Neuroimaging findings of hypercoagulable states: A case report on polycythemia vera (PV)

Introduction

Hypercoagulable states such as myelodysplastic syndromes including Polycythemia Vera (PV) are not uncommon causes of ischemic infarctions in young population. ¹ Patients with hypercoagulable states such as PV are predisposed to a higher risk of thromboembolic complications including deep venous thrombosis, myocardial infarction, retinal occlusion, venous occlusions, and ischemic infarcts.^2,3 Neurological complications including ischemic stroke and dural venous sinus thrombosis can be seen in 50–70% of the patients with PV and can lead to death in up to 8% of patients.^2,3 However, due to the low prevalence and unfamiliarity of the neurological manifestations and the radiological findings, these disorders often go undetected even in patients with recurrent ischemic cerebrovascular events. High index of clinical suspicion and awareness of neurological manifestations of myeloproliferative disorders are important for early detection and to lower the morbidity from neurological complications. There are a limited number of published studies demonstrating neurological manifestations associated with hypercoagulable states, specifically on PV. Hyperdense dural venous sinuses and vasculature of the brain including the Circle of Willis can be associated with hypercoagulable states such as PV. ⁴ Initial imaging workup of stroke (CT and MRI) can play a major role in the early detection of previously unknown PV in these patients.

Here, we present a case of previously unknown PV in a patient who presented with stroke like symptoms. Initial diagnostic imaging workup guided the primary team in our case to promptly investigate the primary and secondary causes of ischemic stroke including PV.

Case report

A 58-year-old Caucasian male with no significant prior medical history presented to emergency as code stroke with slurred speech, right sided weakness, and right facial droop since he woke up in the morning. Patient had no prior history of neurological symptoms. Social history was positive for alcoholism and tobacco smoking. Per EMS, his initial blood sugar level was 114 mg/dl. Upon arrival to ED, physical examination showed right upper extremity weakness (0/5), right sided facial drop, and dysarthria. His GCS was 15. His oxygen saturation (SaO 2) was 100% with 4 L of oxygen.

Stroke protocol non-contrast CT head revealed no acute intracranial hemorrhage, ischemic infarction, a space-occupying lesion or edema. However, dural venous sinuses including transverse sinus, straight sinus, superior sagittal sinus, and confluence of the sinuses were hyperdense (Figure 1). The Circle of Willis also appeared hyperdense (Figure 1(b)). CT attenuation was ranging from 69 to 72 HU at the confluence of the sinuses (Figure 1(b)). Of note, patient did not receive IV contrast prior to the scan. A subsequent CT angiogram and venogram demonstrated no evidence of large arterial occlusions. All dural venous sinus were well opacified without evidence of thrombosis (Figure 2). Subsequent brain MRI demonstrated restricted diffusion in the anterior body of left caudate, tail of caudate, entire left putamen and the left frontal corona radiata, consistent with acute ischemic infarctions (Figure 3). There were foci of acute small infarctions of the right cerebellar hemisphere (Figure 3(d)). There were metachronous subacute infarction of the cortex and subcortical white matter of the left frontal lobe (not shown). There were multiple additional synchronous ischemic infarctions in the subcortical white matter of the right posterior temporal and parietal lobes as well as in the bilateral subcortical centrum semiovale in the frontal and parietal lobes (Figure 3). There was no evidence of hemorrhagic transformation associated with these infarctions. Multiterritorial distribution of these infarctions could suggest embolic mechanism with source of emboli below the aortic arch.

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Figure 1.

Axial non-enhanced CT images of the head showing abnormal hyperattenuation of the dural venous sinuses. Confluence of the superior and transverse sinuses. Inset showing measurement of dural sinus attenuation at the confluence (∼70 HU) (a and b). Hyperdense Circle of Willis (b) and superior sagittal and straight sinus (c).

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Figure 2.

Axial images of CT venogram showing normal opacification of the dural venous sinuses. Normal attenuation measuring attenuation at the confluence of the enhanced superior and transverse sinuses (a), superior sagittal sinus (b), right transvers sinus and left transverse sinus (c).

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Figure 3.

Diffusion weighted images (DWI) images of the brain MRI showing restricted diffusion in the left putamen, bilateral subcortical white matter at parietal lobes and right cerebellum (a through d).

Additional laboratory investigations revealed hemoglobin of 21.1 g/dL with hematocrit of 64% (normal 39.0–50.0%). Serum erythropoietin level was low at 1.7 mU/mL (laboratory reference value 2.6–18.5 mIU/mL). JAK2 V617F and JAK2 exon 12 and CALR mutations were negative. Secondary causes of polycythemia were ruled out. There was no splenomegaly on ultrasound. However, a bone marrow biopsy revealed hypercellularity with panmyelosis. A transesohageal echocardiogram (TEE) showed no evidence of PFO or concern for cardiac cause of stroke.

