Paroxysmal Nocturnal Hemoglobinuria (PNH)

Definition

• Robbins & Kumar Basic Pathology, p. 605
• Goldman-Cecil Medicine, Ch. 146

Pathogenesis

The PIGA Mutation

• Nearly 150 different PIGA mutations have been identified
• Most inactivate PIGA completely → PNH III cells (fully deficient)
• Partial deficiency → PNH II cells (3-5x normal complement sensitivity)
• PNH III cells: 15-25x normal complement sensitivity

Why Does the Clone Expand?

GPI-Linked Proteins Lost in PNH

Clinical Features

Classic Triad

1. Hemolytic anemia - chronic intravascular, often with reticulocytosis less than expected
2. Venous thrombosis - in unusual sites
3. Cytopenias (variable) - neutropenia in 3/5, thrombocytopenia in 2/3 at some point

Hemoglobinuria

Thrombosis - The Major Killer

• Affects ~40% of patients
• 85% venous, often in unusual sites:
  • Hepatic veins (Budd-Chiari syndrome)
  • Portal vein
  • Cerebral veins
  • Abdominal veins
• Mechanism: CD59 absence on platelets → phosphatidylserine externalization → prothrombinase complex assembly; also, free hemoglobin scavenges nitric oxide (NO), causing vasoconstriction and platelet activation
• Abdominal pain in ~1/3 of patients is linked to NO scavenging by free hemoglobin (also causes dysphagia, erectile dysfunction)

Iron Deficiency

Epidemiology

• Incidence: ~2-5 per million/year
• Any age, most common 10-50 years; mean age at diagnosis ~34 years
• Female:male ratio ~1:1
• Median survival ~20 years after diagnosis

PNH Categories

1. Classic PNH - hemolysis predominant, large clone
2. PNH in the setting of another bone marrow disorder (aplastic anemia, MDS) - cytopenias predominant; PNH clone usually small
3. Subclinical PNH - small GPI-deficient clone, no clinical hemolysis
   • Found in 50-60% of aplastic anemia patients
   • Found in 15-20% of MDS patients

Diagnosis

Gold Standard: Flow Cytometry (FLAER-based)

• Neutrophils: FLAER + CD24 + CD15 + CD45
• Monocytes: FLAER + CD14 + CD64 + CD45
• Red blood cells: CD235a / CD59 (two-color)

Other Lab Findings

Treatment

Anti-Complement Therapy (Disease-Modifying)

Meningococcal Vaccination - Mandatory

Allogeneic BMT (Stem Cell Transplant)

• Severe aplastic anemia with PNH
• Refractory disease
• Significant cytopenias
• Carries nonnegligible procedure-related risks

Supportive Care

• Iron supplementation (for hemosiderinuria-related deficiency)
• Folate supplementation
• Anticoagulation for thrombosis (not clearly effective prophylactically in untreated patients; complement inhibitors reduce thrombosis risk more effectively)
• Transfusions when needed (washed RBCs preferred to avoid additional complement triggers)
• Corticosteroids may reduce some hemolytic episodes

Key Associations

• Aplastic anemia - bidirectional; PNH may evolve from AA; AA may follow PNH; autoimmune basis explains the link
• MDS - small subclinical PNH clones in 15-20% of MDS
• Budd-Chiari syndrome - think PNH in any young patient with hepatic vein thrombosis
• Iron deficiency with hemolytic markers - unusual combination that should raise PNH suspicion

Summary Mnemonics

• Robbins & Kumar Basic Pathology, p. 605-606
• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 606
• Goldman-Cecil Medicine, Ch. 146
• Harrison's Principles of Internal Medicine 22E (2025), p. 848-849
• Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 693, 798

Spleen Anatomy

Position and Size

Development

Surfaces and Poles

Visceral Relations

Peritoneal Ligaments

Blood Supply

Arterial

• Splenic artery - from the celiac trunk (occasionally arises from the aorta, SMA, middle colic, left gastric, or left/right hepatic arteries)
• Two branching patterns:
  • Distributed type (more common) - multiple branches spread out before entering the hilum
  • Magistral type - long trunk that divides closer to the hilum into 3-4 compact branches (makes vessel dissection harder surgically)
• The splenic trunk also gives off the left gastroepiploic artery (runs along the greater curvature of the stomach) and short gastric arteries (supply the fundus)
• Inferior polar arteries arise from the left gastroepiploic artery

