What it means

• A positive result supports the presence of an MPN in someone with an abnormal blood count, such as persistent high hemoglobin/hematocrit, platelet count, or white-cell count.
• It can help explain blood clotting, particularly unusual-site clots such as splanchnic vein thrombosis.
• It is not by itself a diagnosis. Results need interpretation with the complete blood count, erythropoietin level where relevant, bone-marrow findings, symptoms, and exclusion of secondary causes. The ASH overview of classic MPNs describes how molecular testing and marrow morphology are used together.

Important distinction

JAK2 gene mutation

Definition

• Polycythemia vera (PV)
• Essential thrombocythemia (ET)
• Primary myelofibrosis (PMF)

Causes / etiology

Why does it occur?

• Usually it is an acquired somatic mutation, arising in a single blood stem cell during life.
• It is generally not inherited and is not usually passed from parent to child.
• The exact initiating cause in most people is unknown.
• Age-related clonal hematopoiesis may permit small mutated blood-cell clones to appear or expand with age.
• Rarely, mutations in other genes contribute to MPN development and disease behavior.

Main types

1. JAK2 V617F
   • Most common.
   • Found in almost all JAK2-positive ET and PMF cases and in most PV cases.
2. JAK2 exon 12 mutations
   • Occur mainly in PV when V617F is negative.
   • Often cause predominantly raised red-cell production.

Symptomatology

General symptoms

• Fatigue, weakness
• Headache, dizziness, light-headedness
• Blurred vision, visual spots
• Night sweats
• Unexplained weight loss
• Low-grade fever
• Bone discomfort
• Fullness or pain under the left ribs due to an enlarged spleen

Symptoms associated with polycythemia vera

• Ruddy or reddish complexion
• Itching, especially after a warm bath or shower
• Headache, dizziness, ringing in the ears
• Burning pain, warmth, or redness in hands and feet, called erythromelalgia
• High blood pressure
• Increased risk of blood clots

Symptoms associated with essential thrombocythemia

• Headache, dizziness, visual disturbance
• Tingling, numbness, or burning in fingers/toes
• Clotting events or, less commonly, abnormal bruising/bleeding
• Splenomegaly in some patients

Symptoms associated with primary myelofibrosis

• Marked fatigue and anemia-related breathlessness
• Enlarged spleen causing early satiety, abdominal fullness, or pain
• Fever, night sweats, weight loss
• Easy bruising or bleeding
• Bone pain

Thrombotic complications

• Deep-vein thrombosis or pulmonary embolism
• Stroke or transient ischemic attack
• Myocardial infarction
• Portal, splenic, hepatic, or cerebral venous thrombosis

Diagnosis

1. Complete blood count and peripheral smear

• High hemoglobin/hematocrit and red-cell count in PV
• High platelet count in ET
• Elevated white cells
• In PMF, anemia and characteristic teardrop red cells or immature blood cells may occur

2. Molecular testing

• Test JAK2 V617F first.
• If PV is suspected but V617F is negative, test JAK2 exon 12 mutations.
• If ET or PMF is suspected and JAK2 is negative, test CALR and MPL mutations.

3. Serum erythropoietin (EPO)

4. Bone-marrow aspiration and biopsy

• Confirm an MPN
• Differentiate ET from prefibrotic or overt PMF
• Assess marrow cellularity, megakaryocyte morphology, and fibrosis
• Exclude reactive causes of increased blood counts

5. Exclusion of other causes

• Oxygen saturation and assessment for sleep apnea, lung or heart disease
• Smoking and medication history
• Iron studies
• Liver and renal evaluation
• BCR::ABL1 testing if chronic myeloid leukemia is a possibility
• Imaging for splenomegaly or unexplained abdominal thrombosis

Myelofibrosis

Definition

Types

1. Primary myelofibrosis (PMF)
   Begins as myelofibrosis without a previous MPN diagnosis.
2. Secondary myelofibrosis
   Develops after another MPN, especially:
   • Polycythemia vera, called post-PV myelofibrosis
   • Essential thrombocythemia, called post-ET myelofibrosis

Causes and pathogenesis

Symptoms and signs

Constitutional symptoms

• Fatigue and weakness
• Fever or low-grade fever
• Night sweats
• Unintentional weight loss
• Reduced appetite
• Bone pain or discomfort

Anemia-related symptoms

• Pallor
• Exertional breathlessness
• Palpitations
• Dizziness
• Marked tiredness