Given hypercellularity with panmyelosis on bone marrow, Hgb >16.5 g/dL, and low serum erythropoietin level, he met the WHO diagnostic criteria 2016 (Table 1) for polycythemia vera. ⁵ Hematology care was established for follow-up and further management.

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Table 1.

WHO criteria for the diagnosis of Polycythemia Vera (PV); Major criteria—(1) Hgb >165 g/L (men); >160 g/L (women) OR HCT >49% (men) and HCT >48% (women) OR increased red cell mass(RCM)*, (2) BM hypercellular for age with trilineage myeloproliferation, (3) Presence of JAK2 V617 F or JAK2 exon 12 mutation. Minor criteria—1) Subnormal serum erythropoietin level. * More than 25% above mean predicted value.

WHO criteria for the diagnosis of Polycythemia Vera (PV)
Major criteria	1) Hgb >165 g/L (men); >160 g/L (women) OR HCT >49% (men) and HCT >48% (women) OR increased red cell mass(RCM)*
	2) Bone marrow hypercellular for age with trilineage myeloproliferation
	3) Presence of JAK2 V617F or JAK2 exon 12 mutation
Minor criteria	1) Subnormal serum erythropoietin level

Discussion

PV is the most common form of myeloproliferative disorder wherein red blood cell (RBC) mass and hematocrit is elevated due to unregulated proliferation of myeloid cells. ⁶ About 7–10% of patients with hypercoagulable states including myeloproliferative disorders develop neurological manifestations secondary to vaso-occlusion during the disease which is a significant cause of morbidity and mortality in this patient population.^1,2,6,7 Identification of neurological manifestations on initial neuroimaging in conjugation with clinical information can guide the clinician towards timely diagnosis and limit morbidity and mortality in previously unknown cases of hematological disorders. For these reasons, it is important that radiologists be familiar with imaging findings of hypercoagulable states on CT and MRI as well as understand the spectrum of vascular occlusions and risk factors.

PV is a unique cause of ischemic stroke. About 15% of patients with PV present initially with stroke or stroke like symptoms.^6,7 There are only a few published case studies demonstrating neurological manifestations associated with hypercoagulable states, specifically on PV. Hyperdense dural venous sinuses and vasculature of the brain including the Circle of Willis can be associated with hypercoagulable states.^4,8 Dural venous sinus can appear dense even without thrombosis when hematocrit exceeds 60%. ⁸ Normal hematocrit ranges from 36 to 45% for women and 40 to 50% for men. At hematocrit of 45%, flowing blood has attenuation of 40–60HU and thus cerebral vasculature appears isodense or minimally hyperdense compared to the gray matter measuring attenuation of 37–45HU. ⁸ Sinus density threshold of 70HU has been suggested to improve the sensitivity to detect dural sinus thrombosis. ⁸ Although in patients with hyperdense dural venous sinuses (attenuation >70 HU), dural venous sinus thrombosis must be the primary concern on non-contrast enhanced CT head, radiologist must always check hematocrit to exclude the rare possibility of PV.

Multiple simultaneous infarcts in multiple bilateral cerebral territories are associated with significant mortality and morbidity. Cardiogenic emboli occluding multiple arterial territories bilaterally are the most common cause of multifocal stroke comprising about 30–40% cases (12). Hematological disorders such as anti-phospholipid antibody syndrome, activated protein C resistance (e.g., factor V Leiden), elevated coagulation factor VIII levels, vasculitis, infection, disseminated intravascular coagulation, malignancies, and thrombotic thrombocytopenic purpura are common causes of synchronous multiterritorial infarctions in younger population. ¹ In the presented case, negative transesophageal cardiac echocardiogram (TEE) was used as a ruled out cardiogenic emboli. Furthermore, clinical history and brain MRI were not suggestive of vasculitis as a potential cause of ischemic infarction in this patient. Elevated hematocrit in this previously healthy individual, and imaging findings of hyperdense dural venous sinus and multi-territorial synchronous and metasynchronous infarctions strongly suggested a hypercoagulable state of stroke in our patient.

In conclusion, hypercoagulable disorders especially PV are relatively rare causes of ischemic infarctions and require different work-up and secondary prevention strategy. Radiologist’s familiarity with the neurological manifestations of hypercoagulable disorders and the spectrum of the imaging findings (Dural sinus thrombosis, venous infarction, and multiterritorial infractions) is vital to help early detection and lower morbidity and mortality. The clinical algorithm must include family history of hematological disorders, vasculitis, medications including contraceptive pills, as well as the patient’s prior thrombotic events or other risk factors (i.e., systemic lupus erythematosus). Overall, recognizing hyperdense dural venous sinuses and multifocal infarctions in the absence of cardiogenic causes or significant atherosclerosis can help prompt the diagnosis of PV, often an underdiagnosed and potentially fatal disease.