Characteristics of arterial stroke in myeloproliferative neoplasms: A French monocentric study
Authors: Léo Plaçais, Constance Rabel, Olivier Chassin, Mariana Sarov, Nicolas Legris, Nicolas Noël, Christian Denier
Journal: American Journal of Hematology (2021)

Stroke is not an uncommon way of revelation of Philadelphia-negative chronic myeloproliferative neoplasms (MPN). In a retrospective study, among 3318 patients with ischemic vascular cerebral events, 17 (0.5%) were diagnosed with MPN, and stroke was the revealing manifestation for 58% of them.1 Moreover, 29% of these patients had a history of repeated ischemic cerebral event preceding the diagnosis of MPN. Nevertheless, in this large cohort, another associated cause existed in all these stroke patients with MPN.1 In the emergency setting of a stroke, diagnosing underlying MPN can be difficult. First, MPN patients share common cardiovascular comorbidities that affects stroke risk in the same way than it does in general population.2 Moreover, erythrocytosis and thrombocytosis are common during acute vascular events, and can be linked to hemoconcentration.3 In a retrospective cohort of patients <60 years old presenting with stroke, 19% had high hematocrit levels, 3.1% had thrombocytosis, and according to authors 14% required further investigations for MPN diagnosis.4 On the other hand, proposing systematic JAK-2 V617F screening in stroke patients is costly and might lead to overdiagnosis, as the prevalence of JAK-2 V617F or calreticulin mutations has recently been estimated at 3.1% in the Danish population, among which only 2.5% had defined MPN.5 We report an institutional study based on a retrospective cohort of patients with ischemic stroke to describe MPN prevalence, clinical and radiological presentation, and outcome, and finally discuss accountability of MPN in stroke pathogeny and its therapeutic in acute and long-term management. We retrospectively collected data from patients hospitalized in the Bicêtre Hospital Stroke unit from 2009–2019. Local recommendations are to consider JAK-2 screening (i) in patients with elevated hemoglobin (>16 g/dL or > 16.5 g/dL in female or male patients respectively) and/or platelets (>450 G/L) and (ii) in patients younger than 55 years old in the setting of cryptogenic stroke. Patients were screened via computer search in the local discharge databases. Inclusion criteria were the association of cerebral infarction or TIA and MPN diagnosis. The diagnosis of MPN followed either 2008 or 2016 recommendations, depending on the date of stroke incidence, and patients with CML were excluded. For each patient, in the case of stroke recurrence in our institution, only the first stroke event was recorded. Stroke etiology was investigated using the TOAST score. Quantitative and qualitative data were reported as median [interquartile range, IQR], and n (%), respectively. For intergroup comparisons of quantitative data, the Wilcoxon-Mann–Whitney test was used. For intergroup comparisons of qualitative data, Fisher's exact test was used. Statistical significance was set to P < .05. All statistical analysis were performed on R-Studio software v1.3.1056. Among 8834 patients hospitalized from January 1, 2009 to January 1, 2019 for arterial stroke, 21 were retrospectively identified with MPN (0.2%): 11/21 (52%) with essential thrombocythemia (ET), 10/21 (48%) with polycythemia vera (PV). At the time of the recorded stroke event, MPN was previously diagnosed for 8/21 (38%), and revealed by stroke for 13/21 (62%). Median age was 70 years old [64–78], and sex-ratio was 1.33 women per men (Table 1). Median follow-up after stroke was 27 months [8–48]. 1 >1 N = 7 (33%) N = 11 (52%) N = 2 (25%) N = 5 (62%) N = 5 (38%) N = 6 (46%) .655 .659 Initial NIHSS (median [IQR]) NIHSS after 3 months Haemorrhagic transformation (with or without symptoms) Death from stroke Recurrent stroke Initial Rankin score (median [IQR]) Rankin score at 3 months (median [IQR]) 0 1 2 3 4 5 6 4 [1–10] 2 [1–4] N = 4 (19%) N = 1 (5%)§§§ N = 3 (14%) 0 [0–0] 1 [1–2.25] N = 4 (19%) N = 10 (48%) N = 1 (5%) N = 2 (10%) N = 2 (10%) N = 0 N = 1 (5%) 3 [0.75–5.25] 1.50 [0.75–4] N = 0 N = 0 N = 2 (25%) 0 [0–0.5] 1 [0.5–2] N = 2 (25%) N = 3 (38%) N = 1 (13%) N = 2 (25%) N = 0 N = 0 N = 0 4 [1–10] 2 [1–5] N = 4 (31%) N = 1 (8%) N = 1 (8%) 0 [0–0] 1 [1–2] N = 2 (15%) N = 7 (54%) N = 0 N = 0 N = 2 (15%) N = 0 N = 1 (8%) .635 .931 .131 .241 .530 .597 .580 Imputable exclusively to MPN Associated multiple causes Large artery atherosclerosis Cardioembolism N = 8 (38%) N = 13 (62%) N = 8a N = 4a N = 8 (100%) - - - - - N = 0 N = 13 (62%) N = 8a N = 4a N = 0 N = 2 Three patients (14%) presented with TIA, and 18 (86%) with cerebral infarction. Clinical presentation was severe for two patients (10%, NIHSS>16), moderate for seven (33%, NIHSS 5–15) and minor for 11 (52%, NIHSS 0–4). A total of 13/21 (62%) were not eligible for either thrombolysis or endovascular therapy, 10 because of delayed care, two because of TIA and one because of formal counter-indication to thrombolysis. After stroke, 10/21 (48%) received antiaggregant therapy, nine received anticoagulation therapy (43%) and one was treated by both. Median initial NIHSS and NIHSS at discharge were four [1–10] and two [1–4] respectively. Three patients experienced a stroke recurrence (two had a history of stroke, and one patient had a stroke recurrence 2 months after the recorded event), and one (5%) patient died from stroke. At 3 months, modified Rankin scale (mRS) scores were 0–1 (full autonomy) in 14/21 patients (67%) (Table 1). The median hemoglobin count was 14.3 g/dL [12.5–17.6], the platelet count 468 G/L [356–584], and the white blood cell count 10.1 G/L [8.3–11.8]. Seven (33.3%) patients presented with an elevated hemoglobin count, and 10 (48%) had elevated platelet counts at the time of stroke. After etiological workout, 13/21 (62%) had an additional stroke etiology: large artery atherosclerosis for 8/21 (38%), cardio-embolism for 4/21 (19%, mostly atrial fibrillation in 75%), and stroke of other determined etiology for 2/21 (10%, dissection for one patient and nephrotic syndrome for the other one)(Table 1). Interestingly, 8/21 (38%) patients (two with previously diagnosed MPN and six with stroke-revealed MPN) had no other determined stroke etiology than MPN (Table S1). Of the two patients with previously-diagnosed MPN and stroke without other determined etiology, one had PV and was not treated before stroke occurrence, and the other had TE and was under hydroxyurea. The only statistically significant difference between patients with MPN-related stroke (n = 8, 38%) and with multiple etiologies (n = 13, 62%) was the hemoglobin count, higher in the former group (median of 17.25 g/dL [15.57–18.52] vs 12.7 g/dL [12.5–14.3], P = .027). Among patients with MPN-related stroke, 75% were stroke-revealed MPN, whereas in patients with multiple etiologies, 64% were stroke-revealed MPN (P = .399). Five of them had PV, and three had ET (Table 1). No difference was observed between stroke-revealed and previously-known MPN in terms of age, gender, risk factors, TOAST score and hematological parameters. Interestingly, patients with stroke-revealed MPN had a higher frequency of middle cerebral artery involvement (P = .03) (Table S1). Over the eight patients with previously-diagnosed MPN, six were treated before the recorded stroke: one by JAK-inhibitors solely, five by hydroxyurea (combined with aspirin in 4/5), and one with anticoagulant therapy. Only one of eight untreated patients had an elevated hemoglobin count, while the seven others had normal hemoglobin and platelets counts at stroke occurrence. All of the 13 patients with stroke-revealed MPN were diagnosed with MPN shortly after the stroke event. After stroke, eight patients initiated hydroxyurea, and five started hydroxyurea and phlebotomy (Table S1). When comparing patients depending on their JAK-2 V617F mutational status, there were no significant differences regarding stroke presentation and severity, but patients with JAK-2 V617F mutation had a significantly higher platelet count at stroke occurrence (516 G/L vs 290 G/L, P = .029, Table S2). There were no statistically significant differences between patients with PV and ET regarding stroke characteristics (Table S3). Our study reports the clinical presentation and outcomes of MPN-associated strokes in a single institution retrospective cohort. Among 8834 patients hospitalized for stroke, we retrospectively identified 21 patients with MPN using diagnostic codes, for a prevalence of 0.2% over 10 years, similar to previously reported frequencies.1 Noticeably, this prevalence might be underestimated since only selected patients (ie, young or with suggestive biological alterations, as described in the methods) were screened for MPN. Arterial stroke revealed MPN in 62% patients, among which 15% had a previous history of thrombosis. The JAK-2 V617F mutation was found in 81% of the patients included. After a thorough etiological workup, up to 38% patients had no other imputable stroke etiology than MPN, contrarily to previous large series which reported additional etiologies in all stroke patients with MPN (atherosclerosis, atrial fibrillation, patent foramen ovale, dissection).1 These patients had a statistically significant higher hemoglobin count than patients with additional causes, providing arguments for the direct accountability of MPN to be the cause of stroke. In our study, 48% of the patients included (38% among patients with previously-diagnosed MPN) were not eligible for emergency stroke treatment because of delayed care, emphasizing the need for improvements in patients' education to stroke symptoms. Moreover, 14% of the patients (and 25% of the patients with MPN-related stroke) presented with recurrent stroke, enlightening the high risk in this population. Overall, our study identifies MPN as a rare cause of arterial stroke, and highlights the importance of an early diagnosis to prevent stroke recurrence. While systematic screening for MPN or JAK-2 V617F mutation would require cost/benefit evaluations from further studies, a thorough investigation should be considered in patients with cryptogenic stroke and/or abnormal blood counts. As stroke in the most frequent severe thrombotic manifestation among MPN patients and responsible for 7% of their long-term mortality,6 we believe that a close cooperation between neurologists and hematologists, both at stroke occurrence and during MPN follow-up, will improve MPN diagnosis at stroke occurrence and prevent recurrence. This study was not funded. The authors declare no conflict of interest. C.D. and L.P. designed the study. C.R., O.C., M.S., N.L. contributed clinical data. L.P., N.N. and C.D. analyzed the results. L.P., N.N. and C.D. wrote the manuscript. All authors read and agreed to the final version of the manuscript. All data are available from the corresponding author upon request. Appendix S1. Supporting information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.