Introduction

Vascular complications are a significant risk factor and prognostic indicator of COVID-19 infections [6]. Although rare, a free-floating carotid thrombus is a variant of these complications and requires immediate management to prevent further cerebral infarction [4, 13]. Patients with a pre-existing disbalance of their hemostatic state, such as those with immune thrombocytopenia (ITP) undergoing thrombopoietin receptor agonist (TPO-RA) therapy, are at a significantly higher risk of thromboembolic events than the general population [12]. ITP is an autoimmune disease characterized by antibodies targeting platelet surface structures, which results in a reduced platelet count and an increased tendency to bleed, accompanied by spontaneous purpura and petechiae. Medical treatment for ITP consists of immunosuppressants and TPO-RAs such as romiplostim and eltrombopag, which promote megakaryocyte differentiation, proliferation, and platelet production [8]. In contrast to most patients with COVID-19-associated thrombocytopenia, ITP patients with and without TPO-RA therapy show a paradoxical increase in platelet count during COVID-19 infection [5].

Case Report

Here, we report a case of a 38-year-old female smoker with a medical history of ITP who contracted COVID-19 and subsequently suffered an acute left hemispheric stroke while receiving eltrombopag therapy at a dose of 75 mg/24 h. The patient was diagnosed with ITP at the age of three years and underwent a splenectomy at six years old. Nine years prior to admission, the patient had switched TPO-RA therapy from romiplostim to eltrombopag. The patient was naïve to any anticoagulation or platelet agglutination inhibitor. On admission day, the patient woke up with dysarthria and a mild distal sensorimotor hemiparesis of the right side, NIH Stroke Scale (NIHSS) 4, modified Rankin Scale (mRS) 2.

At admission, platelet count was significantly increased at 896 × 109/l, and anemia with hemoglobin 8.1 g/dl and leukocytosis 16.5 × 109/l were also apparent. Eight days prior to the onset of symptoms, the platelet count was measured at 26 × 109/l. Initial brain imaging by computer tomography (CT) was unremarkable, but CT angiography (CTA) of the head and neck revealed a nearly occluding intraluminal thrombus (0.7 × 0.9 cm) in the distal left common carotid artery (CCA) extending into the carotid bifurcation and left internal carotid artery (ICA), leading to a >80% stenosis as per NASCET criteria. A second thrombus was detected within the left ICA (0.3 × 0.3 × 0.4) without stenotic effect (Fig. 1A). Due to the risk of further embolization of more distal regions by mechanical intervention, a systemic lysis therapy with 70 mg recombinant tissue plasminogen activator (rt-PA) was immediately initiated at a body weight of 78 kg (receiving 0.9 mg/kg dose), followed by continuous anticoagulation with heparin 24000 IE/24 h after 24 h. Diffusion-based imaging revealed multilocular cortical ischemic areas in the left middle cerebral artery (MCA) territory (Fig. 1B). CT angiographic follow-up imaging three days after admission showed complete lysis of the thrombotic material in the left CCA and ICA bifurcation (Fig. 1C). Eltrombopag was paused upon admission and resumed at a reduced dosage of 25 mg/24 h after the patient’s platelet count reached a cut-off platelet count <500 × 109/l, which occurred five days after stroke onset.

Fig. 1
figure 1

CT Angiography shows the free-floating thrombus of the left common carotid artery before (A) and after (C) systemic thrombolytic therapy at a three-day follow-up. Diffusion-weighted imaging showed multilocular cortical ischemic areas in the left ACM territory caused by ruptured thrombus material (B)

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At discharge, the patient showed very mild sensorimotor paresis of the right side, NIHSS 2, mRS 1. The patient was discharged with lifelong secondary prophylaxis of acetylsalicylic acid 100 mg/24 h and Simvastatin 40 mg/24 h. No antiviral treatment was administered due to the absence of pulmonary symptoms and the fact that the COVID-19 infection had been progressing for 10 days before admission. The patient’s platelet count was monitored daily after discharge. Two months after discharge, the patient’s platelet count remained unstable, ranging between 5 and 419 × 109/l (Fig. 2). As a result, the referral doctor adjusted the patient’s eltrombopag dosage, and acetylsalicylic acid was temporarily paused.

Fig. 2
figure 2

Course of stroke, platelet count, and COVID-19 disease progression. SARS-CoV-2 infection was associated with fever and overall weakness for 5 days (full bar). At admission, the platelet count was 892 × 109/l, and the patient tested positive for COVID-19 without any related pulmonary symptoms (transparent bar). The patient had her first positive SARS-CoV-2 test 14 days before the stroke onset

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Discussion

The presented case exemplifies the neurological complications that hematological patients dealing with multiple risk factors for developing a thrombosis can experience. Moreover, the complex interplay between thrombocyte stimulation by a TPO-RA and a viral infection as a potential trigger for hypercoagulability should raise concerns at the onset of prompt focal deficits.

