Primary Myelofibrosis

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Last updated: March 25, 2026Bookmark

Primary myelofibrosis is characterised by the replacement of bone marrow by fibrous tissue. There are abnormal proliferating megakaryocytes and granulocytes that produce cytokines that stimulate fibrosis. The typical presentation is a patient with anaemia, teardrop RBCs, leukoerythroblastosis, and hepatosplenomegaly. No specific treatment exists.

Primary myelofibrosis is the least common myeloproliferative neoplasm. It peaks at > 60 years of age. It affects men more than women.

Definition of terms

TermDefinition
Pre-fibrotic primary myelofibrosisThere is sustained proliferation of megakaryocytes without significant fibrosis (reticulin fibrosis < grade 1)
Overt fibrosisThere is sustained proliferation of megakaryocytes with significant fibrosis (reticulin fibrosis > grade 1)

Grading of myelofibrosis

GradeDescription
MF-0Scattered linear reticulin with no intersections (normal bone marrow)
MF-1Loose network of reticulin with many intersections
MF-2Diffuse and dense reticulin with extensive intersection. Focal bundles of collagen and focal osteosclerosis
MF-3Diffuse and dense reticulin with extensive intersections. Coarse bundles of collagen and osteosclerosis.
  • Pathophysiology
    • Mutations in JAK2, CALR, or MPL → neoplastic proliferation of megakaryocytes
    • Neoplastic megakaryocytes release TGF-B, PDGF, IL-1, EGF, and FGF → fibroblast proliferation, matrix deposition, and endothelial proliferation
  • Signs and symptoms
    • Asymptomatic (30%)
    • Fever, weight loss, night sweats
    • Fatigue, pallor, breathlessness (due to anemia)
    • Splenomegaly (90%, often considered a hallmark)
    • Hepatomegaly (50%, portal hypertension develops as a complication and may precede the onset of disease)
    • Leukocytosis and thrombocytopenia
    • Leukopenia and thrombocytopenia (less common)
    • Gouty arthritis
    • Renal stones
    • Thrombosis
    • Hemorrhagic episodes (due to marked thrombocytosis), pruritus, and pulmonary hypertension
  • Differentials
  • Investigations
    • Complete Blood Count
      • Anemia
      • Leukopenia
      • Leukocytosis
      • Thrombocytosis
    • Peripheral Blood Film
      • Leukoerythroblastosis with teardrop RBCs
      • Large platelets
      • Blasts
      • Pegler-huet cells
    • Trephine biopsy
      • Dry tap (30%)
      • Patchy hematopoietic cellularity
      • Reticulin fibrosis
      • Megakaryocytes present in clusters (may be dysplastic)
      • Distended marrow sinusoid (frequently containing intravascular hematopoiesis)
    • Molecular studies to detect JAK2, CALR, MPL, BCR-ABL
      • BCR-ABL: negative
      • JAK2 V617F mutations: positive (50-60%)
      • CALR mutations: positive (25-20%) – better prognosis
      • MPL mutation: positive (5-10%)
      • Triple-negative mutation for JAK2, CALR, AND MPL: positive (8-12%)
      • Other mutations in ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2 or SR3B1: positive
      • Karyotype: del(20q), del(13q) in 50% of cases
  • Treatment
    • Splenectomy to reduce symptoms
    • Ruxolitinib has some efficacy in treating constitutional symptoms
    • A bone marrow transplant is the only definitive cure
Reference Intervals ›
Biochemistry
ACTHP: <80 ng/L
ALTP: 5–35 U/L
AlbuminP: 35–50 g/L
AldosteroneP: 100–500 pmol/L
Alk. phosphataseP: 30–130 U/L
