Takotsubo cardiomyopathy

A 64-year-old woman with a history of hypertension presents with sudden-onset chest pain and shortness of breath for 1 hour. She reports recent severe emotional stress related to her husband's terminal illness. Vital signs show a blood pressure of 100/60 mmHg, pulse of 106/min, and oxygen saturation of 92% on room air. Laboratory studies reveal a mild elevation in troponin. ECG shows ST-segment elevation. Echocardiography demonstrates apical ballooning with hypercontractile basal segments. Coronary angiography shows no obstructive coronary artery disease. Diagnosis?

Diagnosis is Takotsubo syndrome, classic apical type.

1. Definition

Takotsubo syndrome (TTS), also called stress cardiomyopathy, is an acute syndrome characterized by transient regional ventricular systolic dysfunction that often mimics acute myocardial infarction but is not explained by a culprit obstructive coronary lesion.

2. Epidemiology

1.      Accounts for approximately 1 to 3% of patients presenting with suspected STEMI

2.      Approximately 90% of patients are women

3.      Predominantly affects postmenopausal women

4.      Most commonly occurs in patients approximately 60 to 70 years of age

3. Pathophysiology

The exact mechanism is incompletely understood.

1.      Often triggered by emotional or physical stress

2.      Excessive sympathetic and catecholamine stimulation is considered central to the pathophysiology.

3.      Proposed mechanisms include:

o    Direct catecholamine-mediated myocardial injury

o    Coronary microvascular dysfunction

o    Altered myocardial adrenergic signaling

4.      These mechanisms produce transient myocardial stunning and characteristic regional wall-motion abnormalities.

5.      A recognizable stressor is common but not required for diagnosis.

4. Clinical Features

1.      Chest pain

2.      Dyspnea

3.      Less commonly:

o    Syncope

o    Arrhythmias

o    Acute heart failure

o    Cardiogenic shock

The initial presentation may be clinically indistinguishable from acute coronary syndrome.

5. Diagnosis

5.1 Cardiac Biomarkers

1.      Troponin is usually moderately elevated.

2.      Troponin elevation is often modest relative to the extent of ventricular dysfunction.

3.      BNP or NT-proBNP is frequently elevated.

5.2 ECG

Possible findings include:

1.      ST-segment elevation

2.      T-wave inversion

3.      QT interval prolongation

4.      Less commonly, ST-segment depression

ECG abnormalities may evolve during the acute illness.

5.3 Echocardiography

Classic apical TTS demonstrates:

1.      Apical and midventricular hypokinesis or akinesis

2.      Apical ballooning

3.      Hypercontractile basal segments

4.      Reduced left ventricular ejection fraction

Other recognized variants include midventricular, basal, and focal patterns.

5.4 Coronary Imaging

1.      Patients presenting with ST-segment elevation require urgent evaluation for acute coronary occlusion, usually with coronary angiography.

2.      Classic TTS has no culprit coronary lesion that explains the ventricular wall-motion abnormality.

3.      Coexisting coronary artery disease does not exclude TTS if it does not explain the pattern of ventricular dysfunction.

4.      Coronary CT angiography may be appropriate in selected stable patients.

5.5 Cardiac MRI

Cardiac MRI may demonstrate:

1.      Myocardial edema

2.      Regional wall-motion abnormalities

3.      Usually no ischemic infarction pattern of late gadolinium enhancement

4.      Helps differentiate TTS from myocardial infarction and myocarditis

6. InterTAK Diagnostic Features

Important diagnostic features include:

1.      Transient left ventricular or right ventricular regional systolic dysfunction

2.      Apical, midventricular, basal, or focal wall-motion abnormalities may occur.

3.      Wall-motion abnormalities usually extend beyond a single epicardial coronary distribution, although focal TTS may involve a single coronary territory.

4.      An emotional or physical trigger may be present but is not required.

5.      New ECG abnormalities are common but are not universally present.

6.      Troponin is usually moderately elevated, while natriuretic peptides are often elevated.

7.      Significant coronary artery disease may coexist and does not exclude TTS.

8.      Infectious myocarditis should be excluded.

9.      Postmenopausal women are predominantly affected.

7. Management

7.1 Initial Management

Because TTS frequently mimics myocardial infarction:

1.      Manage initially as acute coronary syndrome until acute coronary occlusion has been excluded.

2.      Monitor for arrhythmias, heart failure, cardiogenic shock, and left ventricular outflow tract obstruction.

7.2 Hemodynamically Stable Patients

Treatment is primarily supportive and individualized.