Venous

• Splenic vein exits the hilum → joins the superior mesenteric vein to form the portal vein
• Venous drainage goes into the portal circulation

Microscopic (Internal) Anatomy

Red Pulp (~75-80% of volume)

• Contains large amounts of blood
• Made of pulp cords (of Billroth) and splenic sinusoids between them
• Sinusoidal walls are lined by spindle-shaped longitudinal endothelium with slit-like openings (allowing RBCs to squeeze through)
• Discontinuous basement membrane; lined by circumferential reticulin fibers
• Contains macrophages - critical for filtering the blood (removing aged RBCs, opsonized bacteria, immune complexes)

White Pulp (lymphoid tissue)

Marginal Zone

Vascular Architecture (the key to understanding splenic function)

1. Open circulation (~majority): capillaries empty into perisinusoidal cords → blood filters through slit-like openings in sinusoidal walls → splenic sinusoids
2. Closed circulation (~minority): capillaries open directly into sinusoids

Functions (Anatomy-Function Correlation)

Clinical Correlates

• Splenomegaly: palpable below the left costal margin; normal spleen is not palpable. The spleen must enlarge ~2-3x before becoming palpable
• Splenectomy / asplenia: loss of filtration for encapsulated bacteria (pneumococci, meningococci, H. influenzae) → OPSI (overwhelming post-splenectomy infection). Vaccination against these organisms is mandatory
• Splenic rupture: most common from blunt abdominal trauma; protected by ribs 9-12 but vulnerable. Blood collects in left upper quadrant. Managed non-operatively in stable patients (especially children)
• Splenic infarct: most commonly from emboli (e.g., in infective endocarditis, sickle cell disease); presents with left upper quadrant pain radiating to the left shoulder (Kehr's sign - diaphragmatic irritation)
• Accessory spleen (splenunculi): found in ~10-15% of people, most commonly at the splenic hilum or in the gastrosplenic ligament. Clinically important if splenectomy is performed for haematological disease (residual accessory spleen can proliferate and cause disease relapse)
• Wandering spleen: hypermobile spleen due to lax ligaments; can undergo torsion

• Gray's Anatomy for Students, p. 399-400
• Cellular and Molecular Immunology (Abbas), p. 120-122
• Color Atlas of Human Anatomy, Vol. 2 - Internal Organs, p. 662
• Current Surgical Therapy 14e, p. (Surgical Anatomy of the Spleen)
• Bailey and Love's Short Practice of Surgery 28e

Splenic Injury in Surgery

Overview and Epidemiology

1. Blunt trauma - most common; motor vehicle collisions, falls, sporting injuries, assault
2. Penetrating trauma - stab wounds, gunshot wounds; may traverse the anterior/posterior abdominal wall, flank, or transthoracically through the pleura and diaphragm
3. Iatrogenic injury - operative trauma during adjacent procedures (especially colectomy, gastric surgery)
4. Spontaneous rupture - rare; from underlying disease (neoplastic 30%, infectious 27%, inflammatory 20%, drug-related 9%)

AAST Spleen Injury Scale (Grading)

Advance one grade for multiple injuries up to Grade III.

Diagnosis

Clinical

• Left upper quadrant pain, left shoulder tip pain (Kehr's sign - referred pain from diaphragmatic irritation by blood)
• Haemodynamic instability in significant injury
• Decreasing serial haematocrit (ongoing intraperitoneal haemorrhage)
• WBC often rises >15,000/mm³
• Plain films may show: fractured ribs, elevated left hemidiaphragm, enlarged splenic shadow, medial gastric displacement, widening between splenic flexure and preperitoneal fat

Imaging

• Multiphase contrast-enhanced CT: sensitivity and specificity >95%
• Parenchymal laceration: linear low-attenuation defects, almost always with haemoperitoneum
• Haematoma: may be hyperdense or isodense on unenhanced CT; fails to enhance with IV contrast
• Vascular blush (focal area of contrast enhancement within a haematoma): indicates active arterial bleeding - strongly predicts failure of non-operative management and signals need for angioembolisation
• Subcapsular haematoma: crescentic well-defined lesion along splenic margin
• A laceration traversing both capsular surfaces = splenic fracture

