Sinusoidal Obstruction Syndrome

Slide 1 · Sinusoidal Obstruction Syndrome

Pathogenesis • Histopathology • Clinicopathologic diagnosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish sinusoidal microvascular obstruction from major hepatic vein thrombosis.

Explain endothelial injury, red-cell extravasation, and perivenular hepatocyte loss.

Identify acute, organizing, and fibrous-obliterative histologic lesions.

Apply contemporary diagnostic categories while recognizing biopsy limitations.

Connect the pathology with complications and management principles.

Slide 3 · Disease definition

Toxic injury to hepatic sinusoidal endothelium impedes outflow through sinusoids and terminal venules.

The primary lesion is microvascular rather than thrombosis of a major hepatic vein.

Blood-flow obstruction can produce centrilobular congestion, necrosis, and fibrosis.

Slide 4 · Terminology and anatomic target

Former nomenclature

Veno-occlusive disease (VOD)

Emphasized small hepatic venous lesions

Term still used in transplant literature

Current descriptive term

Sinusoidal obstruction syndrome (SOS)

Emphasizes sinusoidal endothelial injury

Common combined usage: SOS/VOD

Slide 5 · Where does hepatic blood flow become obstructed?

Portal vein + hepatic artery

Sinusoidal inflow

Hepatic sinusoids

Site of endothelial injury

Terminal hepatic venule

Small-venule obstruction

SOS lies upstream of the major hepatic veins; Flow impairment is postsinusoidal in its consequences.

Slide 6 · Liver acinus: Why zone 3 matters

Zone 3

Portal inflow

Terminal venule

Sinusoidal flow →

Centrilobular hepatocytes surround the terminal hepatic venule.

Sinusoidal damage and perfusion failure converge at the venous outflow end.

Congestion and necrosis therefore predominate around central veins.

Slide 7 · Normal sinusoidal barrier: Conceptual architecture

Sinusoidal blood: Erythrocytes and plasma

Space of Disse

Hepatocyte

Hepatocyte

Hepatocyte

Hepatocyte

Hepatocyte

Thin endothelial lining

Schematic — not histology

Slide 8 · Historical observation: Pyrrolizidine toxicity

Early cases were described among Jamaican consumers of bush tea containing pyrrolizidine alkaloids.

The original term “veno-occlusive disease” reflected small-venule obliteration.

The toxic-vascular mechanism links botanical exposures and chemotherapy-related disease.

Today, transplantation and selected antineoplastic therapies dominate clinical recognition.

Slide 9 · Major clinical settings

Hematopoietic cell transplantation

Predominantly after allogeneic HCT

Classically develops in the first 3 weeks

Intensity and composition of conditioning matter

Cancer therapy without HCT

Certain cytotoxic or targeted anticancer agents

Sinusoidal injury may occur without transplantation

Interpret the timing relative to drug exposure

Slide 10 · Exposure precedes microvascular dysfunction

Potential exposure

Conditioning drugs or other sinusoidal toxins

Endothelial insult

Activation, swelling and barrier injury

Flow impairment

Sloughed lining and venular narrowing

Organ effects

Portal pressure rise and hepatocyte loss

The clinical syndrome is the downstream consequence of endothelial injury.

Slide 11 · Timing after hematopoietic transplantation

Classical presentation usually arises within 21 days after HCT.

Late-onset disease occurs after day 21; A rigid time cutoff can miss cases.

Clinical surveillance should track evolving weight, abdominal findings, bilirubin, and platelet needs.

Transplantation timing is a diagnostic clue, not proof by itself.

Slide 12 · Conditioning-associated endothelial stress

High-intensity conditioning exposes hepatocytes and sinusoidal endothelium to toxic metabolites.

Zone 3 sinusoidal endothelial cells are particularly vulnerable to injury.

Damage amplifies permeability, cellular detachment, and downstream microvascular obstruction.

The severity reflects both the exposure and the patient’s baseline hepatic reserve.

Slide 13 · Predisposing factors: Patient versus treatment

Baseline susceptibility

Preexisting fibrosis or active liver disease

Iron overload or abnormal liver tests

Prior HCT or previous SOS/VOD

Advanced disease and reduced performance status

Treatment-related burden

Myeloablative conditioning

Busulfan-intensive regimens

Abdominal or hepatic irradiation

Selected prior antibody–drug conjugates

Slide 14 · Anticancer agents outside transplant conditioning

Selected chemotherapy exposures as a major modern context.