1.      ACE inhibitors or ARBs may be considered in patients with significant left ventricular systolic dysfunction.

2.      Diuretics are used for pulmonary congestion or heart failure.

3.      Beta blockers may be considered in selected stable patients, but they have not been proven to prevent recurrence.

4.      Beta blockers should be used cautiously or avoided in patients with hypotension, severe acute heart failure, significant bradycardia, or marked QT prolongation.

7.3 Cardiogenic Shock

Management depends on whether left ventricular outflow tract obstruction (LVOTO) is present.

1.      Assess urgently for LVOTO using echocardiography.

2.      In patients with LVOTO, positive inotropes and therapies that reduce preload or afterload may worsen the obstruction and should generally be avoided.

3.      Severe cardiogenic shock may require mechanical circulatory support.

4.      Treatment should be individualized according to the underlying hemodynamic mechanism.

7.4 Anticoagulation

1.      Therapeutic anticoagulation is indicated when left ventricular thrombus is present, generally until thrombus resolution and recovery of ventricular function.

2.      Anticoagulation should also be considered in patients with extensive apical ballooning and severe left ventricular dysfunction who are at high risk for thrombus formation.

3.      Patients with established LV thrombus commonly require approximately 3 months of anticoagulation, individualized according to follow-up imaging and bleeding risk.

7.5 Follow-Up

1.      Repeat echocardiography should document recovery of ventricular function.

2.      Left ventricular systolic function usually recovers within weeks, classically within approximately 4 to 8 weeks.

8. Complications

1.      Acute heart failure

2.      Cardiogenic shock

3.      Atrial and ventricular arrhythmias

4.      QT prolongation and torsades de pointes

5.      Left ventricular outflow tract obstruction

6.      Mitral regurgitation

7.      Left ventricular thrombus

8.      Systemic thromboembolism

9. Prognosis

1.      Ventricular systolic dysfunction is usually reversible.

2.      TTS is not a benign condition and may cause serious acute complications.

3.      Recurrence occurs in approximately 5% of patients during long-term follow-up.

10. Key Clinical Insight

Acute coronary syndrome-like presentation + emotional or physical stress + transient apical ballooning + wall-motion abnormalities not explained by a culprit coronary lesion = Takotsubo syndrome.

In this patient, severe emotional stress, ST-segment elevation, modest troponin elevation, classic apical ballooning with basal hypercontractility, and absence of obstructive coronary artery disease strongly support classic apical Takotsubo syndrome.

References

1.      Ghadri JR, Wittstein IS, Prasad A, et al. International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology. Eur Heart J. 2018;39(22):2032-2046. doi:10.1093/eurheartj/ehy076.

2.      Ghadri JR, Wittstein IS, Prasad A, et al. International Expert Consensus Document on Takotsubo Syndrome (Part II): Diagnostic Workup, Outcome, and Management. Eur Heart J. 2018;39(22):2047-2062. doi:10.1093/eurheartj/ehy077.

3.      Yalta K, Madias JE, Kounis NG, et al. Takotsubo Syndrome: An International Expert Consensus Report on Practical Challenges and Specific Conditions. Part 1: Diagnostic and Therapeutic Challenges. Balkan Med J. 2024;41(6):421-441. doi:10.4274/balkanmedj.galenos.2024.2024-9-98.

Pheochromocytoma

A 30-year-old man with a history of poorly controlled hypertension presents with recurrent episodes of palpitations, severe headache, and profuse sweating over several months. The episodes begin suddenly, last for several minutes, and resolve spontaneously. He also reports anxiety and a sense of impending doom during the episodes. Examination shows a blood pressure of 160/100 mmHg and a pulse of 140/min. Laboratory evaluation demonstrates elevated 24-hour urinary fractionated metanephrines. CT reveals a right adrenal mass. Diagnosis?

Diagnosis is Pheochromocytoma.

1. Definition

Pheochromocytoma is a neuroendocrine tumor arising from chromaffin cells of the adrenal medulla, usually producing catecholamines.

