Successful thrombolysis in essential thrombocythemia-related acute ischaemic stroke

Abstract

Essential thrombocythemia (ET)-related acute ischaemic stroke (AIS) may account for approximately 0.25%–0.5% of all ischaemic strokes. If left undiagnosed and untreated, patients with ET carry an increased risk of recurrent thrombosis involving major organs including the brain. We report an interesting case of a 67-year-old man, who was successfully thrombolysed for AIS resulting from ET. He presented with sudden onset of left-sided hemiparesis with a left-ventricular clot. His subsequent investigations including positive JAK2 V617F mutation confirmed the diagnosis of ET. He made a significant recovery with thrombolysis, anticoagulation, antiplatelet and hydroxyurea. A fear of post-thrombolytic haemorrhagic complications appears the major reason for the lack of reports of thrombolysis in ET-related AIS. Although the diagnosis of ET was confirmed on subsequent investigations, successful thrombolysis in our case provides preliminary evidence that ET-related AIS cases can undergo successful thrombolysis using tenecteplase. To date, ours is only the second case of ET-related AIS being thrombolysed.

Background

Essential thrombocythemia (ET) is a chronic Philadelphia chromosome-negative myeloproliferative disorder characterised by expansion of the megakaryocytic lineage, leading to an isolated elevation of platelets in peripheral circulation to levels >450×10⁹/L. It is associated with several mutually exclusive mutations involving JAK2, CALR and MPL genes, with JAK2 V617F being the most common, seen in 50%–60% cases.¹ Nearly one-fourth of ET cases may develop thrombotic episodes.² If left undiagnosed and untreated, patients carry an increased risk of recurrent thrombosis involving major organs including brain, thereby significantly affecting their functionality and life expectancy. The data on the acute management of ET-related acute ischaemic stroke (AIS) are scarce, with only a single case reportedly received intravenous tissue plasminogen activator to date.³ It may be related to fear of post-thrombolytic haemorrhagic complications. Here, we report a case of an elderly man with AIS as the initial manifestation of ET and was subsequently thrombolysed safely using tenecteplase. He made a significant recovery with thrombolysis followed by anticoagulation, antiplatelet and hydroxyurea.

Case presentation

A 67-year-old right-handed man, known hypertensive and diabetic with fair control on medications, presented with sudden onset of left-sided hemiparesis along with slurred speech of 2-hour duration. On neurological examination, he was conscious, oriented, had left upper motor neuron facial palsy, spastic dysarthria, grade 0/5 power in the left upper and lower limb with National Institute of Health Stroke Scale (NIHSS) score of 16 and modified Rankin Scale (mRS) of 4. His pulse rate was 82 beats/min with regular rhythm, blood pressure was 160/90 mm Hg and blood glucose was 136 mg/dL. CT scan of the brain revealed acute right middle cerebral artery (MCA) territory infarct without intracerebral haemorrhage (CT the Alberta stroke programme early CT score (ASPECT) score of 7/10, figure 1A). Being in the window period for intravenous thrombolysis, patient was thrombolysed using an intravenous bolus of tenecteplase 16 g (at 0.25 mg/kg) after getting informed written consent from patient’s relatives. A repeat brain imaging, done 24 hours later, ruled out haemorrhagic complication (figure 1B). So, patient was started on aspirin 150 mg orally once a day along with atorvastatin 20 mg p.o. once a day.⁴

Figure 1.

NCCT brain, 2D Echo and bone marrow biopsy images of the patient. NCCT scan of the brain obtained before (A) and 24 hours after (B) thrombolysis, showing the reduction in infarct size without haemorrhagic complication. (C) 2D Echo image showing LV clot. (D) H&E stain of bone marrow biopsy showing the presence of megakaryocytes. (E) H&E stain of bone marrow aspiration showing hypercellularity of bone marrow. 2D Echo, two-dimensional echocardiography; NCCT, non-contrast CT; LV, left-ventricular.