In practice, several alkylating agents and sinusoid-toxic anticancer treatments are implicated.

An isolated post-chemotherapy liver syndrome requires differentiation from diffuse drug-induced hepatitis.

Drug identity, cumulative exposure, and preexisting hepatic disease modify interpretation.

Slide 15 · Pathogenesis: The core morphologic sequence

1. Injury

Toxic endothelial damage

2. Disruption

Swelling and sloughing

3. Obstruction

Cellular debris and edema

4. Congestion

Blood-flow failure

5. Repair

Venular fibrosis

Tissue effects depend on the magnitude and persistence of outflow obstruction.

Slide 16 · Endothelial injury is the initiating lesion

Toxic insult principally involves sinusoidal endothelial cells and terminal venular endothelium.

Activation and swelling disturb the normal blood–parenchyma barrier.

Vascular injury precedes many of the secondary hepatocyte changes.

The histologic appearance therefore differs from a primarily inflammatory hepatitis.

Slide 17 · Endothelial swelling narrows the venular lumen

Schematic cross-section of terminal hepatic venule

Swollen endothelium increases resistance to sinusoidal egress.

Edema and injured lining contribute to luminal narrowing.

The illustration depicts the mechanism, not a real biopsy.

Slide 18 · Barrier rupture permits blood to enter the space of Disse

Sinusoidal gap

Endothelial continuity is disrupted

Extravasation

Erythrocytes leave the vascular lumen

Dissection

Blood separates local tissue planes

Congestion

Effective sinusoidal drainage declines

Extravasated erythrocytes explain hemorrhage and the tissue reaction.

Slide 19 · Red-cell extravasation is mechanistically important

Injured sinusoids permit red cells to enter the space of Disse.

The blood may dissect beneath residual endothelial surfaces.

Extravasation produces an appearance of centrilobular hemorrhage on microscopy.

Space-of-Disse blood is distinct from an uncomplicated dilated vascular lumen.

Slide 20 · Endothelial detachment disrupts normal flow

Necrotic and detached endothelial elements enter sinusoidal channels.

Cellular debris moves toward the terminal hepatic venule.

Detachment also enlarges gaps permitting continued hemorrhage.

The resulting obstruction may be predominantly cellular before collagen is deposited.

Slide 21 · Obstruction moves downstream with sinusoidal drainage

Injured sinusoid

Cellular slough and red-cell leak

Terminal venule

Debris and subendothelial edema

Luminal stenosis

Reduced hepatic venous egress

Small-vessel obstruction can occur without thrombosis of a major hepatic vein.

Slide 22 · Elevated resistance produces hepatic congestion

Impaired venous egress raises hydrostatic pressure within sinusoids.

Centrilobular sinusoidal channels become engorged with blood.

The pressure burden propagates into clinically detectable fluid retention.

Congestion reflects the microvascular obstruction—not a portal vein inflow block.

Slide 23 · Why perivenular hepatocytes die

Venous outflow failure

Sinusoidal perfusion stagnates

Oxygen delivery

Effective microcirculation declines

Zone 3 injury

Perivenular hepatocyte necrosis

Functional injury

Cholestasis and enzyme abnormalities

Hepatocyte loss is downstream of vascular injury and hypoperfusion.

Slide 24 · Organizing injury recruits fibrosis

Persistent endothelial damage triggers extracellular-matrix deposition in the venular wall.

Edema and cellular obstruction evolve toward collagen-rich luminal narrowing.

Chronic lesions may leave a terminal hepatic venule completely obliterated.

The eventual scar can persist after the initiating toxic exposure ends.

Slide 25 · Anatomical progression: Patent, stenosed, obliterated

Patent venule

Acute stenosis

Fibrous closure

Original native-shape schematic — not a clinical specimen

Slide 26 · Early microscopy: Centrilobular congestion

Zone 3 sinusoids contain markedly increased red-cell volume.

Extravasated erythrocytes may occupy space around hepatocyte plates.

