stroke (AIS) following Covid-19 infection have been well described [1] and are attributed to large vessel arteriopathy [2,3] cardiac injury including myocarditis and secondary cardioembolism, development of new onset atrial fibrillation, and extra-cranial dissections. Importantly, AIS following Covid-19 infection was found to be associated with higher rates of novel carotid plaque formation and destabilized plaques [3].

The association of symptomatic carotid stenosis (aSCS) and Covid-19 has been previously described in several cohorts [4,5] but without direct comparison to aSCS patients that did not have a recent Covid-19 infection.

We aim to highlight the clinical and radiological characteristics of Covid-19-aSCS patients by comparison to a cohort of aSCS patients who underwent carotid artery stenting (CAS) before the Covid-19 era.

2. Methods

All patients presenting with an aSCS were prospectively enrolled in an ongoing institutional database. The study was approved by the institutional review board (HMO-0405-20).

Symptomatic carotid was defined by a clinical presentation of either TIA or stroke attributed to ipsilateral carotid stenosis of ≥50% by NASCET criteria as adjudicated by a certified stroke neurologist. All patients underwent multiphasic computed tomography angiography (CTA) upon their presentation and degree of stenosis was measured on maximal intensity projection images on axial and sagittal views. All patients with >50% stenosis of the symptomatic carotid indicated by CTA were sent for digital subtraction angiography (DSA).

During the Covid-19 pandemic, all patients that were admitted as inpatients were routinely tested for Covid-19. Inclusion criteria for the Covid-19 group patients were a positive Covid-19 test result on a combination of both an antigen test and reverse-transcriptase (PCR) test upon admission indicating an active infection by Covid-19.

Consecutive aSCS from our 2019 prospective registry were selected as controls as it was prior to the Covid-19 outbreak. Patients with Covid-19-aSCS patients were treated similarly to those that were Covid-19 negative. All antiplatelet naïve patients were treated according to similar treatment protocols with loading dose of 300 mg of Aspirin and 300 mg of Clopidogrel followed by a daily dose of 100 mg Aspirin and 75 mg of Clopidogrel. Patients that were on single antiplatelet agents prior to admission were loaded with the other antiplatelet agent and continued DAPT. All patients received high dose potent statin therapy with atorvastatin 80 mg/ day and blood pressure was kept at 140–150 systolic.

Exclusion criteria in both groups included any other possible additional etiology for stroke including cardioembolism, dissection, etc. All patients underwent workup included trans-thoracic echocardiogram with injection of agitated saline and a 48-h electrocardiogram-holter to rule out atrial fibrillation.

Patients who were deemed non-eligible for carotid intervention due to short life expectancy or ongoing dementia were not sent for DSA.

As per institutional protocols, all aSCS patients were referred to endovascular treatment with potential stent implantation if feasible. Carotid endarterectomy was avoided in patients with Covid-19-aSCS because of the potential risk of anesthesia and surgery.

All CAS procedures were performed by the same interventional neurosurgeon using a similar institutional protocol.

3. Data collection

We collected demographic and vascular risk factors. Neurological deficits were measured using the National Institutes of Health Stroke Scale (NIHSS) [6] at admission and discharge. Stroke etiology was classified with the TOAST classification [7].

Functional status was assessed with the modified Rankin Score (mRS) prior to stroke, upon discharge, and 90 days after stroke. Due to the relatively young age of the entire cohort and the Covid-19 patients in particular we anticipated significant functional improvement. Therefore, an excellent functional outcome was defined as mRS 0 on day-90.

4. Results

Out of 13 Covid-19-aSCS patients, eight fulfilled entry criteria. Five patients were excluded, of which three patients had concomitant atrial fibrillation, one patient had a carotid dissection and one had severe cardiac failure with poor life expectancy. In comparison to the non-Covid-19 controls (n = 31), Covid-19-aSCS patients were younger (64.2 ± 10.7 vs 73.5 ± 10, p = 0.027), and were less frequently diagnosed with either hypertension (50% vs 90%, p = 0.008) or hyperlipidemia (38% vs 77%, p = 0.029) before admission (Table 1 ) but other risk factors did not differ significantly.

Table 1.

Characteristics of symptomatic carotids stenosis patients with and without Covid-19.

