Home Intravenous Heparin Therapy via a Central Venous Port for Recurrent Cancer-associated Stroke Requiring Repeat Mechanical Thrombectomy

Abstract

Cancer-associated stroke (CAS) presents significant challenges regarding secondary prevention. A 48-year-old woman with pancreatic cancer experienced two episodes of large-vessel occlusion stroke was treated by mechanical thrombectomy. Subcutaneous heparin was discontinued owing to skin reactions, and recurrence occurred despite the use of a direct oral anticoagulant. As an alternative, intravenous heparin was initiated at home via a chemotherapy port, using a portable infusion pump. This individualized approach was implemented without any major complications, and it may represent a practical option for patients with CAS who are either intolerant or refractory to conventional therapies.

Introduction

Cancer-associated stroke (CAS) is a serious complication in cancer patients and it is characterized by a high risk of recurrence, a poor prognosis, and occasional large-vessel occlusion (LVO) (1-3). Heparin is used empirically for secondary prevention, but long-term subcutaneous administration is often limited by poor tolerability and adherence (4-6). Though direct oral anticoagulants (DOACs) offer a convenient alternative, their efficacy in preventing CAS is likely inadequate (7,8). These limitations underscore the unmet need for effective, well-tolerated, and patient-centered long-term anticoagulation strategies for CAS. In this context, we herein report a unique case in which personalized anticoagulation approach-home intravenous heparin administered via a central venous port (CV port) was explored as a novel strategy aimed at maintaining stroke prevention, and ensuring the continuity of cancer treatment, and supporting the patient's quality of life (QOL).

Case Report

A 48-year-old woman with no significant medical history-including no smoking, alcohol use, or conventional vascular risk factors such as hypertension, diabetes mellitus, dyslipidemia, or cardiac disease - presented with acute neurological deficits. Approximately one week prior to admission, she experienced general malaise. The day before admission, she visited an orthopedic clinic with complaints of numbness in her right upper arm. On the day of admission, she was found confused after a minor car accident at her residence and was transported to the hospital by ambulance. On arrival at the emergency department, she was somnolent but arousable. Her vital signs were: blood pressure 112/89 mmHg, heart rate 88 bpm, and body temperature 36.7°C. Electrocardiography showed a sinus rhythm. A neurological examination of her cranial nerves was unremarkable. She exhibited global aphasia and incomplete right-sided hemiparesis. Her National Institutes of Health Stroke Scale score was 16, indicating a moderate to severe stroke. Head computed tomography (CT) showed early ischemic changes in the left frontal lobe. Subsequent magnetic resonance angiography (MRA) demonstrated occlusion of the left accessory middle cerebral artery (MCA), an anatomical variant of the MCA. Diffusion-weighted magnetic resonance imaging (MRI) (DWI) revealed a moderate size infarct in the left frontal lobe, along with multiple small infarcts in the right cerebellum and right cerebral hemisphere - findings consistent with a “three-territory sign,” suggesting CAS (Fig. 1). Following intravenous thrombolysis with alteplase (0.6 mg/kg) and mechanical thrombectomy (MT), her neurological symptoms improved dramatically.

Figure 1.

Initial mechanical thrombectomy for ischemic stroke with a three-territory sign: imaging and procedure. (A) Diffusion-weighted imaging (DWI) on admission shows a moderately sized ischemic lesion in the left middle cerebral artery (MCA) territory, along with multiple scattered lesions in both cerebral hemispheres and the right cerebellum, consistent with a three-territory sign (arrowheads). (B) MRA shows occlusion of the left accessory MCA (arrow). (C, D) Initial recanalization is attempted using a SOFIA 5Fr aspiration catheter (MicroVention, Aliso Viejo, USA) for contact aspiration. (E) A small thrombus is retrieved, but with incomplete initial recanalization. (F, G) A second pass with the catheter advanced slightly more distally resulted in complete recanalization.

A comprehensive evaluation of the stroke etiology was performed. Laboratory tests showed an elevated white blood cell count (12,300 /μL), C-reactive protein (8.4 mg/dL), lactate dehydrogenase (LDH: 540 U/L), and D-dimer (6.3 μg/mL). The N-terminal pro-B-type natriuretic peptide (NT-proBNP) level was mildly elevated (465 pg/mL). A quantitative coronavirus disease 2019 (COVID-19) antigen was negative. Her blood culture results were negative. Transthoracic echocardiography revealed no structural abnormalities or cardiac vegetation. Continuous ECG monitoring for one week did not detect atrial fibrillation. Lower extremity venous ultrasonography revealed no evidence of deep vein thrombosis. A histopathological examination of the retrieved thrombus revealed a predominantly platelet-rich composition (Fig. 2). Contrast-enhanced CT revealed a mass in the pancreatic body with multiple liver metastases (Fig. 3). Serum tumor markers were markedly elevated (CEA 15 ng/mL and DUPAN-2＞1,600 U/mL). The diagnosis of pancreatic adenocarcinoma was confirmed by endoscopic ultrasound-guided fine-needle aspiration, and according to the Union for International Cancer Control (UICC) classification, the cancer was stage IV due to liver metastases. Based on these findings, CAS secondary to pancreatic adenocarcinoma was diagnosed. Given that advanced pancreatic cancer was clearly the cause of the stroke, transesophageal echocardiography was not pursued.