Related tumors arising from extra-adrenal sympathetic or parasympathetic paraganglia are called paragangliomas.

2. Etiology and Genetics

1.      Many cases are apparently sporadic.

2.      Approximately 20 to 40% of pheochromocytomas and paragangliomas (PPGLs) are associated with germline pathogenic variants.

3.      Important hereditary associations include:

o    Multiple endocrine neoplasia type 2 (MEN2) due to RET variants

o    Von Hippel-Lindau syndrome (VHL)

o    Neurofibromatosis type 1 (NF1)

o    Hereditary paraganglioma syndromes due to SDHx variants

o    Less commonly, variants involving genes such as MAX and TMEM127

4.      Because PPGLs have substantial heritability, genetic counseling and germline testing should be considered for all patients.

3. Pathophysiology

1.      Tumors may produce excessive norepinephrine, epinephrine, and occasionally dopamine.

2.      Catecholamine excess causes:

o    Alpha-adrenergic vasoconstriction, producing hypertension

o    Beta-adrenergic stimulation, contributing to tachycardia and palpitations

3.      Catecholamines are metabolized to metanephrine and normetanephrine.

4.      Metanephrines are produced continuously within the tumor and are therefore more reliable biochemical markers than episodically secreted catecholamines.

4. Clinical Features

4.1 Classic Presentation

1.      Paroxysmal or sustained hypertension

2.      Classic triad:

o    Headache

o    Diaphoresis

o    Palpitations

Hypertension may be sustained, episodic, or occasionally absent.

4.2 Other Features

1.      Tachycardia

2.      Tremor

3.      Anxiety or panic-like symptoms

4.      Pallor

5.      Weight loss

6.      Hyperglycemia

7.      Orthostatic hypotension

4.3 Potential Triggers of Catecholamine Release

Episodes or hypertensive crises may be precipitated by:

1.      Emotional or physical stress

2.      Surgery or anesthesia

3.      Tumor manipulation

4.      Certain medications, including:

o    Tricyclic antidepressants

o    Monoamine oxidase inhibitors

o    Sympathomimetics

o    Metoclopramide and other dopamine antagonists

o    Glucocorticoids

5. Pheochromocytoma and Paraganglioma

1.      Pheochromocytoma

o    Arises from the adrenal medulla

o    Represents approximately 80 to 85% of PPGLs

o    Usually produces catecholamines

2.      Paraganglioma

o    Arises from extra-adrenal paraganglia

o    Sympathetic paragangliomas, usually in the thorax, abdomen, or pelvis, are often catecholamine-producing.

o    Parasympathetic head and neck paragangliomas are often nonsecretory.

6. Diagnosis

6.1 Biochemical Testing

Recommended first-line biochemical tests are:

1.      Plasma free metanephrines

2.      24-hour urinary fractionated metanephrines

Important principles:

1.      Both tests have high diagnostic sensitivity and are appropriate first-line tests.

2.      Plasma free metanephrines are particularly sensitive when collected under standardized conditions.

3.      For plasma testing, the patient should ideally rest supine for approximately 20 to 30 minutes before blood sampling to reduce false-positive results.

4.      Metanephrines are preferred over direct catecholamine measurement because their production is more continuous.

5.      Markedly elevated metanephrine concentrations strongly support the diagnosis in the appropriate clinical setting.

6.2 Anatomical Imaging

After biochemical evidence of PPGL:

1.      CT of the abdomen and pelvis is commonly used for initial tumor localization.

2.      MRI is useful when radiation exposure should be minimized and in selected patients with extra-adrenal, head and neck, or metastatic disease.

6.3 Functional Imaging

Functional imaging is not required in every patient. It is selected according to:

1.      Tumor location

2.      Genotype

3.      Suspected multifocal disease

4.      Recurrent disease

5.      Suspected or confirmed metastatic disease

6.      Whether radionuclide therapy is being considered

Options include:

1.      Somatostatin receptor PET/CT, such as 68Ga-DOTATATE PET/CT

2.      123I-MIBG scintigraphy

3.      18F-FDG PET/CT in selected patients

6.4 Biopsy

Percutaneous biopsy of a suspected pheochromocytoma should not be performed until PPGL has been biochemically excluded, because tumor manipulation may provoke severe catecholamine release and a potentially life-threatening hypertensive crisis.