Characteristics	Non-COVID-19 N = 31	COVID-19 N = 8	P
Age, mean (SD)	73.5 (10)	64.2 (10.7)	0.027
Sex male (%)	22 (71)	7 (88)	0.340
Hypertension (%)	28 (90)	4 (50)	0.008
Hyperlipidemia (%)	24 (77)	3 (38)	0.029
Smoking (%)	9 (29)	1 (13)	0.340
Diabetes (%)	12 (39)	2 (25)	0.471
Ischemic heart disease (%)	10 (32)	2 (25)	0.692
Clinical presentation			0.090
Stroke (%)	17 (55)	7 (88)
TIA (%)	14 (45)	1 (12)
Left side (%)	18 (58)	5 (63)	0.820
Stenosis percent, mean (SD)	85 (14)	78 (22)	0.305
Admission NIHSS, mean (SD)	3 (4)	9 (7)	0.004
Discharge NIHSS, mean (SD)	2 (3)	8 (7)	0.002
Delta NIHSS, mean (SD)	1 (2)	1 (4)	0.796
mRS at 3 months, median (IQR)	0 (0–2)	2 (1–3)	0.246
90-day-mRS 0 (%)	18 (58)	1 (13)	0.022
90-day-mRS 0–1 (%)	21 (68)	3 (37)	0.11

Covid-19-aSCS patients tended to present more often with stroke (88% vs 55%, p = 0.09) rather than a transient ischemic attack (TIA) and had higher admission and discharge NIHSS scores (mean 9 ± 7 vs 3 ± 4, p = 0.004) and (mean 8 ± 7 vs 2 ± 3, p = 0.002) respectively.

Radiologically, all Covid-19-aSCS patients that presented with a stroke (n = 7, Table 2 ) had a free-floating thrombus in the carotid (100% vs 6.5%, p < 0.001) (Fig. 1 ). Two patients presented with total occlusion of the internal carotid arteries. One (#8) underwent urgent endovascular thrombectomy to occlusive clots in the LICA and left-M1while the other (#6) already suffered from an extensive cerebral ischemic damage with no mismatch on CT perfusion imaging and was not given EVT.

Table 2.

Covid-19 associated acute symptomatic carotid stenosis.

	Age	Sex	HTN	Lipid*	D.M	Smoking	Previous Anti-PLT treatment	Vaccination status	Neurological Symptoms from Covid-19 diagnosis	NIHSS upon arrival	NIHSS upon discharge	Affected Carotid	% Carotid Stenosis	Free hanging thrombus carotid	M1 involvement on ipsilateral side	EVT	Day of CAS from symptom onset	MRS 90
1	68	M	+	−	−	−	−	−	Day 0	1	1	RICA	60%	+	+ Sub occlusive clot	−	Day 80	1
2	64	F	−	−	−	−	−	−	Day 7	10	10	LICA	50%	+	+ Total occlusion due to clot	+	−	2
3	75	M	−	+	−	−	−	−	Day 7	0	0	LICA	65%	−	−	−	Day 7	1
4	80	M	+	−	+	−	−	−	Day 0	12	10	LICA	90%	+	−	−	Day 7	4
5	64	M	+	+	−	−	Aspirin	+	Day 0	8	8	RICA	90%	+	−	−	Day 14	4
6	61	M	−	−	−	−	−	−	Day 7	15	21	RICA	100%	+	+ Total occlusion due to clot	−	−	4
7	57	M	+	+	+	+	−	−	Day 0	4	1	LICA	90%	+	−	−	Day 21	0
8	45	M	−	−	−	−	−	−	Day 0	20	9	LICA	100%	+	+ Total occlusion due to clot	+	−	3

NIHSS- National Institutes of Health Stroke Scale.

DSA- Digital subtraction angiography.

EVT- Endovascular thrombectomy.

CAS- Carotid artery stenting.

HTN- Hypertension.

D.M.- Diabetes mellitus.

MRS- Modified Rankin scale.

Lipid = Dyslipidemia.

PLT- Platelets.

Fig. 1.

Free hanging clots in the carotid of Covid-19 symptomatic carotid stenosis patients.

A- RICA 90%, patient number 5.

B- LICA 90% stenosis, patient number 7.

C- LICA 70% stenosis, Patient number 3.

Blue arrow- Free floating thrombus, red arrow- atherosclerotic plaque,

Another patient (#2) underwent thrombectomy with an occlusive clot removed from left-M1only.

In the remaining patients with stroke, non-occlusive floating thrombus were found on focal atherosclerotic plaques in proximity to the carotid bifurcation and an additional free-floating thrombus was found at a more distal part of the carotid (Fig. 1) or an additional non-occlusive thrombus along the M1 (Table 2).

Four Covid-19-aSCS patients with free hanging clots were treated with variable dosages of Low Molecular Weight Heparin (LMWH) in addition to DAPT until clot resolution. In three of them full therapeutic dose of LMWH (1 mg/kg BID) was given while in the fourth a reduced dose of LMWH was administered due to the fear of hemorrhagic transformation of his extensive ischemic lesions. In contrast, in the control cohort, none of the patients were treated with LMWH. Two patients who were treated with DAPT without LMWH has experienced recurrent TIA events in the same carotid territory until CAS was instituted.

