Essential Thrombocythemia Complicated by Multivessel Intracranial Dolichoectasia with Subarachnoid Hemorrhage and Recurrent Cerebral Infarction: A Case Report

doi:10.21203/rs.3.rs-4865652/v1

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Essential Thrombocythemia Complicated by Multivessel Intracranial Dolichoectasia with Subarachnoid Hemorrhage and Recurrent Cerebral Infarction: A Case Report

https://doi.org/10.21203/rs.3.rs-4865652/v1

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published 22 Oct, 2024

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Background: Patients with essential thrombocythemia (ET) can develop systemic thrombotic and hemorrhagic vascular complications due to increased and dysfunctional platelets.

Case presentation: We encountered a 49-year-old Japanese woman with a history of essential ET, cerebral infarction, hypertension, and hyperlipidemia. She had been taking anagrelide (2.5 mg/day) and aspirin (100 mg/day) and had vomited at home. At the time of admission to our hospital she was in a deep stupor. Head computed tomography showed severe subarachnoid hemorrhage (SAH) at the interhemispheric fissure, hematoma at the corpus callosum, and intraventricular hemorrhages. Digital subtraction angiography demonstrated multiple dilated, stenotic, tortuous intracranial arteries, and a dissecting aneurysm at the right anterior cerebral artery (ACA). The dissecting aneurysm measured 7.7 × 15.5 mm and a bleb was observed. Our diagnosis was ruptured ACA dissecting aneurysm and diffuse intracranial arterial dolichoectasia (DIADE). We performed stent-assisted coil embolization of the aneurysm. She remained apathetic and manifested unilateral apraxia and alien limb syndrome due to a partial callosal disconnection. Two months thereafter her symptoms gradually improved, her consciousness level and limb function improved and her modified Rankin scale (mRS) score was 2. However, when we tapered her antiplatelet therapy she again developed an acute cerebral infarct.

Conclusions: This is the first presentation of a patient with ET complicated by DIADE, both of which can result in ischemic and hemorrhagic vascular complications including SAH. As antithrombotic therapy in patients with DIADE and ET may be associated with higher hemorrhage rates, its effects must be monitored carefully.

essential thrombocythemia (ET)

diffuse intracranial arterial dolichoectasia (DIADE)

dissecting aneurysm

subarachnoid hemorrhage (SAH)

cerebral infarction

Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by dysfunctional and over-produced platelets. Patients with ET may experience thrombotic and hemorrhagic complications.¹⁾ The incidence of ET is estimated at 1.2–3.0 per 100,000 population per year.²⁾ Treatment aims at preventing vascular events, and treatment decisions are guided by risk stratification. Intracranial arterial dolichoectasia (IADE) is an unusual arteriopathy characterized by the elongation, tortuosity, and dilation of the cerebral arteries. Patients with ET or IADE may develop brain infarction or intracranial hemorrhagic complications. Anti-platelet aspirin therapy is applied in ET patients with a recent ischemic stroke. Antithrombotic therapy may exacerbate IADE and promote hemorrhagic complications. Patients with multivessel diffuse IADE (DIADE), a specific vascular phenotype with a poor natural history, are at a higher risk for aneurysm-related death than patients with isolated vertebrobasilar dolichoectasia.

We present a patient with ET who developed ischemic infarcts and hemorrhagic vascular complications related to DIADE. To our knowledge, the association between ET and DIADE has not been reported.