• Used in initial resuscitation to detect free fluid
• Not sensitive enough to reliably exclude significant splenic injury
• Useful for follow-up of haematoma resolution

Management

Decision Framework

SPLENIC INJURY
      │
      ├─ Haemodynamically UNSTABLE → Emergency laparotomy
      │
      └─ Haemodynamically STABLE
              │
              ├─ Grades I-III (most) → Non-operative management (NOM)
              ├─ Grade IV-V → Consider NOM if no blush; angioembolisation if blush
              └─ Blush on CT → Angioembolisation

1. Non-Operative Management (NOM)

• Haemodynamic stability
• No peritoneal signs requiring laparotomy
• No associated injuries mandating surgery
• Access to ICU monitoring, serial clinical examination, blood products, and operating theatre

• ICU admission and close haemodynamic monitoring
• Serial haematocrit and clinical examination
• Bed rest (duration varies by grade: Grade I-II ~2 days, Grade III ~3-5 days)
• Avoid NSAIDs and anticoagulants
• Activity restriction after discharge (avoid contact sports for weeks to months based on grade)
• Follow-up CT or ultrasound recommended - risk of splenic pseudoaneurysm after trauma is unrelated to injury severity

• Haemodynamic deterioration
• Increasing transfusion requirements
• Signs of peritonitis
• Other intra-abdominal injuries identified

2. Angioembolisation

• Indicated for haemodynamically stable patients with vascular blush on CT, or high-grade injuries (Grade III-V) with ongoing concern for failure
• Can be performed as proximal (main splenic artery) or distal (branch vessel) embolisation
• Preserves splenic tissue and function (especially immune function) better than splenectomy
• Reduces failure rate of NOM in high-grade injuries
• Complication: Post-embolisation pancreatitis if the pancreatica magna vessel is occluded

3. Operative Management

• Haemodynamic instability not responding to resuscitation
• Failed NOM
• Peritonitis or other injuries requiring laparotomy
• Penetrating splenic injury (relative - consider NOM if stable)

A. Splenorrhaphy (Splenic Repair/Conservation)

B. Splenectomy

• Grade V injury (shattered spleen, hilar devascularisation)
• Failure of repair
• Haemodynamic instability
• Multiple intra-abdominal injuries or physiological compromise

1. Midline laparotomy (best access)
2. Manual compression / packing to control haemorrhage
3. Divide the phrenicosplenic and splenocolic ligaments (avascular - safe to cut)
4. Divide short gastric vessels (gastrosplenic ligament) - careful not to injure the stomach
5. Expose the splenic hilum within the splenorenal ligament
6. Ligate and divide splenic artery first (reduces blood loss), then splenic vein
7. Check for accessory spleens (present in ~10-15%) - must remove if operating for haematological disease, though irrelevant in trauma

4. Post-Splenectomy Care

• Thrombocytosis - platelet count rises, may mimic sepsis clinically
• Leucocytosis - WBC rises transiently
• Howell-Jolly bodies appear on blood film (nuclear remnants no longer pitted by spleen)
• Overwhelming Post-Splenectomy Infection (OPSI) - lifelong risk; most dangerous in first 2 years

• Most commonly caused by encapsulated bacteria: Streptococcus pneumoniae (most common), Haemophilus influenzae type b, Neisseria meningitidis
• Presents as rapidly progressive sepsis with high mortality
• Prevention:
  • Vaccination (pneumococcus, meningococcus, H. influenzae) - ideally given 2 weeks pre-operatively for elective; 2-3 weeks post-op if emergency (by which time immune system has partly recovered)
  • Lifelong prophylactic penicillin (especially in children and for first 2 years post-splenectomy)
  • Patient education: seek urgent medical attention for any febrile illness

5. Delayed Splenic Rupture

• Occurs days to weeks after initial trauma, classically after an apparently minor injury
• Mechanism: initial subcapsular haematoma expands and then ruptures through the capsule
• Classic presentation: patient discharged after conservative management, returns with sudden cardiovascular collapse
• Pseudoaneurysm may form and rupture - hence follow-up imaging is recommended regardless of injury severity
• Underscores importance of patient education after NOM and follow-up CT

