Updated: 3/2/2017

Paroxysmal Nocturnal Hemoglobinuria (PNH)

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Snapshot
  • A 25-year-old pregnant woman presents with fatigue and abdominal pain in the emergency room. She reports feeling unwell for the past few days. Every morning, she notices that her urine is tea-colored, which slowly resolves throughout the day. She has a low-grade fever. On physical exam, her skin is jaundiced, her liver edge is palpable, and she has abdominal tenderness to palpation.  Her physicians are suspicious of Budd-Chiari syndrome.
Introduction

  • Clonal stem cell defect from mutation in hematopoietic stem cell
  • Pathogenesis
    • mutation in PIGA gene
    • defect in glycosylphosphatidylinositol (GPI) anchors CD55 (decay-accelerating factor) and CD59 on RBC membrane
      • these protect RBC from complement
      • DAF inhibits C3 convertase 
    • complement-mediated destruction of RBCs
  • "PNH Thrombosis"
    • Pancytopenia
    • with Nocturnal build up of dark urine
    • Coombs negative Hemolytic anemia (complement-mediated)
    • venous Thrombosis
  • Acute hemolysis often triggered by stress, infection, surgery, and other inflammatory states
  • May cause
    • aplastic anemia
    • myelodysplasia
    • acute leukemia
Presentation
  • Symptoms/physical exam
    • episodic dark urine with first urine of the day
      • caused by hemoglobin
    • hemolytic anemia: pallor, fatigue, tachycardia, jaundice, and gross hematuria
    • thrombocytopenia: mucosal bleeding, petechiae,and  ecchymoses
    • leukemia: infections
    • thrombosis
    • renal impairment
Evaluation
  • Flow cytometry – most accurate test
    • CD55/59-negative RBCs
  • Labs
    • anemia
    • thrombocytopenia
    • leukopenia
Differential Diagnosis
  • Aplastic anemia
  • Myelodysplasia
Treatment
  • Eculizumab
    • inactivates C5 in complement pathway
    • decreases red cell destruction
    • complement inhibitor
    • must vaccinate all against Neisseria due to increased risk
  • Allogeneic bone marrow transplant
  • Supportive therapy
    • folic acid
    • transfusions as needed
Prognosis, Prevention, and Complications
  • Prognosis
    • improved with use of eculizumab
  • Complications
    • renal insufficiency
    • thromboembolism
    • 5% develop myelodysplasia
    • 2.5% develop acute leukemias
 

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Questions (2)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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(M1.HE.75) A 42-year-old male presents to his primary care physician with complaints of fatigue and occasionally darkened urine over the past 3 months. Upon further questioning, the patient reveals that he has regularly had dark, 'cola-colored' urine when he has urinated at night or early in the morning. However, when he urinates during the day, it appears a much lighter yellow color. Laboratory work-up is initiated and is significant for a hemoglobin of 10.1 g/dL, elevated LDH, platelet count of 101,000/uL, and leukopenia. Urinalysis, taken from an early morning void, reveals brown, tea-colored urine with hemoglobinuria and elevated levels of hemosiderin. Which of the following is responsible for this patient's presentation? Review Topic

QID: 106774
1

Deficiency of C1 esterase-inhibitor

15%

(25/167)

2

Autosomal dominant deficiency of spectrin protein in the RBC membrane

13%

(22/167)

3

Presence of a temperature-dependent IgG autoantibody

8%

(14/167)

4

Deficiency of CD-55 and CD-59 cell membrane proteins

56%

(94/167)

5

Autosomal recessive deficiency of platelet Glycoprotein IIb/IIIa receptor

2%

(4/167)

M1

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