Investigations

Complete blood count revealed a platelet count of 911×10⁹/L, which remained persistently >450×10⁹/L on repeat test. The number of leukocytes was >11×10⁹/L. Coagulation profile including bleeding time, clotting time and prothrombin time returned normal. Workup for secondary thrombocytosis including BCR-ABL translocation, serum erythropoietin, haematocrit, iron study and ultrasonography of liver came normal. Bone marrow biopsy showed hypercellularity with increased numbers of enlarged, mature megakaryocytes (figure 1D, E). A blood genetic study revealed positive JAK2 V617F mutation. Thus, persistently elevated platelet count ≥450×10⁹/L, hypercellular bone marrow with increased numbers of enlarged and mature megakaryocyte, presence of JAK2 mutation and absence of evidence of reactive thrombocytosis or other myeloproliferative disorders (such as chronic myeloid leukaemia, polycythaemia vera and primary myelofibrosis) lead to the diagnosis of ET in our case, based on 2016 WHO diagnostic criteria for the same.⁵ As a part of the stroke workup, cardiac parameters as well as cerebral arterial patency were assessed. An unremarkable 12-lead ECG and 24-hour Holter monitoring failed to reveal any evidence of ischaemic or arrhythmic cardiac illness including atrial fibrillation (AF), supraventricular tachycardia or atrial flutter. Transthoracic echocardiography revealed the presence of a mobile left-ventricular clot of size 13 mm×18 mm with normal cardiac valves and ejection fraction without any evidence of congenital heart diseases such as atrial or ventricular septal defect or patent ductus arteriosus (figure 1C). Carotid artery Doppler and CT angiography (CTA) of the brain returned normal, ruling out large-artery atherosclerosis, arterial dissection or congenital arterial anomaly. In view of the presence of two potential causes of stroke such as ET as well as intraventricular mobile clot, this patient was classified as having a stroke of undetermined aetiology as per the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification.⁶

Treatment

After diagnosis of ET, cytoreductive therapy using hydroxyurea at 15 mg/kg/day was initiated along with continuation of antiplatelet medications, statin as well as physiotherapy and rehabilitation.⁴ Following the first echocardiogram, the patient was started on anticoagulation therapy using low-molecular-weight heparin with an initial targeted international normalised ratio (INR) of 2–3. After achievement of which, he was switched on to a novel oral anticoagulant (NOAC, tab dabigatran 110 mg p.o. two times per day).⁷

Outcome and follow-up

Post-thrombolysis day 3, patients’ NIHSS score improved to 7 with motor power of 3/5 and 4/5 in the left upper and lower limbs, respectively. He was discharged on hydroxyurea, dabigatran, aspirin and atorvastatin in haemodynamically stable condition with an mRS of 3. At 3 months of follow-up, his NIHSS improved to 4 along with an mRS of 2. At the same time, his repeat echocardiogram showed complete resolution of left-ventricular clot, so his further anticoagulation treatment was discontinued. At 6 months of follow-up, the patient was neurologically stable with having further clinical improvement in NIHSS to 2 and an mRS of 1 without any new thrombotic episode on antiplatelet and cytoreductive therapy.

Discussion

Treatment of ET-associated AIS has always been focused on secondary prevention of recurrent vascular events using cytoreductive and antiplatelet therapy. The use of thrombolytic therapy for acute management of such patients is sparse with a dearth of data regarding its safety. It may have to do with the significant concern of haemorrhagic complications in ET, which might be caused by proteolysis of large von Willebrand factor (vWF) multimers leading to functional vWF deficiency.^{8 9}

Although patients with ET have a paradoxical predisposition to haemorrhagic as well as thrombotic complications, the pathogenesis remains unclear with multiple contributory factors being implicated. Although elevated soluble P-selectin and soluble CD40 ligand may activate platelets, acquired protein C resistance and reduced protein S might activate the coagulation cascade. Elevated soluble thrombomodulin may activate endothelial cells thereby contributing to hypercoagulability in ET. Bleeding manifestations of ET may be linked to acquired von Willebrand syndrome, which results from overt usage and destruction of vWF multimers in the background of recurrent microvascular thrombosis resulting from extreme thrombocytosis.^8–10 Thrombotic complications in ET are more common than haemorrhagic ones. Risk factors for thrombosis include age >60 years, history of thrombotic episodes, presence of cardiovascular risk factors and JAK2 V617F mutation.¹⁰ Interestingly, our patient also had other risk factors for AIS. Being an elderly man, he had a higher risk of large-vessel atherosclerosis. Moreover, the presence of an intraventricular clot, a potential source for cardioembolic events, along with vascular risk factors like hypertension and diabetes might have contributed to AIS. Addressing these contributory factors assumes importance especially to prevent stroke recurrence. For assessing the integrity of large vessels and related abnormalities such as atherosclerosis, available investigations include carotid and vertebral artery, Doppler, CT or MR angiography as well as conventional angiography. In addition to detection of large-vessel atherosclerosis, these tools may help us search other common as well as uncommon anatomical variants of blood vessels including rete MCA anomalies, a fetal variant of posterior cerebral artery or mechanical occlusion of the vertebral artery, especially in patients with undetermined or other determined etiologies as per TOAST classification.^11–13 In our patient, both carotid artery Doppler and CTA of the brain returned normal, ruling out large-artery atherosclerosis, arterial dissection or congenital arterial anomaly. To detect any paroxysmal event such as AF leading to cardioembolic stroke from the intraventricular clot in our patient, we used a short-duration cardiac rhythm monitoring technique in the form of 24-hour Holter monitoring. The documented new AF/flutter detection yield of which is 3.8%–6.1% in various studies.¹⁴ AF may result in about 15% of all ischaemic strokes and is the most common cause of cardioembolism in patients aged >70 years.^{15 16} But AF can evade conventional monitoring strategies of patients with acute cerebral ischemia, due to its paroxysmal and asymptomatic nature.¹⁷ Several measures used to improve the detection rate of AF include in-hospital monitoring, serial ECG and Holter monitoring and use of external events (or loop recorders) or insertable cardiac monitors (ICMs).¹⁸ AF episodes can be successfully detected via continuous monitoring with ICMs in 41% of implanted patients who had a cryptogenic stroke (CS) after a mean time of 6 months (range=2 days–2 years) from ICM and 8 months (range=1 month–2 years) after CS. Although a set guideline about the duration of monitoring for AF in patients who had a suspected stroke is lacking, use of ICMs is advisable in the evaluation of suitable patients who had a CS for at least 6 months to increase rate of paroxysmal AF detection.¹⁸