Splenomegaly-related symptoms

• Fullness or pain below the left ribs
• Early satiety, feeling full after a small meal
• Abdominal enlargement or discomfort
• Weight loss from poor appetite

Bleeding or clotting manifestations

• Easy bruising
• Nose or gum bleeding
• Petechiae
• Deep-vein thrombosis, pulmonary embolism, stroke, or unusual-site venous thrombosis in some patients

Diagnosis

1. Complete blood count and peripheral blood film

• Anemia is common
• White-cell count may be high, normal, or low
• Platelets may initially be high, then decrease in advanced disease
• Teardrop red cells or dacrocytes
• Nucleated red cells and immature granulocytes in blood, called a leukoerythroblastic blood picture

2. Bone-marrow aspiration and biopsy

• Abnormal megakaryocyte proliferation and atypia
• Reticulin or collagen fibrosis
• Hypercellular marrow in earlier disease
• A “dry tap” on aspiration in advanced fibrosis

3. Mutation testing

• JAK2 V617F
• CALR
• MPL

4. Additional tests

• LDH, often elevated
• Uric acid
• Liver and kidney function tests
• Abdominal ultrasound or CT to assess spleen and liver size
• Cytogenetic and broader next-generation sequencing studies for prognostic assessment
• Testing to exclude BCR::ABL1-positive chronic myeloid leukemia and other marrow disorders

Important point

• MPN = umbrella term, myeloproliferative neoplasm.
• PV = polycythemia vera, an MPN dominated by excess red-cell production.
• MF = myelofibrosis, an MPN dominated by bone-marrow fibrosis and impaired blood formation.
• MF can be primary from the outset or develop later from PV, called post-PV myelofibrosis.

Key differentiation

Practical diagnostic approach

1. First identify the dominant blood-count abnormality

• Persistently high hemoglobin/hematocrit suggests PV.
• Anemia with teardrop cells, immature blood cells, or falling platelets suggests MF, particularly advanced disease.
• A high platelet count may instead point to essential thrombocythemia or prefibrotic MF.

2. Test JAK2, but do not rely on it alone

• A positive JAK2 V617F supports an MPN but cannot by itself distinguish PV from MF.
• In suspected PV with negative V617F, check JAK2 exon 12.
• In suspected MF with negative JAK2, test CALR and MPL.

3. Check serum EPO in erythrocytosis

• Low EPO + raised hemoglobin/hematocrit + JAK2 mutation strongly supports PV.
• If EPO is normal/high, investigate secondary erythrocytosis such as hypoxia, smoking, sleep apnea, lung disease, renal disease, or EPO-producing tumors. - Harrison’s Principles of Internal Medicine, 22nd ed., p. 495

4. Bone-marrow biopsy is the decisive test

• PV marrow hypercellularity and panmyelosis
• Essential thrombocythemia
• Prefibrotic MF
• Overt MF with significant reticulin/collagen fibrosis

How to recognize progression from PV to MF

• Progressive anemia or falling hemoglobin despite previous erythrocytosis
• Enlarging spleen
• Teardrop red cells and immature cells in peripheral blood
• Increasing marrow fibrosis on biopsy
• Fever, night sweats, weight loss, or bone pain

Bottom line

• High Hb/Hct + low EPO + JAK2: think PV.
• Anemia + teardrop cells + large spleen + marrow fibrosis: think MF.
• Known PV followed by anemia, splenomegaly, and fibrosis: think post-PV MF.

Myeloproliferative neoplasms (MPNs)

1. Polycythemia vera (PV): mainly excess red blood cells
2. Essential thrombocythemia (ET): mainly excess platelets
3. Primary myelofibrosis (PMF): abnormal marrow function with progressive fibrosis

How the main MPNs differ

Shared symptoms of MPN

• Fatigue
• Headache, dizziness, visual symptoms
• Night sweats, fever, weight loss
• Enlarged spleen causing left upper abdominal fullness or early satiety
• Blood clots or bleeding
• Elevated uric acid and sometimes gout

Key tests used to diagnose and classify MPN

1. Serial CBCs and peripheral smear
2. JAK2 V617F mutation test
3. If negative, JAK2 exon 12 in suspected PV, or CALR/MPL testing in suspected ET/MF
4. Serum EPO, particularly for suspected PV
5. Bone-marrow biopsy with reticulin fibrosis grading
6. BCR::ABL1 test to exclude chronic myeloid leukemia
7. LDH, uric acid, iron studies, and abdominal imaging when indicated