7. Management

7.1 Preoperative Preparation

Patients with a catecholamine-secreting PPGL generally require preoperative adrenergic blockade.

1.      Alpha-adrenergic blockade is initiated first.

o    Phenoxybenzamine

o    Selective alpha-1 blockers such as doxazosin

2.      Alpha blockade is usually established for approximately 7 to 14 days before surgery, with treatment individualized according to blood pressure and symptoms.

3.      High sodium intake and adequate fluid intake, if not contraindicated, are commonly used after alpha blockade to correct catecholamine-associated volume contraction and reduce postoperative hypotension.

4.      Beta blockers may be added only after adequate alpha blockade when clinically significant tachycardia persists.

5.      Starting a beta blocker before alpha blockade can cause unopposed alpha-adrenergic vasoconstriction and severe hypertension.

7.2 Definitive Treatment

1.      Surgical resection is the definitive treatment for most localized pheochromocytomas.

2.      Minimally invasive adrenalectomy is preferred for most localized adrenal pheochromocytomas when oncologically appropriate.

3.      Open surgery may be required for large, invasive, or otherwise surgically complex tumors.

8. Complications

Catecholamine excess can cause:

1.      Hypertensive crisis

2.      Cardiac arrhythmias

3.      Acute coronary syndrome or myocardial injury

4.      Stroke

5.      Catecholamine-induced cardiomyopathy

6.      Acute heart failure

7.      Multiorgan dysfunction in severe pheochromocytoma crisis

9. Follow-Up

1.      In functioning PPGLs, plasma free or urinary fractionated metanephrines should be measured approximately 2 to 6 weeks after recovery from surgery to confirm biochemical remission.

2.      Annual biochemical surveillance is generally recommended after resection.

3.      All patients should undergo follow-up for at least 10 years because recurrent or metastatic disease may occur after apparently successful surgery.

4.      Lifelong annual surveillance is recommended for higher-risk patients, including those with:

o    Hereditary disease

o    Paraganglioma

o    Large tumors

o    Younger age at diagnosis

o    Multifocal or recurrent disease

o    Other features associated with increased metastatic risk

10. Key Clinical Insight

Episodic headache + diaphoresis + palpitations + hypertension + elevated plasma free or urinary fractionated metanephrines + adrenal mass = pheochromocytoma.

In this patient, the classic catecholamine-associated triad, paroxysmal symptoms, hypertension, elevated urinary fractionated metanephrines, and adrenal mass strongly establish the diagnosis of pheochromocytoma.

References

1.      Tanabe A, Katabami T, Hashimoto S, et al. Japan Endocrine Society Clinical Practice Guideline for the Diagnosis and Management of Pheochromocytoma and Paraganglioma 2025. Endocr J. 2026;73(1):115-157. doi:10.1507/endocrj.EJ25-0165.

2.      Lenders JWM, Kerstens MN, Amar L, et al. Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension. J Hypertens. 2020;38(8):1443-1456. doi:10.1097/HJH.0000000000002438.

3.      Plouin PF, Amar L, Dekkers OM, et al. European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma. Eur J Endocrinol. 2016;174(5):G1-G10. doi:10.1530/EJE-16-0033.

Polycythemia vera

A 55-year-old man presents with persistent headaches, dizziness, and episodic blurred vision over the past few months. He also reports a burning sensation in his hands and feet and generalized pruritus after hot showers. Examination reveals splenomegaly. Blood pressure is 140/90 mmHg. Laboratory studies show a hemoglobin of 20 g/dL, hematocrit of 56%, leukocytosis, and thrombocytosis. Serum erythropoietin is low. Bone marrow biopsy shows hypercellularity with trilineage proliferation (panmyelosis). Molecular testing reveals a JAK2 mutation. Diagnosis?

Diagnosis is Polycythemia vera.

1. Definition

Polycythemia vera (PV) is a chronic BCR::ABL1-negative myeloproliferative neoplasm characterized by clonal erythrocytosis, usually accompanied by varying degrees of leukocytosis and thrombocytosis, and driven by an acquired JAK2 mutation.