Endothelial damage need not be easily recognized on routine H&E alone.

Examine terminal venules for complementary evidence of obstruction.

Slide 27 · Venular wall edema and endothelial necrosis

Swelling and loss of venular endothelial cells are early components of obstruction.

Subendothelial material narrows the lumen even before mature collagen appears.

The lesion is centered on terminal hepatic venules rather than the main hepatic veins.

Patchiness may limit the sensitivity of a small biopsy.

Slide 28 · Centrilobular hepatocellular necrosis

Failure of sinusoidal blood transit injures perivenular hepatocytes.

Hepatocytes can become atrophic, necrotic, or absent near the central vein.

Extensive injury may resemble other causes of zone 3 necrosis.

Coexisting venular injury and exposure history provide specificity.

Slide 29 · Hemosiderin-laden macrophages mark prior hemorrhage

Extravasated erythrocytes are degraded locally by phagocytic cells.

Hemosiderin-containing macrophages may accumulate within affected areas.

The finding fits prior hemorrhage but is not independently diagnostic of SOS.

Interpret iron pigment with the spatial pattern of congestion and venular change.

Slide 30 · Organized disease: The terminal venule becomes stenotic

Schematic cross-section of terminal hepatic venule

The venular lumen is encroached upon by edematous tissue and organizing material.

Local sinusoidal congestion persists upstream.

The lesion may be conspicuous on connective-tissue stains.

Slide 31 · Masson trichrome: The purpose of a collagen stain

Special connective-tissue stains demonstrate perivenular or intraluminal fibrous tissue.

Tracing the venular wall helps recognize a distorted or nearly obliterated lumen.

Collagen-rich narrowing supports an organizing/chronic obstructive lesion.

Do not infer a histologic diagnosis from a diagram or staining color alone.

Slide 32 · Late disease: Complete fibrous venular obliteration

Schematic cross-section of terminal hepatic venule

Collagen replaces the functional lumen of a terminal hepatic venule.

Perisinusoidal fibrosis and parenchymal loss may coexist.

Advanced fibrosis documents injury but may not reveal its original cause.

Slide 33 · Why histology can be heterogeneous

The disease process affects small sinusoidal and terminal venular channels.

Tissue sections may sample patent and obstructed venules together.

Local severity and time since injury vary across the biopsy.

Multiple levels and suitable stains can improve lesion recognition.

Slide 34 · Morphologic timeline

Acute / early disease

Sinusoidal dilation and congestion

Red-cell extravasation

Edema and endothelial necrosis

Perivenular hepatocellular loss

Organizing / healed disease

Venular lumen narrowing

Intraluminal or perivenular collagen

Persistent sinusoidal fibrosis

Potential complete fibrous closure

Slide 35 · Gross morphology: Assess with restraint

Microscopic venular obliteration and centrilobular hemorrhagic injury.

Gross liver appearance alone does not establish SOS.

Congestion and hepatomegaly may have several hepatic vascular causes.

For diagnosis, prioritize exposure, clinical course, microvascular changes, and imaging.

Slide 36 · Clinical phenotype: Congestion plus fluid retention

Tender hepatomegaly + weight gain/ascites ± jaundice

After HCT, the pattern should prompt consideration of SOS/VOD.

None of these manifestations alone is sufficiently specific to establish the diagnosis.

Slide 37 · Tender hepatomegaly is a consequence of congestion

Outflow resistance

Small hepatic venules obstruct

Hepatic expansion

Sinusoidal blood accumulates

Capsular tension

Liver enlarges and becomes painful

Pain localizes clinically to the right upper quadrant.

Slide 38 · Why ascites and weight gain often evolve together

Microvascular pressure

Sinusoidal hydrostatic pressure rises

Fluid shift

Extracellular fluid accumulates

Clinical observation

Ascites and weight gain emerge

Weight gain signals fluid accumulation, not necessarily nutritional change.

Slide 39 · Hyperbilirubinemia and jaundice

Jaundice may develop as hepatocellular injury and cholestatic dysfunction progress.

Bilirubin is required for the EBMT “clinical” category in adults, not “probable.”

Late-onset and pediatric disease may present without obligatory jaundice.