A 49-year-old Japanese woman with a history of hypertension, hyperlipidemia, and ET developed visual disturbance and was brought to our Department of Hematology Medicine. Her home medications included rosuvastatin (2.5 mg/day) and amlodipine (5 mg/day). Due to several cardiovascular risk factors and evidence of extreme thrombocytosis she had also been taking aspirin (100 mg/day). Eight months into this therapy her platelet count was elevated (1623 × 10⁹/l) and aspirin was stopped and replaced by anagrelide (2.5 mg/day). Her consciousness at the time of admission was clear. She had no significant family-, social-, environmental-, or employment history. She reported only a slight visual defect. Dysarthria, weakness, ataxia, apraxia, agnosia, and aphasia were absent. Head diffusion-weighted imaging (DWI) revealed acute infarction at the junction of the right temporal and parietal lobes (Fig. 1A). Magnetic resonance angiography (MRA) showed several mild stenotic changes in bilateral middle cerebral arteries (MCA). (Fig. 1B). As her platelet count was only slightly elevated (478 × 10⁹/l) aspirin (100 mg/day) was restarted. Because 19 months later she developed deep stupor and vomiting she was admitted to our hospital in a severely drowsy state. Her Glasgow Coma Scale (GCS) score was 10 (E2V2M6). Her pupil reflexes were normal and her facial responses were symmetrical. In the right upper- and bilateral lower limbs her muscle strength was decreased (2/5 and 3/5, respectively) and we noted sensory deficits on both sides of her body. She appeared well-nourished, her body mass index (BMI) was 35. Her blood pressure was 145/95 mmHg, her pulse rate was 68/min without arrhythmia and her temperature was 36.6°C. Her white blood cell count was 14.4 × 10⁹/l, hemoglobin was 12.5 g/dl, the platelet count was 143 × 10⁹/l, the activated partial thromboplastin time was 26.4/sec, blood urea nitrogen was 9.3 mg/dl, and creatinine was 0.61 mg/dl. Her liver function was normal. Echocardiography and electrocardiography were normal.

An emergency head computed tomography (CT) scan showed severe subarachnoid hemorrhage (SAH) at the interhemispheric fissure, hematoma at both frontal lobes and the anterior midbody of the corpus callosum, and intraventricular hemorrhages (Fig. 1C-E). MRA revealed no obvious abnormality of the anterior cerebral artery (ACA). Digital subtraction angiography (DSA) demonstrated multiple dilated, stenotic, tortuous intracranial arteries (Fig. 2A-H) and an enlarged fusiform aneurysm with a bleb at the right A2 portion of the ACA whose largest diameter exceeded 5.0 mm. The string sign suggested a dissection. On a 3D rotational angiogram the dissecting aneurysm measured 7.7 × 15.5 mm (Fig. 3A, B). Our diagnosis was ruptured ACA dissecting aneurysm and IADE. We introduced a nicardipine drip for hemodynamic control; the goal was a systolic blood pressure < 140 mmHg. She was then transferred to the medical intensive care unit for observation and monitoring with frequent neurological examinations. Using an endovascular approach, she was treated with clopidogrel (300 mg loading dose once a day) and cilostazol (100 mg twice a day). The next morning she underwent stent-assisted coil embolization of the right ACA-dissecting aneurysm under general anesthesia. The aneurysmal bleb was embolized, flow in the parent artery was maintained, and there was neither in-stent stenosis nor thrombosis (Fig. 3C, D). Thereafter we administered aspirin (100 mg/day), anagrelide (2.5 mg/day), and clopidogrel (75 mg/day). She was apathetic and tetraplegia, hypoesthesia were observed. Her alien limb syndrome persisted due to a partial callosal disconnection.

Follow-up DSA performed 4 weeks after the development of SAH showed that the former bleb of the ruptured dissecting aneurysm was obliterated; the irregular vessel wall of the aneurysm was smooth (Fig. 4A, C). However, multiple intracranial arteries remained dilated, stenotic, and tortuous (Fig. 4A-D). Because brain CT showed hydrocephalus two months after SAH onset we placed a lumbar-peritoneal shunt. Her clinical symptoms, including her alien limb syndrome, improved significantly, her consciousness became clear, tetraplegia improved dramatically, and she was able to walk with some assistance. In the course of 4-month in-hospital follow-up her platelet levels were normal and there was no major stroke event. However, in the 5th month when clopidogrel was stopped, her left hemiparesis and hypoesthesia suddenly worsened and she again suffered a major stroke. Head DWI indicated acute cerebral infarction in the cortical area of the dilated right MCA (data not shown). Despite the risk for recurrent intracerebral hemorrhagic complications, we continued double antiplatelet therapy with aspirin (100 mg/day), clopidogrel (50 mg/day) and cilostazol (200 mg/day) for 6 weeks and closely monitored her blood pressure. In the course of 4 weeks she gradually improved, her limb function recovered, her the Montreal Cognitive Assessment-Japanese version score was 21/30, and her modified Rankin scale (mRS) score was 2. She was discharged and continued daily treatment with aspirin (100 mg), anagrelide (2.5 mg), and clopidogrel (50 mg). Six months after her discharge her condition was stable.