Splenic Injury in Specific Surgical Contexts

During Colectomy / Splenic Flexure Mobilisation

• Most common iatrogenic splenic injury
• Caused by traction on splenocolic ligament, inadvertent avulsion
• Prevention: gentle retraction, early identification of splenorenal ligament, avoid excessive traction on the colon near the splenic flexure
• If identified intra-operatively: attempt topical haemostasis → splenorrhaphy → splenectomy if uncontrollable

During Gastric Surgery / Bariatric Surgery

• Short gastric vessel avulsion during fundoplication or sleeve gastrectomy
• Traction on gastrosplenic ligament → capsular tear or parenchymal injury
• Splenic haematoma may be managed conservatively if haemodynamically stable (as illustrated in Maingot's: a large splenic haematoma after gastric bypass resolved without intervention)

During Left Nephrectomy / Adrenalectomy

• Spleen is immediately adjacent to the left adrenal and upper pole of the left kidney
• Retractor injury or inadvertent capsular tear possible

Splenic Artery Aneurysm (related surgical consideration)

• Most common visceral artery aneurysm
• Higher rupture risk in pregnancy - rupture of aneurysms <2 cm reported; maternal mortality 22%, fetal mortality 15%; 69% rupture in third trimester
• Surgical indications: all symptomatic aneurysms; asymptomatic aneurysms >2 cm; all aneurysms detected in pregnancy
• Proximal lesions: resection ± end-to-end anastomosis or ligation (spleen preserved via collaterals)
• Distal/hilar lesions: laparoscopic splenectomy with aneurysm resection
• Endovascular options available but <90% success rate with risks of pancreatitis and abscess

• Maingot's Abdominal Operations, Ch. 62 (Splenic Surgery)
• Bailey and Love's Short Practice of Surgery 28e, Table 19.1
• Schwartz's Principles of Surgery 11e
• Grainger & Allison's Diagnostic Radiology (CT of Splenic Trauma)

Why CECT (Contrast-Enhanced CT) for Splenic Injury?

1. The Spleen Is Vascular - Contrast Reveals Its Architecture

• Normal splenic parenchyma enhances brightly and uniformly in the venous phase
• Injured/non-perfused areas fail to enhance - standing out as dark defects
• This contrast between enhancing normal tissue and non-enhancing injured tissue is what makes lacerations, haematomas, and devascularisation visible

2. The Vascular Blush - The Most Important Finding

"Active bleeding can be identified by visualizing extravasation of contrast material (i.e., high-density blush or accumulation of contrast-laden blood). At times, this extravasation will be free into the peritoneal space or contained within an intraparenchymal pseudoaneurysm."

• Sabiston Textbook of Surgery

• Active arterial haemorrhage is occurring right now
• Non-operative management (NOM) is likely to fail without intervention
• Angioembolisation is needed urgently
• If free into peritoneum → may need operative intervention

3. Multiphase CECT - What Each Phase Adds

4. Why Not Ultrasound?

• Not sensitive enough to exclude significant splenic injury reliably
• Cannot characterise the injury or assign a grade
• Cannot detect active bleeding / vascular blush
• Operator-dependent, limited by body habitus, bowel gas, rib shadowing

5. CECT Drives the Management Decision

6. Specific Contrast-Related Findings to Know

In Summary

1. Unenhanced CT misses isodense haematomas and gives no vascular information
2. The vascular blush - the single most important finding that changes management - is only detectable with contrast
3. It grades the injury precisely (Grades I-V) to guide NOM vs. embolisation vs. surgery
4. It detects pseudoaneurysms that would be missed and can cause delayed rupture
5. It shows associated injuries (liver, pancreas, kidney, mesentery, bowel) which may themselves mandate surgery
6. Sensitivity/specificity 96-100% - no other modality comes close in the stable patient

• Sabiston Textbook of Surgery 21e, Ch. 36 (Splenic Injuries)
• Grainger & Allison's Diagnostic Radiology (Splenic Trauma section)
• Maingot's Abdominal Operations, Ch. 62