2. Etiology and Molecular Basis

1.      PV is caused by an acquired somatic activating mutation in JAK2.

2.      JAK2 V617F is present in approximately 95% of patients.

3.      JAK2 exon 12 mutations account for most remaining JAK2 V617F-negative cases.

4.      JAK2 activation causes constitutive signaling through the JAK-STAT pathway, promoting cytokine-independent and cytokine-hypersensitive hematopoiesis.

3. Pathophysiology

1.      Clonal proliferation of a hematopoietic stem cell produces panmyelosis involving:

o    Erythroid cells

o    Granulocytes

o    Megakaryocytes

2.      Excessive erythrocytosis increases blood viscosity and contributes to hyperviscosity symptoms and thrombosis.

3.      Leukocytosis and other disease-related factors may further contribute to thrombotic risk.

4.      Marked thrombocytosis may cause acquired von Willebrand syndrome, increasing bleeding risk.

5.      Increased cell turnover may cause hyperuricemia and gout.

6.      Aquagenic pruritus is characteristic of PV. Its mechanism is incompletely understood but is thought to involve abnormal basophil, mast-cell, and cytokine signaling.

7.      Increased red-cell mass suppresses renal erythropoietin production, resulting in low serum erythropoietin.

4. Clinical Features

4.1 Hyperviscosity and Microvascular Symptoms

1.      Headache

2.      Dizziness

3.      Blurred vision

4.      Tinnitus

5.      Paresthesias

6.      Erythromelalgia, characterized by burning pain, warmth, and erythema of the hands or feet

4.2 Thrombotic Manifestations

PV increases the risk of both arterial and venous thrombosis, including:

1.      Stroke or transient ischemic attack

2.      Myocardial infarction

3.      Deep vein thrombosis

4.      Pulmonary embolism

5.      Splanchnic vein thrombosis, including Budd-Chiari syndrome

4.3 Bleeding Manifestations

1.      Epistaxis

2.      Easy bruising

3.      Gastrointestinal bleeding

4.      Bleeding associated with acquired von Willebrand syndrome, particularly with extreme thrombocytosis

4.4 Other Features

1.      Aquagenic pruritus, often triggered by a warm bath or shower

2.      Splenomegaly

3.      Facial plethora

4.      Early satiety

5.      Constitutional symptoms

6.      Hyperuricemia or gout

5. Diagnosis

5.1 Laboratory Findings

Typical findings include:

1.      Elevated hemoglobin and hematocrit

2.      Leukocytosis

3.      Thrombocytosis

4.      Subnormal serum erythropoietin

5.      JAK2 mutation

Iron deficiency may develop because of increased erythropoiesis or repeated phlebotomy and can sometimes mask the degree of erythrocytosis.

5.2 Bone Marrow

Bone marrow typically demonstrates:

1.      Age-adjusted hypercellularity

2.      Trilineage proliferation (panmyelosis)

3.      Prominent erythroid and granulocytic proliferation

4.      Increased pleomorphic, mature megakaryocytes

5.3 Molecular Testing

1.      A JAK2 V617F or JAK2 exon 12 mutation is present in virtually all patients with PV.

2.      JAK2 testing is therefore central to the diagnostic evaluation.

6. WHO 5th-Edition Diagnostic Criteria

Major Criteria

1.      Elevated:

o    Hemoglobin >16.5 g/dL in men or >16.0 g/dL in women, or

o    Hematocrit >49% in men or >48% in women

2.      Bone marrow biopsy showing age-adjusted hypercellularity with trilineage proliferation (panmyelosis), including erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic mature megakaryocytes

3.      Presence of JAK2 V617F or JAK2 exon 12 mutation

Minor Criterion

1.      Subnormal serum erythropoietin level

Diagnosis requires:

1.      All three major criteria, or

2.      The first two major criteria plus the minor criterion

Measured red-cell mass is no longer included as a WHO 5th-edition diagnostic criterion.

7. Risk Stratification

The conventional thrombotic risk categories are:

7.1 Low Risk

1.      Age <60 years

2.      No previous thrombosis

7.2 High Risk

Either:

1.      Age ≥60 years, or

2.      History of thrombosis

Cardiovascular risk factors such as hypertension, smoking, diabetes, and hyperlipidemia should also be actively managed.

This 55-year-old patient with no reported previous thrombosis would be classified as low risk for thrombosis by the conventional risk model.

