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Ischemic stroke
Original research
Intravenous heparin for the treatment of intraluminal thrombus in patients with acute ischemic stroke: a case series
  1. Maxim Mokin1,2,
  2. Tareq Kass-Hout1,2,
  3. Omar Kass-Hout1,2,
  4. Vladan Radovic1,2,
  5. Adnan H Siddiqui3,4,5,6,
  6. Elad I Levy3,4,5,6,
  7. Kenneth V Snyder3,5,6
  1. 1Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA
  2. 2Department of Neurology, Millard Fillmore Gates Hospital, Kaleida Health, Buffalo, New York, USA
  3. 3Department of Neurosurgery, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA
  4. 4Department of Radiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA
  5. 5Toshiba Stroke Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA
  6. 6Department of Neurosurgery, Millard Fillmore Gates Hospital, Kaleida Health, Buffalo, New York, USA
  1. Correspondence to Dr Kenneth V Snyder, University at Buffalo Neurosurgery, 100 High Street, Buffalo NY 14203, USA; ksnyder{at}ubns.com

Abstract

Background and Objectives Current American Stroke Association/American Heart Association recommendations on the management of acute ischemic stroke do not recommend the early use of heparin because of an increased risk of bleeding complications. However, for select patients, such as those with strokes associated with non-occlusive intraluminal thrombus, intravenous heparin might prove to be beneficial.

Methods A retrospective analysis of acute ischemic stroke cases associated with non-occlusive intraluminal thrombus of intracranial and extracranial arteries in the corresponding vascular territories was conducted to identify patients in whom treatment with intravenous heparin resulted in near-complete or complete lysis of the thrombus. Imaging findings from CT perfusion and angiography, MRI, and/or digital subtraction angiography were used to describe the location of intraluminal thrombus immediately before and after treatment with intravenous heparin.

Results 18 patients with nonocclusive intraluminal thrombus confirmed by CT angiography (CTA) received treatment with intravenous heparin alone (median duration 3.5 days; range 1–8 days). The median National Institutes of Health stroke scale score was 2.5 (range 0–15) on admission and 1 (range 0–9) at discharge. Nine patients had complete lysis, and nine patients had partial lysis of the thrombus with improved flow distal to the location of the thrombus. None of the patients developed intracranial hemorrhage.

Conclusion For strokes associated with intraluminal thrombus, intravenous heparin might prove to be an effective treatment strategy. Further studies are necessary to evaluate the efficacy and safety of treatment with intravenous heparin in those patients.

  • Acute ischemic stroke
  • aneurysm
  • artery
  • arteriovenous malformation
  • brain
  • catheter
  • cranial nerve
  • CT perfusion
  • intravenous heparin
  • intraluminal thrombus
  • MR perfusion
  • non-occlusive
  • spine
  • subarachnoid
  • subdural
  • thrombectomy
  • tumor

https://doi.org/10.1136/neurintsurg-2011-010134

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    Since the discovery of heparin nearly a century ago by McLean,1 this anticoagulant agent has been widely used in clinical practice. Thrombus formation can be triggered by either extrinsic pathway reactions (vessel injury causing release of subendothelial tissue factor and binding to factor VII) or intrinsic pathway reactions (through contact activation of the plasma protease factor XII). Both pathways converge, leading to fibrin formation. Heparin potentiates the activity of antithrombin, which further causes inactivation of factors II, IX, X, XI and XII, thus preventing fibrin formation.2 The use of intravenous heparin in the setting of acute ischemic stroke remains a controversial topic.3 Several studies have concluded that there is no evidence to recommend the use of heparin in acute stroke, given the higher risk of bleeding complications associated with its use.4 ,5 At the same time, some authors advocate that in a certain population of patients, such as patients with strokes from arterial dissection or cardioembolic strokes, intravenous heparin might prove to be beneficial.6 ,7 Case reports indicate that treatment with intravenous heparin could be considered an option in cases of ischemic stroke associated with mobile intraluminal thrombus.8 ,9 Patients with non-occlusive thrombus can demonstrate spontaneous early improvement of neurological deficits but are at risk of recurrent symptoms associated with persistent neurological deficits.10 Here, we report a series of 18 patients with acute ischemic stroke who were found to have non-occlusive intraluminal thrombus and were treated with intravenous heparin, resulting in partial or complete resolution of the thrombus. We also discuss the current literature and controversy regarding the use of intravenous heparin in the setting of acute ischemic stroke.