Figure 2.

Macroscopic and histopathological findings of the retrieved thrombus. (A) The retrieved thrombus appeared to be white, which is typical of CAS. (B) Hematoxylin and Eosin staining (×100) showed a platelet-rich thrombus.

Figure 3.

Contrast-enhanced abdominal CT. (A) Pancreatic tumor (arrow). (B) Liver metastases (arrowheads, UICC Stage IV).

Following her initial neurological recovery, the patient was discharged, but she was subsequently re-admitted for the initiation of systemic chemotherapy. The first-line regimen was gemcitabine plus nab-paclitaxel (GEM+nab-PTX). During hospitalization, the patient was treated with continuous intravenous unfractionated heparin (10,000-20,000 units/day). At discharge, anticoagulation therapy was switched to subcutaneous heparin (5,000 units, twice daily). However, this regimen was discontinued due to severe injection site pain and skin reactions characterized by a clear demarcation, swelling, warmth, and itching, followed by desquamation and post-inflammatory hyperpigmentation. A dermatologist advised that the continued daily subcutaneous heparin injections was not feasible because of these reactions. Oral edoxaban (60 mg/day), a DOAC, was subsequently administered.

Despite being on edoxaban, the patient experienced a recurrent ischemic stroke eight months after the initial event (six months after switching to a DOAC). Head CT showed no abnormality, while DWI and MRA confirmed a new infarct associated with occlusion of the distal left internal carotid artery (Fig. 4). Thrombolysis was not performed because of the bleeding risk associated with pancreatic cancer and ongoing DOAC therapy. The National Institutes of Health Stroke Scale (NIHSS) score at the time of the second stroke was 8. A second MT was performed, leading to complete neurological recovery. However, this event underscores the ongoing challenge of preventing CAS recurrence. Following approval from the institutional ethics committee, low-molecular-weight heparin (LMWH) was initiated immediately after recurrence, but skin reactions similar to those caused by unfractionated heparin led to its discontinuation. Given her intolerance to subcutaneous heparin and the failure of DOAC, a more personalized and tolerable regimen for this case was therefore needed. After approval from the second ethics committee, home intravenous heparin therapy via a portable infusion pump (Terufusion Syringe Pump TE-362; Terumo, Tokyo, Japan; Fig. 5) was started using the CV port originally implanted for chemotherapy, simultaneously with the initiation of second-line chemotherapy with nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV). This device is compact (189 mm in length), lightweight (300 g), and compatible with 10-mL syringes, allowing it to be easily carried in a bag with minimal disruption to daily life. The new regimen involved the overnight infusion of intravenous heparin (e.g., 10,000 units per night) via the CV port, combined with daytime oral aspirin, to balance effective anticoagulation with a reduced treatment burden. As the CV port was primarily reserved for chemotherapy, heparin infusion was therefore occasionally unavailable. During this period, subcutaneous LMWH was administered temporarily. Owing to the short duration of subcutaneous use, only mild skin reactions occurred, and treatment adherence was maintained.

Figure 4.

Second mechanical thrombectomy for recurrent ischemic stroke: imaging and procedure. (A) DWI showing small, faint ischemic lesions in the left cerebral hemisphere (arrowhead). (B) MRA shows occlusion of the distal left internal carotid artery (arrow). (C-E) For the occluded site of the left internal carotid artery, an EmboTrap Revascularization Device (CERENOVUS, Johnson & Johnson Medical Devices, Irvine, USA) is deployed distal to the thrombus. A React 71 catheter (Medtronic, Irvine, USA) is advanced to the proximal end of the thrombus. The EmboTrap is then retrieved into the React 71 catheter, followed by aspiration through the catheter for 30 seconds. This maneuver results in complete recanalization.

Figure 5.

Portable infusion pump used for home intravenous heparin therapy. A photograph of the syringe pump (Terufusion Syringe Pump TE-362; Terumo, Tokyo, Japan) used by the patient. This compact and lightweight device (189 mm in length, 300 g) was connected to an existing CV port to deliver overnight intravenous unfractionated heparin at home.

The patient visited our hospital approximately every 1-2 weeks, primarily for chemotherapy administration and CV port management. Blood tests - including activated partial thromboplastin time (APTT) and D-dimer - were routinely performed. During hospitalization for cholangitis (the third admission after the recurrent stroke), D-dimer levels showed a transient elevation, likely reflecting infection and inflammation (Fig. 6). At that time, a very small thrombus around the CV port was suspected. Anticoagulation, usually administered only at night, was temporarily switched to continuous intravenous heparin at a dose of 10,000-15,000 units/day, and oral aspirin was replaced with edoxaban. The patient was admitted for a fourth hospitalization to initiate third-line chemotherapy with modified FOLFIRINOX, prompted by the progression of liver metastases. Because an enlargement of the thrombus around the CV port was suspected, heparin was again temporarily administered as continuous infusion at a dose of 15,000 units/day. Brain MRI during this admission revealed two small punctate high-intensity lesions in both cerebral hemispheres on DWI, which were clinically asymptomatic. Throughout the follow-up period after the initiation of home intravenous heparin therapy, no symptomatic stroke recurrence was observed. The patient maintained her activities of daily living until shortly before death. She experienced a sudden clinical deterioration due to cholangitis, sepsis, and multi-organ failure associated with progressive pancreatic cancer, and died unexpectedly approximately six months after the recurrent stroke.