8. Management

The primary treatment goal is prevention of thrombosis and hemorrhage while controlling erythrocytosis and disease-related symptoms.

8.1 Treatment for All Patients

1.      Phlebotomy to maintain hematocrit below 45%

2.      Low-dose aspirin, typically 81 to 100 mg daily, unless contraindicated

3.      Aggressive management of cardiovascular risk factors

Low-dose aspirin may need to be withheld in patients with active bleeding or clinically significant acquired von Willebrand syndrome, particularly in the setting of extreme thrombocytosis.

Maintaining hematocrit below 45% significantly reduces cardiovascular death and major thrombosis.

8.2 Low-Risk PV

Standard therapy consists of:

1.      Phlebotomy

2.      Low-dose aspirin

Cytoreductive therapy may be considered despite low-risk status when there is:

1.      Poor tolerance of or excessive requirement for phlebotomy

2.      Progressive or symptomatic splenomegaly

3.      Persistent leukocytosis >15 × 10⁹/L

4.      Progressive leukocytosis

5.      Extreme thrombocytosis >1500 × 10⁹/L

6.      Persistent high symptom burden

7.      Persistently high cardiovascular risk

When cytoreduction is required in a low-risk patient, preferred interferon-based options include:

1.      Ropeginterferon alfa-2b

2.      Pegylated interferon alfa-2a

8.3 High-Risk PV

High-risk patients generally receive:

1.      Phlebotomy to maintain hematocrit below 45%

2.      Low-dose aspirin

3.      Cytoreductive therapy

First-line cytoreductive options include:

1.      Hydroxyurea

2.      Ropeginterferon alfa-2b

3.      Pegylated interferon alfa in appropriate patients

8.4 Additional Therapy

1.      Ruxolitinib, a JAK1/JAK2 inhibitor, is an important option for patients who are resistant or intolerant to hydroxyurea and can improve hematocrit control, splenomegaly, and disease-related symptoms.

2.      Rusfertide, a hepcidin mimetic, is FDA-approved for the treatment of erythrocytosis in adults with PV.

3.      Rusfertide restricts iron availability for erythropoiesis and can reduce the need for therapeutic phlebotomy.

4.      Treatment selection should be individualized according to thrombotic risk, symptom burden, phlebotomy requirement, prior therapy, and comorbidities.

8.5 Symptom Management

1.      Erythromelalgia often responds rapidly to low-dose aspirin.

2.      Management of aquagenic pruritus begins with adequate control of the underlying PV.

3.      Additional therapies for persistent pruritus may be individualized.

4.      Allopurinol may be used for gout or clinically significant hyperuricemia when indicated.

9. Complications

1.      Arterial and venous thrombosis

2.      Hemorrhage

3.      Acquired von Willebrand syndrome

4.      Hyperuricemia and gout

5.      Progression to post-PV myelofibrosis

6.      Transformation to acute myeloid leukemia

Thrombotic complications are a major cause of morbidity and mortality in PV.

10. Key Clinical Insight

Aquagenic pruritus + erythromelalgia + splenomegaly + erythrocytosis + low erythropoietin + panmyelosis + JAK2 mutation = polycythemia vera.

In this patient, the markedly elevated hemoglobin and hematocrit, leukocytosis, thrombocytosis, low erythropoietin, bone marrow panmyelosis, JAK2 mutation, splenomegaly, aquagenic pruritus, and microvascular symptoms establish the diagnosis of polycythemia vera.

References

1.      Loghavi S, Kanagal-Shamanna R, Khoury JD, et al. Fifth Edition of the World Health Classification of Tumors of the Hematopoietic and Lymphoid Tissue: Myeloid Neoplasms. Mod Pathol. 2024;37(2):100397. doi:10.1016/j.modpat.2023.100397.

2.      Ellis MH, Barbui T, Tefferi A. Polycythemia vera. Mayo Clin Proc. 2026;101(5):826-845. doi:10.1016/j.mayocp.2026.01.008.

3.      Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular Events and Intensity of Treatment in Polycythemia Vera. N Engl J Med. 2013;368(1):22-33. doi:10.1056/NEJMoa1208500.

4.      U.S. Food and Drug Administration. MIMRYLO (rusfertide) for injection: Prescribing Information. 2026. NDA 220605.