Challenges in Diagnosing Polycythemia Vera in Primary Care: A 55-Year-Old Malaysian Woman with Atypical Presentation

Introduction

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) characterized by elevated hemoglobin (>16.5 g/dL in men, >16 g/dL in women) and hematocrit (>49% in men, >48% in women), which is often incidentally detected [1,2]. PV accounts for 38.1% of MPN cases in Malaysia. Among patients with JAK2 V617F mutations, 46.6% had PV compared to 22.1% without the mutation. Individuals with JAK2 V617F mutations were typically older (average age 55.9 years), more often female (49.2%), and predominantly Malay (48.1%) compared to those with MPNs who were negative for the JAK2 V617F mutation [3].

Symptoms of PV can range from incidental findings to more severe manifestations, such as fatigue, pruritus, headaches, splenomegaly, hepatomegaly, and hypertension, which may not immediately suggest a clear diagnosis [4–7]. Yap et al [3] found that PV patients with the JAK2 V617F mutation are at higher risk for vasomotor symptoms, splenomegaly, and thrombosis compared to those without the mutation. Importantly, the presence of vague symptoms can lead to missed or delayed diagnoses and suboptimal treatment, increasing the risk of serious complications like acute coronary syndrome, ischemic stroke, non-cirrhotic portal hypertension, and cerebral venous thrombosis [8–10].

Diagnosing PV adheres to the WHO criteria, requiring either all 3 major criteria – elevated hemoglobin or hematocrit or increased red cell mass, specific bone marrow findings, and JAK2 mutations – or 2 major criteria plus the minor criterion of subnormal serum erythropoietin. According to the 2016 revised WHO classification of myeloid neoplasms and leukemia, bone marrow biopsy (BMB) is not essential for diagnosis but is crucial for identifying or predicting disease progression [2,11,12].

Thrombotic risk stratification is of crucial importance to evaluate patient prognosis at diagnosis. PV risk stratification categorizes patients into high-risk and low-risk groups, with patients under age 60 years without a history of thrombosis being considered low risk, while those aged 60 or older or with a history of thrombosis are deemed high risk. The presence of the JAK2 V617F mutation is associated with a higher risk of arterial thrombosis; however, it does not significantly impact survival patterns or mortality outcomes [2,13,14].

Treatment strategies for PV have evolved to emphasize reducing thrombo-hemorrhagic risks, which are the leading causes of morbidity and mortality. Management is guided by the patient’s thrombotic risk, influenced by age and thrombosis history. The standard treatment includes phlebotomy to lower hematocrit levels below 45% and low-dose aspirin for patients at low risk. For those with worsening splenomegaly, elevated leukocyte and platelet counts, or those who cannot tolerate phlebotomy, hydroxyurea is recommended as a first-line cytoreductive therapy [15,16].

Here, we report the case a 55-year-old Malaysian woman with atypical symptoms of PV who was misdiagnosed after multiple visits to various clinics and specialist centers before her condition was accurately identified in a primary care setting. This led to urgent referral to a hematologist, resulting in effective treatment and significant improvements, while preventing complications like thrombosis. The case highlights the critical gap in PV awareness among Malaysian physicians, underlining the urgent need for enhanced education and systematic evaluation to ensure timely and accurate diagnosis and management of this complex disorder.

Case Report

A 55-year-old Malaysian woman presented to a primary care clinic on December 26, 2022, with recurrent eye redness and dizziness over the past 8 months. She reported persistent, painless bilateral eye redness since mid-2022, initially noticed by her daughter. However, she did not pursue further investigation until October 2022, when she began experiencing dizziness described as a spinning sensation, accompanied by vomiting and imbalance during walking, but without limb weakness and blurred vision.

The patient sought treatment at local primary care clinics and the hospital multiple times. Initially, dry eyes were considered the cause of her eye redness, and various topical eye drops were prescribed. Subsequently, she was referred to the ear, nose, and throat (ENT) team due to recurrent episodes of dizziness, vomiting, and walking imbalance. The diagnosis was benign paroxysmal positional vertigo (BPPV), and she was prescribed prochlorperazine for symptom relief.

Despite receiving those treatments, her symptoms persisted, prompting her to seek further evaluation at our primary care clinic. We aimed to explore potential underlying causes for the persistent eye redness and dizziness, considering alternative diagnoses to her ongoing symptoms.

A physical examination showed bilateral conjunctival redness and her tongue appeared red and smooth, suggestive of glossitis. However, there was no facial redness or plethora. Her blood pressure was slightly elevated at 163/84 mmHg. Her abdominal examination revealed an enlarged, non-tender liver with a smooth surface measuring 14 cm, while the spleen was 3 cm below the costal margin, indicative of splenomegaly. Other physical findings were unremarkable.