Simple way to remember

• PV: “too many red cells”
• ET: “too many platelets”
• MF: “marrow fibrosis, anemia, large spleen”
• MPN: “the group that includes PV, ET, and MF”

Treatment principles

• PV: phlebotomy to control hematocrit, low-dose aspirin when appropriate, and cytoreductive therapy for selected higher-risk patients.
• ET: observation or aspirin in selected patients; cytoreduction for higher-risk thrombosis or severe symptoms.
• MF: observation in low-risk asymptomatic disease, anemia-directed therapy and transfusion when needed, JAK-inhibitor therapy for symptomatic splenomegaly/constitutional symptoms, and allogeneic stem-cell transplantation for carefully selected higher-risk patients.

Polycythemia vera (PV)

Definition

Cause

• JAK2 V617F mutation: present in about 95%-98% of cases
• JAK2 exon 12 mutation: accounts for most remaining JAK2-negative-V617F cases

Symptoms and signs

• Headache, dizziness, light-headedness
• Blurred vision or visual spots
• Fatigue
• Ruddy or red complexion
• Itching after a warm bath or shower, called aquagenic pruritus
• Burning pain, redness, or warmth of hands and feet, called erythromelalgia
• Tingling or numbness
• Fullness or pain below the left ribs from an enlarged spleen
• High blood pressure
• Gout or high uric acid

Major complications

• Deep-vein thrombosis or pulmonary embolism
• Stroke or transient ischemic attack
• Heart attack
• Portal, hepatic, splenic, or cerebral venous thrombosis

Diagnosis

Key investigations

1. Complete blood count
   • Persistent raised hemoglobin, hematocrit, or red-cell count
   • White-cell and platelet counts may be raised too
2. JAK2 mutation testing
   • Test JAK2 V617F first
   • If negative but PV remains suspected, test JAK2 exon 12
3. Serum erythropoietin (EPO)
   • Usually low in PV
   • Helps distinguish PV from secondary erythrocytosis due to hypoxia, smoking, sleep apnea, lung disease, high altitude, or excess EPO production
4. Bone-marrow biopsy
   • Often shows hypercellular marrow with increased red-cell, white-cell, and megakaryocyte production, called panmyelosis
   • Helps distinguish PV from ET, MF, and secondary causes of raised red-cell count
5. Excluding other causes
   • Oxygen saturation
   • Smoking and medication history
   • Sleep-apnea or cardiopulmonary assessment when relevant
   • Iron studies
   • Abdominal imaging if splenomegaly or abdominal thrombosis is suspected

Treatment principles

• Phlebotomy (venesection): removes blood to reduce hematocrit. A common target is hematocrit below 45%.
• Low-dose aspirin: often used to lower clot risk, but only if a clinician judges bleeding risk acceptable.
• Cytoreductive therapy for higher-risk disease, significant symptoms, or difficult-to-control counts. Options can include hydroxyurea or interferon-based therapy.
• Ruxolitinib, a JAK inhibitor, may be used in selected people who do not respond adequately to or cannot tolerate hydroxyurea.
• Control modifiable cardiovascular risks: do not smoke, and manage hypertension, diabetes, cholesterol, and obesity.

PV versus secondary polycythemia

Progression

Alport syndrome

1. Persistent hematuria - blood in the urine, often microscopic
2. Progressive kidney disease with proteinuria and possible kidney failure
3. Sensorineural hearing loss
4. Eye abnormalities in some people

Cause and genetics

Pathology

• Early: basement-membrane thinning
• Later: irregular thickening, splitting, and lamellation
• Electron microscopy: characteristic “basket-weave” appearance

Symptoms and signs

Kidney manifestations

• Persistent microscopic hematuria, often beginning in childhood
• Episodes of visible blood in urine, sometimes after infections or exercise
• Proteinuria or albuminuria
• Hypertension
• Progressive decline in eGFR and chronic kidney disease
• Kidney failure in more severe disease

Hearing manifestations

• Bilateral sensorineural hearing loss, commonly affecting high frequencies
• Often develops in late childhood or adolescence in more severely affected individuals

Eye manifestations

• Anterior lenticonus, a cone-shaped protrusion of the lens that is highly suggestive of Alport syndrome
• Dot-and-fleck retinopathy
• Corneal changes
• Reduced vision in some cases

Diagnosis

Important investigations

1. Urinalysis and urine albumin-creatinine ratio
   • Persistent hematuria
   • Proteinuria/albuminuria
2. Kidney function tests
   • Serum creatinine and eGFR
3. Genetic testing
   • Testing for COL4A3, COL4A4, and COL4A5 variants is now the preferred confirmatory test.
   • It identifies the inheritance pattern and helps assess risk for relatives.
4. Hearing assessment
   • Formal audiometry, even if hearing seems normal.
5. Eye examination
   • Slit-lamp examination and retinal assessment.
6. Kidney biopsy
   • May be useful when genetic testing is unavailable or uncertain.
   • Electron microscopy may show the basket-weave basement membrane.
   • It is no longer always necessary if a pathogenic collagen-IV variant is identified.