    Methods

    The study was approved by our local institutional review board. We performed a retrospective analysis of the prospectively collected neurovascular database at our hospital to identify cases of acute ischemic stroke associated with non-occlusive intraluminal thrombus of intracranial and extracranial arteries in the corresponding vascular territories. Then, we selected patients who were treated only with intravenous heparin, with or without an antiplatelet agent. Patients who received intravenous or intra-arterial thrombolysis with tissue plasminogen activator (tPA) or any endovascular therapy for acute stroke were excluded. Study patients underwent multimodal CT imaging as a part of the initial stroke evaluation, consisting of a non-contrast brain CT scan, CT angiography (CTA), and whole-brain CT perfusion study, as described previously,11 using a Toshiba Aquilion 320-detector-row CT scanner (Toshiba America Medical Systems, Tustin, California, USA), with the exception of two patients in whom the CT perfusion study was performed using a 64-detector-row CT scanner (Toshiba America Medical Systems). Brain MRI was obtained on admission to characterize further stroke size and location. The presence of non-occlusive intraluminal thrombus in the corresponding vascular territory was confirmed by CTA, on the basis of previously published neuroradiological criteria.10 Briefly, these lesions were differentiated from occlusive thrombus or atherosclerotic disease by the presence of angiographic evidence of residual lumen located within large vessels (internal carotid artery (ICA), proximal middle cerebral artery (MCA), basilar or vertebral artery), the absence of vessel wall calcifications, and well-defined thrombus margins. The intravenous heparin infusion protocol was started at the emergency department once the lesion was confirmed on imaging and the decision was made not to do immediate diagnostic angiography. Patients with a high risk of hemorrhagic transformation, such as those with MCA or posterior cerebral artery territory strokes with CT perfusion demonstrating volume loss greater than 50% of the perfusion deficit area, did not receive systemic anticoagulation acutely. The average time frame from presentation to infusion was 7 h, 52 min. According to the protocol, the initial heparin infusion was 12 units/kg per hour and was further adjusted to maintain a partial thromboplastin time (PTT) range of 50–70 s, with PTT values obtained every 6 h. A follow-up CTA or a conventional digital subtraction angiogram (DSA) was used to evaluate the degree of lysis of the thrombus. Demographic information, vascular risk factors, clinical description of initial stroke symptoms, duration of treatment with intravenous heparin, and long-term treatment plan at the time of discharge were obtained from paper and electronic records.

    Results

    We identified a total of 18 patients (age range 50–86 years; mean 68 years) with a diagnosis of acute ischemic stroke who met our study criteria. Demographic data, distribution of vascular risk factors, and median National Institutes of Health stroke scale (NIHSS) score upon arrival at the emergency department are listed in table 1. The median NIHSS score on admission was 2.5 (range 0–15). There were 11 patients with the thrombus in the anterior circulation and seven patients with the thrombus in the posterior circulation.

    View this table:
    Table 1

    Demographics, vascular risk factors, and NIHSS scores of patients on admission

    A summary of the clinical presentation, CT perfusion and MRI findings, location of non-occlusive intraluminal thrombi, description of flow limitation distal to the occlusion site, and treatment details for each patient is provided in table 2. The median duration of the intravenous heparin infusion was 3.5 days (range 1–8 days) before a repeat CTA or a conventional DSA was obtained. All patients received an antiplatelet agent and a statin within the first 24 h of admission. On the basis of the results of the repeat CTA or the DSA, nine patients had complete lysis of the thrombus and nine patients had partial lysis of the thrombus with improved flow distal to the location of the thrombus. None of the patients developed intracranial hemorrhage. At discharge, the median NIHSS score was 1 (range 0–9), and the median modified Rankin scale (mRS) was 1 (range 0–5). Long-term outcomes, based on mRS scores, were available for 12 patients, with a median follow-up duration of 3 months. Nine of 12 patients had a favorable outcome (defined as mRS score ≤2) at 3 months. One patient developed significant gastrointestinal bleeding after discharge while being treated with warfarin. This patient was given comfort measures and subsequently died. Below, we present four illustrative cases of strokes with non-occlusive intraluminal thrombus in different vascular territories.

    View this table:
    Table 2

    Summary of clinical and radiographic findings and hospital course

    Illustrative cases

    Basilar artery thrombus

    This patient (whose age was in the early 80s) with a history of hypertension and dyslipidemia woke up in the morning with ataxia, dysarthria, and a left facial droop (NIHSS score 6). Brain MRI showed acute ischemic stroke in the left cerebellar hemisphere (figure 1A). An intravenous heparin infusion was started after an intraluminal thrombus was found on CTA; this thrombus was located in the middle and distal basilar artery segments and was causing near-complete occlusion (figure 1B,C). The following day, the patient's NIHSS score was only 2, and a DSA revealed near-complete thrombus lysis and significantly improved flow (figure 1D,E). The patient had an uneventful hospital course and was discharged home on a combination of oral warfarin anticoagulation, aspirin, and high-dose statin therapy.