A comprehensive assessment, including a full blood count (FBC), is essential. This approach ensures a thorough exploration of potential diagnoses including sleep apnea, pulmonary disorder, renal disorder, liver disorders (eg, hepatitis), connective tissue disorders (eg, systemic lupus erythematous ([SLE]), hematological causes such as myeloproliferative diseases like polycythemia vera, or essential thrombocythemia and leukemia.

The FBC showed elevated hemoglobin (20.2 g/dL) and hematocrit (65.5%), accompanied by leukocytosis (Table 1). Given the leukocytosis observed in the FBC, a peripheral blood film was analyzed, revealing erythrocytosis (Figure 1). These findings and the patient’s clinical symptoms raised suspicion of PV, leading to an urgent hematologist referral. Subsequently, she was admitted for comprehensive investigations to delineate the underlying diagnosis.

Throughout her hospitalization, she was further assessed for PV. A further history revealed that she had negative classic polycythemia symptoms such as aquagenic pruritus, erythromelalgia, facial plethora, or paresthesia, and no signs of hyper-viscosity like headache, blurred vision, or chest pain. Furthermore, there was no history of hormonal therapy, smoking, heart disease, kidney disease, or lung disease, and no known family history of erythrocytosis or other blood disorders.

The hematologist ordered serum erythropoietin (EPO) and JAK2 tests, which revealed a low EPO level (<1.0 IU/L) and a positive JAK2 V617F mutation (Table 2). After careful consideration and discussion between the treating hematologist and the patient, bone marrow biopsy (BMB) was not performed. This is supported by World Health Organization (WHO) criteria, which allow for diagnosis without a BMB if specific major and minor criteria are met. In this case, the major criteria included hemoglobin (Hb) levels >16 g/dL, hematocrit (HCT) levels >48%, and the presence of the JAK2 V617F mutation, while the minor criterion was a subnormal serum erythropoietin level. After thorough evaluation, she was diagnosed with low-risk PV due to her age (<60 years) and lack of a history of thrombosis.

In the ward, aspirin was initiated to mitigate thrombosis and cardiovascular risk. The patient underwent therapeutic phlebotomy, extracting 350–400 ml of blood daily, maintaining proper hydration through intravenous drip with strict input-output charting. An ophthalmologist referral was made for screening due to potential complications associated with PV, such as central retinal vein occlusion (CRVO) or central retinal artery occlusion (CRAO). However, the findings only indicated the presence of glaucoma (Table 3).

To address other symptoms, including a 5-kg weight loss in 3 months, a gastroenterological consultation was sought, leading to an upper gastrointestinal endoscopy (OGDS). The OGDS revealed gastropathy changes with antral gastritis and erosions, along with duodenitis, without signs of portal hypertension or varices. A gastric biopsy confirmed and successfully treated helicobacter-associated gastritis. Throughout this admission, the patient remained well without thrombosis complications. A follow-up in 2 weeks was planned, involving a FBC, weekly phlebotomy, and a discussion on BMB. However, the patient continued to decline the procedure.

Despite undergoing 10 phlebotomies in the initial 2 months, the patient’s hematocrit remained persistently at 53–54%, prompting the initiation of hydroxyurea at a daily dose of 500 mg. This decision was influenced by the patient’s veins easily tearing during phlebotomy and her challenges in adhering to regular appointments. Furthermore, heightened thrombotic risk in PV necessitated comprehensive cardiovascular screening, revealing underlying diabetes mellitus and dyslipidemia with transaminitis. Subsequently, she was started on suitable medications to address these newly identified conditions. Her blood pressure normalized after several phlebotomies.

During the 12-month follow-up with the hematologist, positive outcomes were observed. The conjunctival redness significantly improved, as shown in Figure 2, while a gradual decline in hemoglobin and hematocrit levels was noted, as shown in Table 1.

Discussion

This clinical case report underscores the crucial importance of timely recognition and accurate diagnosis in uncovering underlying pathologies, exemplified by the near-missed diagnosis of polycythemia vera (PV) in a middle-aged woman presenting with persistent bilateral eye redness and lightheadedness. It highlights the imperative for heightened vigilance among primary care practitioners and the necessity for comprehensive diagnostic approaches, including FBC, JAK2 V617F mutation, and serum EPO level measurement, to avert diagnostic oversights and ensure optimal patient outcomes.

PV presents a broad spectrum of symptoms, encompassing asymptomatic cases to vasomotor symptoms such as fatigue, headaches, and visual disturbances, which can escalate to severe complications like thrombosis. This case highlights the challenges in promptly recognizing PV, especially in primary care settings where symptoms can be vague. Nonspecific symptoms like dizziness and eye redness often cause clinicians to overlook the importance of performing FBCs. To prevent delays in initial blood screening, as occurred in this case, there must be a paradigm shift towards greater clinical suspicion and the routine use of simple screening tests like FBC. Initiating an FBC in primary care, with particular attention to hemoglobin (Hb) and hematocrit (HCT) levels, followed by full blood testing before referral to a hematologist, can expedite appropriate diagnostic strategies [17,18]. Fortunately, this patient did not develop complications, unlike a case reported by Tachi in 2022, where a patient developed non-cirrhotic portal hypertension despite undergoing an FBC, possibly due to insufficient scrutiny of abnormalities [10].