Treatment and follow-up

Main management

• ACE inhibitor or an ARB to reduce proteinuria and protect kidney function
• Regular monitoring of:
  • Blood pressure
  • Urine albumin/protein
  • Creatinine and eGFR
• Avoid smoking and manage blood pressure, weight, and cardiovascular risk
• Avoid unnecessary nephrotoxic drugs, especially frequent NSAID use
• Hearing aids and audiology support when needed
• Ophthalmology follow-up for eye complications
• Genetic counselling and cascade testing of family members

Kidney failure

Alport versus thin basement membrane nephropathy

Causes of Alport syndrome

• COL4A5: most common, causes X-linked Alport syndrome
• COL4A3 and COL4A4: cause autosomal recessive or autosomal dominant Alport syndrome

Inheritance patterns

Airway involvement in Alport syndrome

Rare exception: Alport syndrome with diffuse leiomyomatosis

• Esophagus
• Trachea and bronchi
• Gastrointestinal tract
• Female genital tract

Possible airway/respiratory symptoms in this rare form

• Noisy breathing or stridor
• Wheeze not responding as expected to asthma treatment
• Breathlessness
• Recurrent chest infections
• Cough
• Airway narrowing due to tracheobronchial leiomyomatosis

Anesthesia implications

• Renal function and dialysis status
• Blood pressure
• Anemia and electrolyte abnormalities
• Hearing impairment for communication needs
• Any history of stridor, wheeze, breathing difficulty, dysphagia, or known diffuse leiomyomatosis

Anesthesia precautions in Alport syndrome

Preoperative assessment

• Latest creatinine, eGFR, urea, electrolytes, especially potassium and bicarbonate
• Urinalysis/proteinuria and fluid status
• Blood pressure and cardiovascular history
• Hemoglobin and platelet count, particularly if chronic kidney disease is advanced
• Current drugs, especially ACE inhibitors/ARBs, diuretics, antihypertensives, anticoagulants, and dialysis-related medications
• Whether the person has a kidney transplant or receives dialysis
• Hearing impairment, so communication and consent support can be arranged
• History of stridor, wheeze, swallowing difficulty, recurrent chest infections, or known diffuse leiomyomatosis

Kidney-protection measures during anesthesia

• Maintain adequate circulating volume and blood pressure to preserve kidney perfusion.
• Avoid prolonged hypotension, hypoxia, major blood loss, and dehydration.
• Use perioperative fluids carefully. Too little fluid can worsen renal perfusion; excessive fluid can cause pulmonary edema in advanced CKD.
• Adjust doses and intervals of drugs that are substantially eliminated by the kidneys, especially in reduced eGFR.
• Avoid or minimize nephrotoxins where alternatives exist, including NSAIDs, aminoglycosides, and unnecessary iodinated contrast.
• Monitor urine output when appropriate, though it is not reliable in advanced renal failure or dialysis-dependent patients.
• Recheck creatinine and electrolytes after major surgery or any episode of hypotension, bleeding, or sepsis.

Medication considerations

• ACE inhibitors/ARBs: these are commonly used in Alport syndrome to reduce proteinuria and slow kidney decline. Whether to take them on the morning of surgery must be decided individually by the anesthetist and prescribing clinician because they may contribute to intraoperative hypotension.
• NSAIDs: generally avoid for postoperative analgesia if there is CKD or risk of kidney injury. Paracetamol/acetaminophen, local or regional techniques, and carefully selected opioids may be used instead.
• Opioids: dose selection may need adjustment in renal impairment because some opioid metabolites can accumulate.
• Antibiotics and anticoagulants: require renal-dose review when kidney function is reduced.