    Figure 1
    Figure 1

    Case 1. (A) Diffusion-weighted sequence of a brain MRI study shows hyperintense signal in the left cerebellar hemisphere consistent with acute ischemic stroke. (B) Axial and (C) sagittal views of CT angiogram show intraluminal thrombus in the distal segment of the basilar artery (arrow in each panel). (D) Anteroposterior and (E) lateral views of a conventional digital subtraction angiogram performed 24 h later demonstrate significantly improved flow and near-complete intraluminal thrombus lysis.

    Vertebral artery thrombus

    This patient (whose age was in the early 50s) with a history of hypertension presented with acute-onset confusion that was followed by loss of consciousness. His symptoms rapidly improved, and when he arrived at the emergency room, his only deficit was partial left hemianopia (NIHSS score 1). Brain MRI revealed findings consistent with multiple small bilateral strokes of the posterior circulation (figure 2A). A CTA showed a partially occlusive filling defect in the left vertebral artery indicating the presence of intraluminal thrombus (figure 2B–D). An intravenous heparin infusion was started; a conventional DSA performed the next day revealed almost complete resolution of the thrombus with markedly improved flow through the dominant distal left vertebral artery (figure 2E). Six days later, the patient was changed to a long-term oral anticoagulation regimen of aspirin and warfarin. At the time of discharge, his only symptom was blurred vision on the left side, corresponding to an NIHSS score of 1.

    Figure 2
    Figure 2

    Case 2. (A) Diffusion-weighted MRI consistent with acute ischemic infarction in the left occipital lobe (arrow). (B) CT angiogram shows a partially occlusive filling defect in the left vertebral artery, indicating the presence of intraluminal thrombus (arrow). (C) Axial and coronal (D) higher magnification views of the intraluminal thrombus (arrow in each panel). (E) Follow-up digital subtraction angiogram shows almost complete resolution of the thrombus (arrow) with markedly improved flow through the distal left vertebral artery.

    MCA thrombus

    This patient (whose age was in the mid-80s) with a history of previous stroke, hypertension, and dyslipidemia developed aphasia and a dense right hemiparesis that improved en route to the emergency room (NIHSS score 7 upon arrival). A CT perfusion study revealed a large area of increased time to peak corresponding to the left MCA territory but preserved cerebral blood volume and flow (figure 3A–D). CTA showed intraluminal thrombus in the distal M1 segment of the left MCA with significantly reduced flow distally to the thrombus (figure 3E,F). After 4 days of treatment with heparin, time-to-peak map demonstrated significant improvement of the perfusion deficit and complete resolution of the intraluminal thrombus on CTA (figure 3G–L). The patient's weakness resolved, but he remained aphasic (NIHSS score 6) and was discharged to a rehabilitation facility on aspirin and a statin.

    Figure 3
    Figure 3

    Case 3. (A) CT perfusion study shows preserved cerebral blood volume, with just a small area of decreased volume in the left parietal area from a previous ischemic stroke. (B) There is a large area of increased time-to-peak in the left middle cerebral artery (MCA) territory. (C) Cerebral blood flow and (D) mean transient time maps are preserved. (E) Three-dimensional reconstruction view and (F) coronal view of CT angiography demonstrate intraluminal thrombus in the distal M1 segment of the left MCA (arrow in each panel) is seen on CT angiography. (G) Repeat CT perfusion study demonstrates stable cerebral blood volume and (H) significant improvement of perfusion deficit on time-to-peak maps. (I) Cerebral blood flow and (J) mean transient time perfusion maps are stable. Repeat CT angiography shows complete resolution of intraluminal thrombus (arrow in each panel) with excellent flow, seen on (K) three-dimensional reconstruction and (L) coronal views.

    ICA thrombus

    This patient (whose age was in the early 50s) with a history of smoking, colon cancer, and hypertension presented with the chief symptom of right arm weakness of a fluctuating degree, which started 1 week earlier. Brain MRI findings were consistent with multiple strokes in the left hemisphere, in the ‘water-shed’ territory of the anterior cerebral/middle cerebral arteries (figure 4A). CTA revealed a linear filling defect in the proximal left ICA that was suspicious for a floating intraluminal thrombus (figure 4B,C). An intravenous heparin drip was started, and repeat CTA 7 days later revealed complete thrombus lysis (figure 4D). Because of the high risk of gastrointestinal bleeding due to the diagnosis of colon cancer, the patient was discharged home on an antiplatelet agent instead of long-term anticoagulation with warfarin. The NIHSS score was 1 at discharge.