Despite the initial delay in diagnosis, this case underscores the critical importance of prompt referral to a hematologist and vigilant screening for complications. These measures ultimately facilitated effective treatment, stabilized comorbid conditions, and significantly improved patient outcomes. Even though this did not occur in our case, the delay in referral to a hematologist for symptomatic treatment increased the risk of thrombotic complications. Consequently, cases like that reported by Chaudhary focused on vaso-occlusive secondary PV, where the patient experienced an ischemic stroke [19]. Complications can arise, culminating in thrombotic events like acute myocardial infarction or splenic infarct [20–22], and even more serious outcomes such as myelofibrosis or acute myeloid leukemia [23–25].

According to the 2016 WHO revised criteria, diagnosing PV requires meeting all 3 major criteria or the first 2 major criteria and the minor criterion. While bone marrow biopsy is the criterion standard for diagnosis and disease prognosis, it is an invasive procedure requiring patient consent. In cases where the patient refuses the procedure but has sustained erythrocytosis, JAK2 V617F mutation, and subnormal erythropoietin, bone marrow biopsy may be omitted [2, 26]. This case report exemplifies the application of diagnostic principles for PV. Despite the patient’s refusal of a bone marrow biopsy, the diagnosis was confirmed based on elevated Hb, high HCT, the presence of JAK2 V617F mutation, and low serum erythropoietin levels. This confirmed the validity of the PV diagnosis and highlights the importance of integrating clinical judgment with available laboratory tests for accurate diagnoses, even when invasive procedures are not pursued.

Patients with polycythemia vera (PV) are at increased risk for cardiovascular events, such as stroke, heart attacks, and peripheral arterial disease, with hypertension being the most prevalent risk factor. A Malaysian study linked hypertension to the JAK2V617F mutation and identified it as a major thrombosis risk in PV patients [3]. Elevated blood viscosity from high hematocrit levels exacerbates hypertension and thrombotic risks. Our case report illustrates that timely phlebotomy and aspirin therapy not only significantly improved the patient’s condition but also effectively controlled blood pressure, highlighting the importance of comprehensive cardiovascular risk management in PV. This case underscores the role of combining blood pressure control with appropriate hematological treatments to mitigate cardiovascular risks and prevent thrombotic complications. While some studies reported minimal reductions in 24-h ambulatory blood pressure with phlebotomy alone, our findings demonstrate its efficacy when paired with aspirin therapy [27–30].

Managing PV presents a complex challenge, requiring a delicate balance between thrombosis prevention and treatment tolerability. Guidelines recommend phlebotomy and aspirin for low-risk cases and cytoreductive therapy for high-risk patients. However, individualized patient factors often necessitate treatment adjustments [13,30]. This case underlines the importance of guideline adherence while acknowledging the imperative for personalized approaches. Initially receiving standard therapy aligned with low-risk PV guidelines, the patient’s transition to cytoreductive therapy due to challenges with phlebotomy, follow-up, and persistently high hematocrit highlights the dynamic nature of PV management. Regular assessments are essential in optimizing outcomes amidst evolving clinical scenarios.

In conclusion, this case report highlights the critical importance of prompt and accurate diagnosis in managing PV to mitigate complications and provide optimal treatment. The fact that diagnosis was achieved without bone marrow aspiration demonstrates an alternative approach for challenging cases. Moreover, the modification of treatment from standard low-risk management to cytoreduction, based on individualized clinical judgment, exemplifies adaptability in optimizing patient care. The delay in diagnosis, especially in primary care settings, is a reminder of the need for improved clinical judgment and referral protocols. To enhance survival rates and prevent complications, it is imperative to promptly refer patients to a hematologist for further evaluation and remain vigilant for recurring symptoms. This case underscores the vital importance of timely and personalized diagnosis and treatment of PV, making its publication a valuable contribution to the literature on nuanced diagnostic and therapeutic approaches in PV management.

Conclusions

Polycythemia vera (PV) poses significant risks, with complications including thrombotic events (26%), fibrotic issues (16%), and leukemic transformations (4%). Early diagnosis and intervention are critical to preventing these severe outcomes and improving patient survival. Enhancing diagnostic accuracy through targeted educational programs and clinical decision support tools is essential. These initiatives address challenges such as vague symptoms, the absence of bone marrow aspiration, and the need for tailored treatment strategies in low-risk cases. Vigilance in primary care settings is crucial for timely symptom recognition, comprehensive screening, and prompt referral to hematologists. Effective management hinges on swift action to prevent complications and optimize patient outcomes.