This is the first presentation of a patient with ET who developed ischemic and hemorrhagic strokes due to multiple vessel anomalies related to DIADE. Her ET and extreme thrombocytosis had been treated with rosuvastatin (2.5 mg/day), amlodipine (5 mg/day), and aspirin (100 mg/day). Eight months into this therapy her platelet count was 1623 × 10⁹/l; aspirin was stopped and replaced by anagrelide (2.5 mg/day). However, one year later she developed a cerebral infarct at the junction of the right temporal and parietal lobes that we diagnosed as ET-related. Because of her history of thrombosis she was at high risk for thrombocytosis¹⁾ and we added aspirin to her daily drug regimen. However, 19 months later she developed severe SAH and intracranial hemorrhage; her platelet count remained within normal limits. On DSA images, large portions of the bilateral ACA, MCA, and posterior cerebral artery were dilated, stenotic, and tortuous. An aneurysm at the right ACA harbored a dissecting aneurysm. Our diagnosis was SAH and intracerebral hemorrhage due to rupture of the ACA dissecting aneurysm. Her platelet count at the time of admission was 143 × 10⁹/l and we considered acquired von Willebrand factor deficiency unlikely. Watershed infarction, as observed in our patient, is one of the most common stroke subtypes attributable to ET.³⁾ However, we suspect that SAH and her multiple vascular lesions were not directly related to ET but were evidence of DIADE.

ET and Thrombosis

In a population-based study of 6281 Swedish patients with myeloproliferative neoplasms, registered between 2000 and 2014, the age-standardized incidence for all MPNs was 4.45/100 000 person-years, for ET 1.6.¹⁾

Platelets play a critical role in hemostasis. They are also important in the development of pathological processes including atherosclerosis and arterial thrombosis.⁴⁾ Patients with ET may experience thrombotic and hemorrhagic

complications that contribute to their mortality and morbidity. The reported risk stratification for thrombosis in the presence of ET divided patients into low- and high-risk categories based on their age and history of thrombosis.¹⁾ Previous studies identified age greater than 60 years, thrombosis history, cardiovascular risk factors, and JAK2V617F, which is one of the most typical mutations in ET, as independent risk factors for thrombosis. ^1,5) Our patient did not have the JAK2V617F mutation.

Patients at high- but not those at low risk for thrombosis have been subjected to cytoreduction and antiplatelet therapy.⁵⁾ Others reported that in younger patients with no thrombosis history despite either cardiovascular risk factors or a JAK2 V617F mutation, aspirin is prophylactic.¹⁾ On the other hand, in patients with a platelet count of > 1000–1500 × 10⁹/l, aspirin might elicit hemorrhagic events and cytoreduction is recommended.^1,5)

ET and SAH

Paradoxically, patients with ET and thrombocytosis can suffer minor bleeding or major hemorrhagic complications. A platelet count greater than 1,000 x 10⁹/l may result in a von Willebrand factor deficiency, which can be associated with hemorrhagic complications due to the loss of von Willebrand factor multimers.¹⁾ As low-dose aspirin may elicit hemorrhagic events, the platelet count must be reduced by cytoreduction to restore the von Willebrand factor, although the thrombotic tendency persists as long as platelet counts are above the upper limit of normal. Her platelet count at the time of admission was 143 × 10⁹/l and we considered acquired von Willebrand factor deficiency unlikely.

Our search of the literature found only 6 ET patients with SAH;^6–10) only one required coil embolization for a dissecting aneurysm of the left superior cerebellar artery.⁸⁾ Sugiyama et al.⁹⁾ reported a 47-year-old woman with a dissecting aneurysm of right vertebral artery on MRA scans; she was treated conservatively. In two patients with reversible cerebral vasoconstriction syndrome that elicited SAH, Sugiyama et al.⁹⁾ and Momozaki et al.¹⁰⁾ detected multifocal stenotic changes and severely irregular walls in the peripheral cerebral arteries on MRA- or DSA images. There was no obvious aneurysm formation and follow-up imaging revealed marked improvement of almost all arterial anomalies. In 2 other cases^6,7) no obvious hemorrhagic source and mechanism were found.