    Figure 4
    Figure 4

    Case 4. (A) Patchy areas of hyperintense diffusion-weighted signal in the left cerebral hemisphere are seen on the initial brain MRI indicating acute ischemic stroke. (B) Coronal and (C) axial CT angiography views show intraluminal thrombus in the left internal carotid artery suggested by the vessel with lack of central contrast filling (arrows in each panel). By comparison, the left external carotid artery shows complete filling with contrast (arrowhead in panel C). (D) A repeat CT angiogram 7 days later demonstrates complete lysis of the intraluminal thrombus, with the filling defect no longer observed (arrow). The arrowhead indicates the left external carotid artery.

    Discussion

    Treatment of patients with ischemic stroke who are found to have intraluminal thrombus within the corresponding vascular territory remains a controversial topic. In patients who present within the first 3 h (now 4.5 h, subsequent to the publication of the results of the third European Cooperative Acute Stroke Study (ECASS III))12 of symptom onset, intravenous thrombolysis with tPA should be considered unless contraindicated on the basis of the American Heart Association/American Stroke Association exclusion criteria.4 In acute stroke, occlusions of larger diameter arteries respond poorly to intravenous thrombolysis, which calls to question the efficacy and safety of this treatment approach in such a group of patients.13 In one study, the rate of complete recanalization of proximal MCA occlusion was found to be 35% and the rate of complete recanalization of ICA occlusion was only 10% following intravenous thrombolysis.14 Endovascular therapy for acute stroke shows high recanalization rates for large vessel occlusions, including in patients in whom treatment with intravenous thrombolysis is contraindicated or has failed.15 However, there is a higher risk of distal vessel occlusion in the setting of intraluminal thrombus as a result of clot manipulation, which should be considered in cases when distal protection cannot easily be achieved. Current American Stroke Association/American Heart Association recommendations on the early management of acute ischemic stroke do not recommend the early use of heparin due to the increased risk of bleeding complications, including hemorrhagic transformation of ischemic stroke, especially in cases when the stroke is large.4 This statement also applies to cases of cardioembolic strokes, which often involve the occlusion of large diameter intracranial or extracranial arteries. The guidelines, however, do acknowledge that there are currently insufficient data on the role of anticoagulation in high-risk groups, such as patients with intra-arterial thrombus. In cardiology, the 2007 updated guidelines recommend the use of heparin products in patients with ST-elevated myocardial infarction who are not undergoing acute reperfusion therapy.16 Interventional cardiology and endovascular neurosurgery share many common principles when it comes to reperfusion therapy, and careful analysis of data that come from cardiology trials might prove to be helpful in designing more effective treatment strategies for acute ischemic stroke.

    In our clinical practice, we utilize the following principles, which we believe can substantially reduce the risk of hemorrhagic complications associated with intravenous heparin use. First, we typically do not utilize intravenous heparin in stroke cases when early ischemic changes (ie, hypodensity on a brain CT scan) occupy more than one-third of the MCA territory, because such strokes are at higher risk of undergoing spontaneous hemorrhagic transformation, and the addition of intravenous heparin might further increase this process. Second, all patients who receive treatment with intravenous heparin require admission to the intensive care unit for surveillance. Close blood pressure monitoring is extremely important; our goal of systolic blood pressure is typically below 160 mm Hg. Third, our heparin ‘stroke protocol’ requires a very narrow range of PTT (50–70 s) and does not include a bolus loading dose, because higher doses of heparin are known to increase the risk of hemorrhagic transformation. Fourth, in cases when there are additional risk factors of hemorrhagic complications, such as poorly controlled blood pressure or hyperglycemia, we often obtain a repeat brain CT scan 24 h after the initiation of the heparin protocol to exclude early hemorrhagic transformation.

