Hemorrhagic Transformation after Ischemic Stroke in a Case of Essential Thrombocythemia with Hyperfibrinolysis on Thromboelastography

Abstract

Essential thrombocythemia (ET) is a myeloproliferative neoplasm that is characterized by thrombocytosis. Because it is characterized by thromboembolic and hemorrhagic events, balancing the coagulation status is essential. Thromboelastography (TEG) is a point-of-care viscoelastic test that evaluates whole-blood coagulation dynamics. We herein describe the case of a patient with ischemic stroke accompanied by ET who underwent TEG. The lysis index after 30 min (LY30) was elevated when hemorrhagic transformation occurred. After augmentation with cytoreductive therapy, the platelet count and LY30 levels rapidly normalized. Our findings indicate that TEG may be therefore useful for monitoring the complicated coagulation status of ET patients.

Introduction

Hemorrhagic transformation (HT) after ischemic stroke is one of the most fatal complications associated with a fluctuating coagulation status (1). Antithrombotic therapy is often suspended to prevent HT and hematoma expansion; however, it sometimes results in additional thrombotic events (1). Although balancing the risks of thrombosis and bleeding is essential to prevent HT, particularly in cases with a high risk of hemorrhage, no effective method for evaluating the coagulative status has so far been established.

Essential thrombocythemia (ET) is a myeloproliferative neoplasm that is characterized by thrombocytosis. Patients with ET often experience thromboembolic complications including ischemic stroke, ischemic heart disease, and deep vein thrombosis (2-4). To prevent these complications, patients are usually treated with antiplatelet therapy such as low-dose aspirin with or without cytoreductive therapy with hydroxyurea (5). ET is also a known risk factor for hemorrhagic complications (2) owing to an impaired platelet function and acquired von Willebrand syndrome (3). In a previous study, HT was observed in 71% of the patients with ET-related ischemic stroke (6). Patients with ischemic stroke and ET are more susceptible to HT.

Thromboelastography (TEG) is a point-of-care in vitro viscoelastic test that evaluates the whole-blood coagulation dynamics (7). It is usually performed at the bedside and can rapidly assess coagulation cascade, the platelet function, and fibrinolysis. Previous studies have described the usefulness of evaluating the coagulation status in various conditions such as ischemic stroke and traumatic brain injury (8,9). However, the use of TEG for ET has rarely been described. We herein describe the case of a patient with ET who had an ischemic stroke and was tested using TEG. The potential benefits of TEG in patients with ischemic stroke accompanied by ET are also discussed.

Case Report

A 75-year-old man was admitted to the emergency department because of an altered mental state and dysarthria. He had been diagnosed with ET with a V617F mutation in the JAK2 gene 6 years prior and had been taking aspirin and hydroxyurea. His consciousness level on admission was E3V4M5 on the Glasgow Coma Scale and right lower limb weakness was observed. Laboratory test results included a platelet count of 670,000/μL, prothrombin time-international normalized ratio of 1.10, and activated partial thromboplastin time of 30.0 seconds. Magnetic resonance imaging (MRI) revealed multiple acute ischemic lesions, including some in the left thalamus (Figure a). He was diagnosed with ischemic stroke associated with ET and clopidogrel was administered. However, on day 8 of hospitalization, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel was discontinued, and TEG^Ⓡ 6s (Haemonetics, Boston, USA) was used to assess the coagulation status due to hemorrhagic changes in the infarcted area (Figure b). TEG reveled the reaction (R) time to be 5.6 min (normal range 4.2-9.0 min), K time (the time from the end of R until the clot reaches 20 mm) was 0.8 min (normal range 1.0-2.9 min), alpha angle (AA) was 81.1 degrees (normal range 57-75 degrees), maximum amplitude (MA) was 67.1 mm (normal range 53-68 mm), and percent lysis 30 min after MA (LY30) was 8.8% (normal range 0.0-2.6%), which indicates the status of hyperfibrinolysis. On hospital day 12, MRI revealed new ischemic lesions in the cerebellar hemisphere. His platelet count was elevated to 992,000/μL, and LY30 level increased to 10.1%. We were concerned that restarting DAPT would result in hemorrhaging. Therefore, single antiplatelet therapy with aspirin was initiated, and the dosage of hydroxyurea was increased as cytoreductive therapy. After the reinitiation of aspirin and augmentation of cytoreductive therapy, LY30 levels decreased to 4.9% on day 18 and 0.2% on day 25. His platelet count also successfully normalized to 213,000/μL when he was discharged from the hospital. He had not experienced any recurrence of ischemic or hemorrhagic stroke for six months.

Figure.

Magnetic resonance imaging findings in case 1. (a) On admission MRI showed multiple acute ischemic lesions with left thalamus involvement. (b) Hemorrhagic transformation was observed on the eighth day.

Discussion

We encountered a case of ischemic stroke accompanied by an ET. Two notable points in the clinical course warrant further attention. The LY30 levels were elevated when HT occurred. In addition, after the hydroxyurea dose was increased, the platelet count and LY30 levels rapidly returned to normal.

A remarkable elevation in the LY30 levels was observed at the time of HT. While the R time, K time, AA, and MA reflect the process of clot formation (8), LY30 is regarded as a biomarker associated with fibrinolysis (10). In a prospective study of severely injured trauma patients, LY30 ＞3% was significantly associated with massive transfusion within 6 h of injury and the necessity for antifibrinolytic therapy (11). Reperfusion injury after ischemic stroke is a major risk factor for HT (1). In the hyperfibrinolytic state, thrombi may be more prone to spontaneous dissolution, thus resulting in reperfusion. As a result, elevated LY30 levels may have been associated with HT in this case.

The immediate normalization of LY30 and the platelet count associated with cytoreductive therapy was observed in the current case. Since aspirin may not be significantly associated with LY30 (7), this finding suggests that cytoreductive therapy may improve the hyperfibrinolytic state and platelet count. In addition to an abnormal increase in the platelet count, functional abnormalities in ET, such as an atypical morphology, membrane defects, acquired storage pool disorders, and impaired arachidonic acid metabolism, may contribute to coagulation instability (12). In one observational study there was a significant elevation of the LY30 levels in patients with ET compared to those in normal controls (13), thus suggesting a hyperfibrinolytic state. As hydroxyurea has been reported to improve the platelet function in ET cases (14), it might be associated with the normalization of LY30 and the platelet count in the current case.

Several limitations may limit the conclusions drawn from this study. First, the LY30 levels were not measured before HT. Therefore, it is possible that the elevated LY30 levels observed were caused by hemorrhagic changes. However, in a previous study, the LY30 levels were not elevated in patients with an intracranial hemorrhage (15). Second, evidence regarding TEG, particularly LY30, in patients with acute ischemic stroke is limited (8). Reperfusion and associated hemorrhagic transformation are well-known complications of ischemic stroke (1). As our findings are not sufficient to clarify the potential association between LY30 and HT, further research involving a larger number of patients is therefore warranted. Third, the antithrombotic therapy regimen was changed during the clinical course. However, the effects of clopidogrel and DAPT on the LY30 levels have not yet been thoroughly investigated. Notably, antiplatelet therapy mainly inhibits clot formation (7,8), which is reflected by the R and K times, AA, and MA. LY30 is a fibrinolysis parameter that is not strongly affected by antiplatelet therapy.

The present case highlights a potential connection between the LY30 expression and hemorrhagic complications. In addition, the augmentation of cytoreductive therapy may be associated with the normalization of LY30. Although further investigations are necessary, LY30 may serve as a potential indicator in the management of ischemic stroke in patients with ET.

The authors state that they have no Conflict of Interest (COI).