If the patient is on dialysis

• Coordinate surgery with the nephrology and dialysis teams.
• Elective procedures are often scheduled after a recent dialysis session to optimize volume status and potassium, but timing is individualized.
• Check potassium, acid-base status, volume status, and hemoglobin.
• Protect the arteriovenous fistula or graft: do not use that arm for blood pressure cuffs, IV access, or blood sampling unless specifically directed.

Airway precautions

• Preoperative ENT or respiratory assessment
• Review of prior CT, bronchoscopy, or airway reports
• A prepared difficult-airway plan if tracheal or bronchial narrowing is known or suspected

Hearing and eye precautions

• Hearing impairment may require hearing aids to remain in place until induction, written communication, or an interpreter/family support where appropriate.
• Inform staff of any known eye abnormality, including lenticonus or reduced vision. This does not normally change anesthetic technique, but helps prevent injury and improve communication.

Bottom line

1. Assess renal function, potassium, BP, anemia, and dialysis status.
2. Avoid kidney injury from hypotension, dehydration, nephrotoxic drugs, and unadjusted medication doses.
3. Plan communication for hearing impairment.
4. Investigate airway symptoms only if there is concern for the rare diffuse-leiomyomatosis variant.

• Valve narrowing or leakage, especially aortic stenosis or significant mitral regurgitation
• A hole between heart chambers, such as a ventricular septal defect
• High-flow states, such as severe anemia, fever, thyroid overactivity, or pregnancy
• An arteriovenous fistula, including a dialysis fistula
• A forceful or displaced heartbeat from an enlarged/strained ventricle, called a heave or prominent apical impulse
• Rapid or irregular rhythm causing awareness of the heartbeat, called palpitations

• Muscle twitching
• Chest-wall vibration from coughing or wheeze
• Anxiety-related tremor/palpitations
• A vibration from an implanted device or a nearby dialysis fistula

What evaluation is needed

• Blood pressure, pulse, oxygen saturation
• Heart and lung examination for a murmur, thrill, heave, or crackles
• ECG
• Echocardiogram, the key test for heart size, pumping function, and valve disease
• Chest X-ray and blood tests if heart failure or anemia is suspected

Seek urgent care now if there is

• Chest pain or pressure
• New or worsening shortness of breath, particularly at rest or lying flat
• Fainting, severe dizziness, or confusion
• A sustained fast/irregular heartbeat
• Blue lips, sweating, or severe weakness
• Leg swelling with breathlessness

How an AVF can affect the heart

• Forceful, hyperdynamic heartbeat or precordial heave
• Enlarged heart chambers or hypertrophy
• Left and/or right ventricular dysfunction
• Pulmonary hypertension
• High-output heart failure

Important clarification

Recommended evaluation

1. Echocardiography
   • LV and RV size and function
   • Ejection fraction
   • Valve disease
   • Pulmonary artery pressure
   • Cardiac output/index if possible
2. AVF Doppler ultrasound
   • Access flow, called Qa
   • Evidence of stenosis, aneurysmal dilatation, or excessive flow
3. Clinical assessment
   • BP, pulse rate, oxygen saturation
   • Signs of heart failure: raised JVP, lung crackles, leg edema, enlarged liver
   • Hemoglobin to exclude severe anemia, another high-output cause
   • Renal function, potassium, bicarbonate, and volume status
   • BNP/NT-proBNP may help, but interpretation is difficult in advanced kidney disease
4. Chest X-ray
   • To assess cardiac silhouette and pulmonary congestion when breathlessness or heart failure is suspected.

Management if high-flow AVF is confirmed

• Optimizing fluid removal and BP control
• Treating anemia or other high-output contributors
• AVF flow-reduction procedures, such as banding/revision
• AVF ligation only when necessary and after planning alternative dialysis access if dialysis is still needed

Seek urgent assessment today if there is

• Breathlessness at rest, orthopnea, or waking breathless at night
• New leg swelling
• Chest pain, syncope, confusion, or oxygen desaturation
• Persistent tachycardia or low blood pressure
• Rapidly worsening fatigue or reduced exercise tolerance

• Left upper-limb AV fistula
• ECG suggesting biventricular hypertrophy
• CXR showing cardiomegaly
• A strong chest pulsation/vibration

Next important tests

1. 2D echocardiography with Doppler: chamber sizes, LV ejection fraction, RV function, valve disease, pulmonary artery pressure, pericardial effusion, and estimated cardiac output.
2. AVF Doppler ultrasound: measure fistula flow and identify a high-flow access.
3. CBC, renal function, electrolytes, hemoglobin, volume status, and blood pressure.
4. Cardiology and nephrology review.