    On the basis of reports in the literature, the frequency of strokes associated with non-occlusive intraluminal thrombus is relatively low, ranging from 1% to 3%.10 ,17 The actual number might be higher because angiographic studies of intracranial and extracranial vessels are not routinely performed in every patient with acute stroke, and carotid Doppler ultrasound studies might not be adequate to detect smaller thrombi of the ICA. Clinically, patients often show early improvement of neurological status; however, the risk of recurrent stroke symptoms and poor functional outcome is high, especially in cases when large vessels are affected.18 Puetz et al 10 identified 23 patients with non-occlusive intracranial thrombus in the setting of acute ischemic stroke. Although 19 patients demonstrated rapid improvement of symptoms based on 24-h and discharge NIHSS scores, four patients (17%) with non-occlusive thrombus located in the ICA or proximal MCA developed persistent neurological deficits and were dependent at discharge (three patients had an mRS score of 4; one had an mRS score of 5 at discharge). No information about long-term functional status was provided in the study to determine whether any of the patients with rapidly improving symptoms later developed recurrent neurological deficits.

    The mechanisms underlying early neurological improvement in patients with partially occlusive thrombus are not well defined. Toni et al 19 proposed that rapid improvement of neurological deficits in the setting of large artery non-occlusive thrombus could be secondary to partial spontaneous recanalization of previously occluded vessels. In a study of acute ischemic stroke patients who underwent serial transcranial Doppler studies, they found that early and even delayed (after 24–48 h of stroke onset) recanalization in patients with MCA occlusion was associated with improvement in neurological examination.19 However, the limited ability of transcranial Doppler to characterize the degree of intracranial arterial occlusion should be considered when interpreting the results of that study. Although direct evidence is lacking, partial recanalization of previously occluded vessels could potentially explain spontaneous rapidly improving symptoms in patients 1, 7, 8, 13, and 17 from our case series. Patients with strokes with rapidly improving symptoms were recently shown to be at high risk of poor short-term outcomes. In a large nationwide study of patients with acute ischemic stroke who were not given systemic thrombolysis with tPA because of rapidly improving stroke symptoms, approximately one-third of patients were not able to ambulate without assistance at hospital discharge (which corresponds to an mRS score of >3).20 The study also included patients with baseline mild stroke symptoms and, although information about ischemic stroke type or mechanism was not collected, it provides evidence that comprehensive diagnostic evaluation of patients with strokes with rapid improvement is necessary to identify those at risk of subsequent clinical deterioration.

    Several case reports demonstrate that non-occlusive intraluminal thrombus in patients with stroke can be successfully treated with intravenous heparin.8 ,9 ,21 In one series of patients with stroke and transient ischemic attack associated with intraluminal non-occlusive thrombus, intravenous heparin was used in 12 patients.10 Of those, nine patients had a follow-up CTA or magnetic resonance angiography to evaluate response to treatment; four patients showed significant improvement in flow with clot lysis. In another study focused on surgical treatment of intraluminal thrombus in patients with stroke and transient ischemic attacks, heparin was used as a part of the initial medical management strategy before surgery.17 Eight patients had repeat angiography; seven patients showed partial or complete resolution of the thrombus.

    To our knowledge, the case series we present in this paper has the largest number of patients with successful treatment of intraluminal thrombus using intravenous heparin. The question arises as to how long the treatment with intravenous heparin should be continued for cases of intraluminal thrombus. The average duration of heparin treatment in our series of patients was 3 days. However, three patients showed evidence of clot lysis after the first 24 h of treatment. Results from other studies also confirm that heparin-treated patients can have complete thrombus lysis after the first 20–24 h, although on average, the treatment is continued for a period of 4–8 days before a repeat angiographic study is performed.9 ,10

    Several major prospective trials in ischemic stroke (including the International Stroke Trial,22 and the Trial of ORG 10172 in Acute Stroke Treatment)23 showed that the risk of symptomatic intracerebral hemorrhage is higher in patients who received treatment with heparin products, in comparison with the placebo arm. The risk of hemorrhagic complications was dose dependent; higher doses of heparins were associated with higher rates of symptomatic intracerebral hemorrhage. Critics of the International Stroke Trial, however, argue that the lack of proper monitoring of activated PTT or a baseline brain CT scan evaluation, as well as the concurrent use of aspirin in some patients, might have contributed to higher complication rates.7

    In conclusion, at present, there is no strong evidence either to support or oppose the use of intravenous heparin in selective groups of patient with ischemic stroke, such as patients with non-occlusive intraluminal thrombus. In our case series, treatment with intravenous heparin resulted in complete thrombus lysis in 50% of patients, with only minimal complications. Further studies are necessary to evaluate the efficacy and safety of treatment with intravenous heparin in those patients.

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    Footnotes

    • Competing interests None.

    • Ethics approval The institutional review board at the University at Buffalo, State University of New York (Buffalo, New York, USA) approved this study (HSIRB project no NEU3300611E).

    • Provenance and peer review Not commissioned; externally peer reviewed.