Cerebral Venous Sinus Thrombosis in Polycythemia Vera Patients with JAK2V617F Mutation
Polycythemia vera (PV) is a chronic, progressive myeloproliferative neoplasm (MPN) characterized by the clonal proliferation of myeloid cells. This condition is marked by an abnormal increase in erythrocytes, leukocytes, and platelets, which can predispose patients to venous thromboembolism. Among the various thrombotic complications associated with PV, cerebral venous sinus thrombosis (CVST) is a rare but serious manifestation. This article delves into the clinical presentation, diagnostic challenges, and management strategies for CVST in PV patients, particularly those with the JAK2V617F mutation, based on a study of five cases.
Clinical Presentation and Diagnostic Challenges
CVST is an uncommon cerebrovascular disorder that often presents with nonspecific symptoms, making early diagnosis challenging. In the study, all five patients experienced CVST as the initial manifestation of PV. The most common symptom was a severe, refractory headache, which was present in all cases. Other associated symptoms included nausea, vomiting, blurred vision, diplopia, papilledema, and, in one case, mild hemiparesis and seizures. These symptoms are indicative of increased intracranial pressure (ICP), which was confirmed in all patients through lumbar puncture.
The diagnosis of CVST was established using imaging techniques such as magnetic resonance venography (MRV), computed tomography venography (CTV), and cerebral digital subtraction angiography (DSA). MRI revealed parenchymal lesions in four patients, with cerebral infarction observed in these cases. MRV and DSA showed multiple sinus involvement in four patients, with the transverse sinus being the most frequently affected site, followed by the sigmoid sinus.
Role of JAK2V617F Mutation
All five patients in the study were confirmed to have the JAK2V617F mutation, which is present in 75% to 98% of PV patients. This mutation is associated with an increased risk of venous thrombosis, although the precise mechanisms remain unclear. The JAK2V617F mutation status is a critical diagnostic marker for PV and may also serve as a parameter for stratifying thrombosis risk. However, the study was unable to determine the JAK2V617F allele burden due to technical limitations, which is a more effective predictor of thrombosis risk.
Treatment Strategies
The management of CVST in PV patients involves both anticoagulation and cytoreductive therapy. All patients in the study were initially treated with low molecular weight heparin (LMWH) at a dose of 90 U/kg subcutaneously twice daily, followed by oral anticoagulation with warfarin or dabigatran. Two patients who experienced clinical deterioration despite anticoagulation underwent endovascular thrombectomy, which resulted in improved outcomes without complications.
For PV, all patients received cytoreductive therapy with hydroxyurea. In one case, interferon-alpha (IFN-α) was also administered. The combination of anticoagulation and cytoreductive therapy was effective in preventing CVST recurrence, with most patients showing favorable outcomes during follow-up.
Case Illustration
A detailed case (case 4) highlights the clinical course of CVST in a PV patient. A 52-year-old woman presented with a two-month history of nausea and headache, initially misdiagnosed as antral gastritis. Her symptoms progressed to include blurred and double vision. Neurological examination revealed limited abduction of the right eye and papilledema. Lumbar puncture confirmed high ICP, and abdominal ultrasound showed splenomegaly. Elevated erythrocyte and hemoglobin levels were noted, and bone marrow biopsy and genetic testing confirmed the JAK2V617F mutation.
MRI demonstrated thrombosis of the bilateral transverse sinus, left sigmoid sinus, and left jugular vein, along with bilateral parietal cerebral venous infarction. DSA revealed stenosis of the bilateral transverse sinus and reflux disturbance of the left sigmoid sinus and internal jugular vein. The patient was treated with LMWH, warfarin, aspirin, hydroxyurea, and IFN-α. Due to markedly high ICP and visual impairment, optic nerve sheath fenestration (ONSF) was performed, resulting in gradual symptom improvement. No CVST events occurred during the subsequent two-year follow-up.
Discussion
PV is characterized by hypercoagulability, which predisposes patients to venous thromboembolism, including CVST. The JAK2V617F mutation is a significant risk factor for thrombosis in PV patients. Clinical manifestations of CVST are highly variable, and the indolent course of PV often leads to delayed diagnosis. Therefore, CVST should be considered in PV patients presenting with severe unexplained headaches or stroke-like symptoms.
Imaging techniques such as MRV, CTV, and DSA are essential for diagnosing CVST. Multiple sinus involvement is common, with the transverse and sigmoid sinuses being the most frequently affected sites. Treatment involves systemic anticoagulation and cytoreductive therapy, with endovascular thrombectomy considered for patients who fail to respond to anticoagulation.
Conclusion
CVST can be the initial presentation of PV due to hypercoagulability associated with the JAK2V617F mutation. Early diagnosis and aggressive treatment with anticoagulation and cytoreductive therapy are crucial for preventing recurrence and improving outcomes. The JAK2V617F mutation serves as a valuable diagnostic marker and risk stratification parameter for thrombosis in PV patients.
doi.org/10.1097/CM9.0000000000001484
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