Figure 6.

Trends in APTT and D-dimer levels. Solid and dotted lines represent the APTT and D-dimer levels, respectively. Key clinical events, including chemotherapy, hospitalization, and initiation of aspirin or edoxaban, are indicated in the timeline. APTT: activated partial thromboplastin time, GEM+nab-PTX: gemcitabine plus nab-paclitaxel, nal-IRI plus 5-FU/LV: nanoliposomal irinotecan plus 5-fluorouracil and leucovorin, mFOLFIRINOX: modified FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin)

Discussion

This case highlights the clinical challenges associated with secondary prevention in CAS patients. Subcutaneous heparin was initially used in the present patient, but it had to be discontinued owing to poor tolerability. Although she was subsequently switched to a DOAC, the patient experienced a recurrent ischemic stroke caused by LVO, requiring a second MT. Several previously reported CAS cases requiring multiple MTs experienced recurrence despite the use of standard anticoagulants such as warfarin, DOACs, or LMWH (9-11). In particular, some reports describe recurrence during DOAC therapy, as in the present case (11,12). In one case, it was also noted that patients refused subcutaneous LMWH (13). Previous studies have shown that patients with CAS generally have a poor prognosis, with the median overall survival reported to be only 84 days following stroke onset and a high risk of recurrent thromboembolism (approximately 34%) (14). Pancreatic cancer appears to be particularly aggressive; one study reported that approximately 85% of patients with distant metastases died within six months (15). These findings reflect the difficulty of maintaining effective and sustained anticoagulation in CAS and underscore the ongoing need for more effective, better-tolerated, and individualized treatment strategies.

It is important to note that most clinical evidence for anticoagulation in cancer-associated thrombosis is based on studies of venous thromboembolism (VTE) (16,17). In this setting, DOACs have shown non-inferiority to LMWH, making them a recognized treatment option (18). However, their role in arterial thrombotic events such as CAS remains unestablished and it appears to be insufficient due to limited supporting evidence, reported treatment failures, and the complex, heterogeneous mechanisms underlying CAS (19). Heparin, although primarily studied in the context of VTE, has been reported to show potential benefits in arterial thrombosis, including CAS (6,7). As a result, heparin is often preferred over DOACs for patients with CAS in current clinical practice (16). Despite these benefits, long-term use of subcutaneous heparin presents practical challenges. Injection site pain, skin reactions, and the need for daily injections often lead to poor adherence (5,6). In this context, a novel strategy to deliver unfractionated heparin via continuous intravenous infusion at home using a portable infusion pump connected to an existing CV port initially placed for chemotherapy was adopted in the present case. This method provides stable anticoagulation while minimizing treatment burden. This strategy avoids the discomfort of subcutaneous injections and enables flexible, precisely titrated dosing, which is especially important, given the dynamic thrombotic risk associated with malignancy.

However, this approach is not without limitations. The need for the daily operation of the pump and syringe can be burdensome, particularly for elderly patients, those with physical limitations, or those without dedicated caregivers. Furthermore, because intravenous heparin was only administered overnight, there is a theoretical possibility of increased thrombotic risk during the daytime. In the present case, antiplatelet therapy with daytime oral aspirin was initially combined with overnight intravenous heparin. Nevertheless, a small thrombus around the CV port still developed, thus suggesting the limitations of this treatment strategy in preventing device-associated thrombosis. The addition of aspirin to the regimen, which aimed to improve its efficacy, also increased the risk of bleeding. This decision was based on the presumed limited efficacy of overnight intravenous heparin and the presence of a platelet-rich thrombus in the present patient, which is a commonly observed feature of CAS (3). Although clinical evidence supporting the use of antiplatelet agents for the prevention of CAS remains limited, some small-scale or exploratory studies have suggested potential benefits (5,20). As a result, antiplatelet agents are now being considered as potential alternatives or additions in future treatment strategies (1). As this strategy has not yet been officially approved, further studies are needed to establish its long-term safety, efficacy, and cost-effectiveness in broader patient populations.

Conclusion

This case report presents a novel patient-centered approach to anticoagulation therapy for CAS using long-term intravenous heparin via a CV port. This strategy offers a feasible alternative when conventional subcutaneous or oral options are limited, potentially improving the quality of life and enabling uninterrupted cancer treatment. Although not yet established as a standard practice, it could be a valuable option for managing patients with CAS.

Author’s disclosure of potential Conflicts of Interest (COI).

Dr. Shigeru Fujimoto has received lecture fees from Daiichi Sankyo, Pfizer, and Bristol Myers Squibb, and research funding from Daiichi Sankyo.