α-AmylaseP: 0–180 IU/dL
α-FetoproteinS: <10 kU/L
Angiotensin IIP: 5–35 pmol/L
ADHP: 0.9–4.6 pmol/L
ASTP: 5–35 U/L
BicarbonateP: 24–30 mmol/L
BilirubinP: 3–17 μmol/L
BNPP: <50 ng/L
CRPP: <10 mg/L
CalcitoninP: <0.1 mcg/L
Calcium (ionized)P: 1.0–1.25 mmol/L
Calcium (total)P: 2.12–2.60 mmol/L
ChlorideP: 95–105 mmol/L
CholesterolP: <5.0 mmol/L
VLDLP: 0.128–0.645 mmol/L
LDLP: <2.0 mmol/L
HDLP: 0.9–1.93 mmol/L
Cortisol AMP: 450–700 nmol/L
Cortisol MidnightP: 80–280 nmol/L
CK ♂P: 25–195 U/L
CK ♀P: 25–170 U/L
CreatinineP: 70–100 μmol/L
FerritinP: 12–200 mcg/L
FolateS: 2.1 mcg/L
FSHP: 2–8 U/L ♂; >25 menopause
GGT ♂P: 11–51 U/L
GGT ♀P: 7–33 U/L
Glucose (fasting)P: 3.5–5.5 mmol/L
Growth hormoneP: <20 mu/L
HbA1C (DCCT)B: 4–6%
HbA1C (IFCC)B: 20–42 mmol/mol
Iron ♂S: 14–31 μmol/L
Iron ♀S: 11–30 μmol/L
Lactate (venous)P: 0.6–2.4 mmol/L
Lactate (arterial)P: 0.6–1.8 mmol/L
LDHP: 70–250 U/L
LHP: 3–16 U/L
MagnesiumP: 0.75–1.05 mmol/L
OsmolalityP: 278–305 mosmol/kg
PTHP: 0.8–8.5 pmol/L
PotassiumP: 3.5–5.3 mmol/L
Prolactin ♂P: <450 U/L
Prolactin ♀P: <600 U/L
PSAP: 0–4 mcg/mL
Protein (total)P: 60–80 g/L
Red cell folateB: 0.36–1.44 μmol/L
Renin (erect)P: 2.8–4.5 pmol/mL/h
Renin (recumbent)P: 1.1–2.7 pmol/mL/h
SodiumP: 135–145 mmol/L
TBGP: 7–17 mg/L
TSHP: 0.5–4.2 mU/L
T4P: 70–140 nmol/L
Free T4P: 9–22 pmol/L
TIBCS: 54–75 μmol/L
TriglyceridesP: 0.50–2.3 mmol/L
T3P: 1.2–3.0 nmol/L
Troponin TP: <0.1 mcg/L
Urate ♂P: 210–480 μmol/L
Urate ♀P: 150–390 μmol/L
UreaP: 2.5–6.7 mmol/L
Vitamin B12S: 0.13–0.68 nmol/L
Vitamin DS: 50 nmol/L
Arterial Blood Gases
pH7.35–7.45
PaCO₂4.7–6.0 kPa
PaO₂>10.6 kPa
Base excess±2 mmol/L
Urine
Cortisol (free)<280 nmol/24h
Hydroxyindole acetic acid16–73 μmol/24h
Hydroxymethylmandelic acid16–48 μmol/24h
Metanephrines0.03–0.69 μmol/mmol cr.
Osmolality350–1000 mosmol/kg
17-Oxogenic steroids ♂28–30 μmol/24h
17-Oxogenic steroids ♀21–66 μmol/24h
17-Oxosteroids ♂17–76 μmol/24h
17-Oxosteroids ♀14–59 μmol/24h
Phosphate (inorganic)15–50 mmol/24h
Potassium14–120 mmol/24h
Protein<150 mg/24h
Protein/creatinine ratio<3 mg/mmol
Sodium100–250 mmol/24h
Haematology
WCC4.0–11.0 ×10⁹/L
RBC ♂4.5–6.5 ×10¹²/L
RBC ♀3.9–5.6 ×10¹²/L
Hb ♂130–180 g/L
Hb ♀115–160 g/L
PCV ♂0.4–0.54 L/L
PCV ♀0.37–0.47 L/L
MCV76–96 fL
MCH27–32 pg
MCHC300–360 g/L
RDW11.6–14.6%
Neutrophils2.0–7.5 ×10⁹/L (40–75%)
Lymphocytes1.0–4.5 ×10⁹/L (20–45%)
Eosinophils0.04–0.44 ×10⁹/L (1–6%)
Basophils0–0.10 ×10⁹/L (0–1%)
Monocytes0.2–0.8 ×10⁹/L (2–10%)
Platelets150–400 ×10⁹/L
Reticulocytes0.8–2.0% / 25–100 ×10⁹/L
Prothrombin time10–14 s
APTT35–45 s
Paediatric
Pulse Rate (bpm)
Neonate140–160
Infant <1yr120–140
1–5 years110–130
5–12 years80–120
>12 years70–100
Respiratory Rate (tachypnoea)
0–2 months≥60/min
2–12 months≥50/min
1–5 years≥40/min
>5 years≥30/min
Blood Pressure (mmHg)
Term65/45
1 year75/50
4 years85/60
8 years95/65
10 years100/70
Weight Formulas
3–12 months(a + 9)/2 kg
1–6 years2a + 8 kg
>6 years(7a − 5)/2 kg
Haemoglobin (g/dL)
Term newborn13–20
1 month11–18
2 months10–15
1–2 years10–13
>2 years11–14
MUAC (6 months–5 years)
Obese>17.5 cm
Normal13.5–17.4 cm
At risk12.5–13.4 cm
Moderate malnutrition11.5–12.4 cm
Severe malnutrition<11.5 cm
Developmental Milestones
Social smile1.5 months
Head control4 months
Sits unsupported7 months
Crawls10 months
Stands unsupported10–12 months
Walks12–13 months
Talks18 months
CSF WBC (/mm³)
Term newborn0–25
>2 weeks0–5
Calculator ›

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