DIADE

IADE has been used to describe the visualization of at least one ectatic and/or enlarged cerebral artery; its incidence is approximately 0.08–6.5% in the general population, post-stroke it is up to 12%.^11,12) The association of IADE with traditional vascular risk factors including an advanced age and male gender has been documented; cigarette smoking, a high BMI, hypertension, dyslipidemia, and diabetes mellitus were not associated.¹³⁾ IADE may lead to ischemic stroke, intracranial hemorrhage, the compression of cranial nerves or surrounding neural structures, and death.^11,13)

Brinjikji et al.¹⁴⁾ suggested DIADE to be a specific vascular phenotype with a poor natural history; the incidence of aneurysm-related deaths among patients with DIADE was higher than in those with isolated vertebrobasilar dolichoectasia. In the absence of established treatments, the management of IADE must rely on best care practices for patients with hemorrhagic or ischemic stroke and should include antiplatelet therapy, strict blood pressure control, and the administration of statins to control vascular risk factors.¹¹⁾ In DIADE patients the aneurysm growth- and cerebral infarction rates tended to be higher than in patients with IADE and they were more likely to suffer SAH in the follow-up period. Multivariate analysis, adjusted for the patient age and smoking history, showed that a diagnosis of DIADE was independently associated with higher odds for aneurysmal rupture and new ischemic stroke.¹⁴⁾

ET can induce endothelial damage by activating leukocytes and by releasing elastase and alkaline phosphatase that play a role in the pathogenesis of the prothrombic state.¹⁵⁾ Others⁹⁾ reported that endothelial injuries associated with the JAK2 V617F mutation were induced in patients with ET. At present there are no controlled clinical trials to determine the effectiveness of secondary prevention in IADE patients who suffered a stroke and the safety of anticoagulation and antiplatelet therapy that may elicit hemorrhagic complications needs further investigation.¹¹⁾ Bleeding events may be increased when ET patients with extreme thrombocytosis are treated with aspirin.⁵⁾ Consequently, regular imaging follow-up of patients with ET and multiple vascular lesions is necessary to evaluate lesion progression.

This is the first presentation of a Japanese woman with ET who developed ischemic infarcts and SAH due to the rupture of a dissecting aneurysm related to DIAED. While we cannot confirm a causal relationship between ET and DIADE, we suspect that DIADE was an aggravating pathophysiological factor in our patient and not directly related to ET.

Both ET and DIADE may elicit ischemic- as well as hemorrhagic vascular events including SAH and antithrombotic therapy may exacerbate DIADE. Randomized controlled trials of patients with DIADE are needed to establish effective and safe treatments; their blood pressure must be strictly controlled. In any case, we recommend serial imaging studies to monitor arterial multifocal stenotic changes and the expansion of DIADE.

ET: essential thrombocythemia

SAH: subarachnoid hemorrhage

ACA: anterior cerebral artery

IAED: intracranial arterial dolichoectasia

mRS: modified Rankin scale

DIADE: diffuse intracranial arterial dolichoectasia

DWI: diffusion-weighted imaging

MRA: magnetic resonance angiography

MCA: middle cerebral arteries

GCS: Glasgow Coma Scale

BMI: body mass index

CT: computed tomography

DSA: digital subtraction angiography

MPN myeloproliferative neoplasms

Ethics approval and consent to participate: Not applicable

Consent for publication: Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Availability of data and materials: Not applicable

Competing interests:

The authors declare that they have no competing interests.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Authors' contributions

TK, KT, SU, TM, and HU participated in patient management. All authors read and approved the final manuscript.

Acknowledgements

None of the authors have received any financial assistance for this manuscript.

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Essential Thrombocythemia Complicated by Multivessel Intracranial Dolichoectasia with Subarachnoid Hemorrhage and Recurrent Cerebral Infarction: A Case Report

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Abstract

Figures

Background

Case presentation

Discussion

ET and Thrombosis

ET and SAH

DIADE

Conclusions

Abbreviations

Declarations

References

Supplementary Files

Status:

Journal Publication

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