Five patients underwent CAS, three of them had a near-total occlusion and one of them had a free-floating clot but no occlusion. In these cases, CAS was delayed until imaging proved clot resolution. Consequently, CAS procedure was performed within longer interval from symptom onset in the Covid-19-aSCS patients (26 ± 27 vs 12 ± 7, p < 0.001).

All patients included in our study, from both the Covid-19 and the control group, survived after 90 days from stroke onset. Covid-19-aSCS patients less frequently achieved excellent outcome, defined as mRS score of 0 after 90-day (13% vs 58%, p = 0.022), and tended to less frequently achieve good functional outcome, defined as 90-day mRS 0–1 (37% vs 68%, p = 0.11).

Notably, 88% (7/8) of the Covid-19-aSCS patients were unvaccinated for Covid-19 upon presentation. Upon admission, three COVID-19 patients were systemically asymptomatic, three had mild respiratory illness and two had substantial respiratory illness requiring oxygen support. One patient required mechanical ventilation at a later stage of the admission due to substantial Covid-19 respiratory illness. In contrast, none of the control group presented with respiratory illness or either required oxygen support or mechanical ventilation during their course of admission.

5. Discussion

The main findings of the current analysis are that in comparison to non-Covid-19-aSCS patients, those patients with concomitant Covid-19 infection and aSCS are younger, more often present with stroke, more often harbor complex plaques with free-floating thrombi, and generally have poorer outcomes.

In our study, Covid-19 -aSCS patients were younger and this is in accordance with previous studies [3]. Covid-19-aSCS patients had lower rate of cardiovascular risk factors and possibly Covid-19 was a trigger for an active atherosclerotic plaque in patients with milder atherosclerotic disease. Again, this is accordance with a previous study describing AIS in Covid-19-aSCS patients due to fulminant carotid thrombosis overlying mild atherosclerotic plaque [4].Moreover, the affinity of Covid to the carotid endothelial wall is well known and may occur even in young patients without vascular risk factors [8].

Covid-19-aSCS patients tended to present more often with stroke rather than a TIA compared to the non-covid-19 population. Possible explanations to this observation include higher clot burden within the carotid lumen [4,5] and the overall hypercoagulable state found in Covid-19 [6].

Covid-19-aSCS patients more frequently presented with free-floating-thrombus. This radiological finding has been previously described [4,5] and could also contribute to the higher rate of observed strokes rather than TIAs. Possible pathogenesis for accelerated thrombus formation in Covid-19 patients include systemic inflammation that may cause atherosclerotic plaque rupture, and the affinity of Covid-19 to the carotid endothelial cells through ACE-2 receptors causing local endotheliosis [7]. When taken together, these two processes promote thrombi formation. Additionally, the hypercoagulable state seen in Covid-19 may promotes clot extension and disintegration until reaching large sizes [6].

Unfortunately, it is possible that positive Covid-19 status may have resulted in delayed medical attention, imaging and consequently treatment that may contribute to the worse outcome of the Covid-19-aSCS patients. Importantly, the fact that only one of the Covid-19-aSCS patients was vaccinated possibly contributed to an increased systemic inflammation and pro-coagulable state [9].

Our findings favor treating Covid-19-aSCS patients with LMWH in addition to DAPT due to high burden of free hanging clots that predispose to recurrent ischemic events. Further larger scale studies could shed light on the required dosage and duration of LMWH treatment in Covid-19-aSCS patients.

Our treatment decision paradigm was not risk free. We have tried to treat conservatively whenever possible with either anticoagulation whenever a clot was visible on CT-angiography or dual antiplatelet treatment whenever clot was not clearly visible. Repeated imaging would allow to observe resolution of the clot thus allowing carotid stenting with reduced risk of periprocedural stroke. Imaging was performed on different time interval on an individual basis. Additionally, we tried to delay intervention to allow the body to overcome the Covid-19 illness and assumed diminished pro-coagulable state.

Finally, the minority of the Covid-19-aSCS patients had severe respiratory illness further highlighting the increased risk of stroke in mildly symptomatic Covid-19 patients and may suggest additional treatment with anticoagulants such as low molecular weight heparin in addition to antiplatelet treatment whenever clots are seen in order to dissolve the floating clots [8].

Our study limitations include a single center setting with a small number of included patients. Further, larger scale studies could reinform our findings and shed more-light on the phenomenon and the best suited treated strategies.