ET-related AIS may account for approximately 0.25%–0.5% of all ischaemic strokes.^19–21 Transient ischaemic attack, AIS or cerebral venous thrombosis may be the initial manifestation in approximately 12% of patients with ET.^{19 20} AIS was the initial manifestation of ET in our patient aged 67 years with a positive JAK2 V617F mutation. Even without any significant past or family history of recurrent thrombosis in our case, persistent thrombocytosis and LV clot in absence of structural cardiac disease lead us towards a high degree of suspicion of ET, which was confirmed with subsequent investigations. This illustrates that a high degree of suspicion and a directed investigation may help diagnose ET and prevent thrombotic recurrence, because AIS may be an initial manifestation of ET.

Although data on thrombolysis in AIS related to ET is lacking,³ the use of antiplatelet and/or anticoagulants in combination with a cytoreductive therapy significantly reduces the risk of recurrent thrombotic events in ET.⁴ Our case was safely thrombolysed using tenecteplase and was started on dabigatran along with hydroxyurea. He was doing well at a 6-month follow-up, with no new vascular events reported. The literature is scant on choice and duration of anticoagulation as well as follow-up period of left-ventricular thrombus (LVT)-related AIS. Anticoagulation is not commonly recommended in AIS due to the risk of intracranial bleeding. However, LVT-related AIS especially those with AF have an increased risk of early recurrent embolisation and may benefit from immediate anticoagulation. Anticoagulant therapy in such patients may prevent embolic complications as well as aid in thrombus resolution. Non-randomised trials have established the efficacy and safety of vitamin K antagonists including warfarin, with a target INR range of 2–3. Although NOACs can be used with prefixed dosing and do not require regular monitoring, data on their use to treat LVT are limited. Although the American College of Cardiology Foundation/American Heart Association recommendations do not specify a duration of anticoagulation in LVT, the American College of Chest Physicians recommends anticoagulation for 3 months and the European College of Cardiology guidelines suggest 6 months of anticoagulation.⁷ A recommendation on follow-up duration for LVT is also lacking. It is advisable to repeat an echocardiography imaging of the left ventricle every 3 months until the resolution of the LVT by adequate anticoagulation therapy.²²

Thus, successful thrombolysis in our case provides preliminary evidence of the safety of intravenous thrombolytic therapy in ET-related AIS, even in the presence of extreme thrombosis and elevated leucocyte count, predictors of haemorrhagic complication.

Learning points.

• Acute ischaemic stroke (AIS) may be an initial manifestation of essential thrombocythemia (ET), so a high index of suspicion in an appropriate case is important for its timely diagnosis and management.

• Our case highlights the possible safety of thrombolysis using tenecteplase in ET-related AIS.

• The use of antiplatelet and/or anticoagulants in combination with a cytoreductive therapy significantly reduces the risk of recurrent thrombotic events in ET.

• Cardiovascular risk factors including atrial fibrillation and anatomical variations in cerebral circulation must be ruled out even in patients with predisposing conditions such as ET.