In the presented case, systemic lysis therapy effectively dissolved a thrombus in a carotid artery, leading to the patient’s swift recovery without any significant adverse effects. The systemic lysis approach was preferred over carotid thromboendarterectomy and percutaneous transluminal angioplasty (PTA) with direct clot aspiration or a stent retriever due to the risk of the thrombus spreading to more distal regions. Although previous data indicate that neither medical nor interventional treatment is superior to the other in treating free-floating thrombus of the carotid artery [1], authors report the effectiveness of recombinant-plasminogen activator in dissolving embolic occlusions predominantly derived from fibrin-rich-clotted platelet material at the presence of COVID-19-associated-dysregulated platelet homeostasis [7].

The post-stroke procedure included the initiation of the platelet agglutination inhibitor with acetylsalicylic acid and, after a brief interruption, a continuation of eltrombopag at a reduced daily dosage of 25 mg/24 h, with weekly platelet count control for the next three months. Although recent guidelines published for ITP are not specific regarding the risk-benefit ratio in adapting eltrombopag and starting with acetylsalicylic acid [10], eltrombopag was interrupted in other cases of thromboembolic events under eltrombopag in ITP after a COVID-19 infection while a stable platelet count was observed [2].

ITP patients undergoing TPO-RA therapy have a low but significant risk of developing thromboembolic events compared to the general population [14], and thromboembolic events occur independently of the patients’ platelet count or of the duration of eltrombopag intake. While most patients who develop embolic events show a reduced platelet count, some rare cases report thromboembolic events with normal or even elevated platelet numbers, as observed in the present case with a significant thrombocytosis [3]. Bussel et al. [3] further identified at least one risk factor in each ITP patient with thromboembolic events; however, there was no consistent factor apparent in the majority of thromboembolic cases. As such, the present case suggests close monitoring of ITP patients’ platelet count and signs of thromboembolic events during a presumptive temporal hypercoagulability as triggered by an acute COVID-19 infection, given that previous case reports and studies on COVID-19 patients with free-floating thrombus material indicate that a single risk factor and a COVID-19-related hypercoagulable state can trigger the development of a thrombus [4].

The complex mechanisms leading to COVID-19–associated thromboembolic events are not fully understood. However, an underlying hypercoagulable state in COVID-19 involves a prothrombotic malfunction of the endothelium, which involves the loss of glycocalyx, cytoprotective signaling, and antithrombotic effectors to instead promote fibrin formation, platelet adhesion, and complement activation [6]. The reported patient developed thrombocytosis, while most patients with COVID-19-associated thromboembolic events are usually associated with mild-to-severe thrombocytopenia [15].

The phenomenon of thrombocytosis following COVID-19 infection in ITP patients receiving TPO-RA therapy has been described in a few cases before (Table 1) [5, 9, 11]. Similar to our case, Pantic et al. reported severe thromboembolic complications in their patient cohort associated with post-COVID-19 thrombocytosis approximately seven days after COVID-19 onset. Although the specific cause for the acute thrombocytosis in these patients is unclear, COVID-19-associated lymphopenia has been suggested as a possible trigger. A reduced number of auto-reactive lymphocytes may lead to inhibition of ITP-related platelet destruction, and TPO-RA may promote reactive thrombocytosis due to ongoing stimulation of thrombopoiesis [5]. Maekura et al. [9] suggested an association between elevated platelets in chronic ITP patients and the development of SARS-CoV-2 neutralizing antibodies after a COVID-19 infection. Four out of 13 cases, including our case, revealed severe thromboembolic complications during elevated platelet counts after COVID-19 infection in ITP patients. The severity of the COVID-19 infection does not appear to be related to the relative increase in platelet count in the reviewed cases.

Table 1 Clinical Features of the 13 cases of chronic ITP under TPO-R who developed a COVID-19 Infection-associated thrombocytosis, including the present case
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As a single case report, the findings cannot be generalized. Furthermore, compliance with eltrombopag dosage was based on self-report by the patient and was not validated by serological measurements. Prospective studies are needed to further systemically assess a potential association between COVID-19 infection, chronic ITP under TPO-RA therapy, and early thrombocytosis after COVID-19 onset.

Overall, the findings of this case suggest that acute infection with SARS-CoV-2 promotes a hypercoagulable state with platelet disbalance in ITP patients receiving eltrombopag therapy. In the rare event of ischemic stroke in a patient with ITP and COVID-19 exhibiting a free-floating thrombus of the carotid, systemic lysis therapy can successfully and safely dissolve thromboembolic material and prevent further ischemic lesions. A slight reduction of the daily dosage of TPO-RA as well as the initiation of an antiplatelet aggregation may be a feasible strategy for secondary stroke prophylaxis in these patients.