A normal early bilirubin does not fully exclude SOS/VOD.

Slide 40 · Transfusion-refractory thrombocytopenia

Post-transplant platelet transfusion requirements may rise early in SOS/VOD.

It is especially important in pediatric EBMT diagnostic criteria.

This finding is not specific; Infection, consumption, and marrow dysfunction remain alternatives.

Interpret platelet refractoriness in the full transplant context.

Slide 41 · Laboratory results complement, rather than replace, morphology

Track total bilirubin and the trajectory of aminotransferases.

Renal function contributes to determining clinical severity.

An isolated enzyme rise is not a disease-defining test.

Laboratory kinetics and evolving clinical findings are more useful than one uncontextualized result.

Slide 42 · Diagnostic reasoning in the HCT setting

Risk and timing

Recent transplant or toxic exposure

Bedside pattern

Tender liver, fluid retention, jaundice

Noninvasive data

Ultrasound ± elastography

Exclusions

Other causes of injury and congestion

Clinical diagnosis is common because biopsy can carry significant bleeding risk.

Slide 43 · Ultrasound and Doppler findings

Ultrasound may document hepatomegaly, ascites, and vascular flow changes.

Attenuated or reversed flow is suggestive but not universally present.

Doppler abnormalities may evolve later than initial endothelial injury.

Use the entire ultrasound assessment; No single nonspecific sign proves SOS.

Slide 44 · Elastography: A modern complementary modality

Increased liver stiffness can reflect vascular congestion after transplantation.

EBMT includes suggestive ultrasound or elastography among “probable” criteria.

The measurement is context-dependent and not uniquely specific to SOS.

Availability and operator experience influence its utility.

Slide 45 · Adult EBMT 2023: Diagnostic certainty

Probable

Clinical

Proven

≥2 of 5 features

Bilirubin ≥2 mg/dL

Histology consistent with SOS

Bilirubin; Painful liver

Plus ≥2 of: Pain,

Or HVPG ≥10 mmHg

Weight gain >5%; Ascites

Weight gain >5%, ascites

(EBMT definition)

Suggestive US/elastography

Symptoms not otherwise explained

See EASL 2025 caveat

Slide 46 · Probable SOS is intended to improve early recognition

Adult EBMT probable disease requires at least two of five findings.

Those include bilirubin ≥2 mg/dL, painful hepatomegaly, >5% weight gain, ascites, or suggestive ultrasound/elastography.

The category may be met before the full conventional clinical criteria.

Alternative explanations must be assessed before assigning SOS/VOD.

Slide 47 · Clinical SOS requires a more restrictive combination

Adult EBMT clinical SOS includes bilirubin ≥2 mg/dL.

Two additional features are required: Painful hepatomegaly, weight gain >5%, or ascites.

The combination documents a compatible syndrome but is not itself a biopsy.

Apply adult HCT criteria to their intended population.

Slide 48 · “Proven” SOS: An important guideline difference

EBMT 2023 framework

Histologic confirmation qualifies

Hemodynamic confirmation with HVPG ≥10 mmHg also qualifies

The categories reflect diagnostic certainty

EASL 2025 approach

Reserves “proven” SOS for histology

HVPG ≥10 mmHg supports suspicion only

A low HVPG does not exclude the disease

Slide 49 · Children require pediatric-specific criteria

Pediatric EBMT rules do not impose a 21-day onset limit.

Two or more features are assessed, including rising bilirubin, evolving weight, new ascites/hepatomegaly, and refractory thrombocytopenia.

Anicteric SOS is important in children; Adult bilirubin requirements should not be copied.

Pretransplant imaging establishes a baseline for liver size and ascites.

Slide 50 · Biopsy: Informative but often difficult

Why histology matters

Can show distinctive small-venule obstruction

Separates morphological phenotypes

Helps resolve competing diagnoses

Why biopsy can be hazardous

Post-HCT thrombocytopenia

Coagulopathy and fragile clinical condition

Sampling may miss patchy lesions

Slide 51 · Differential I: SOS versus Budd–Chiari syndrome

SOS / small vessels

Sinusoids and terminal hepatic venules

Common toxic/conditioning-associated context

May not show thrombosis of major veins

Budd–Chiari syndrome

Obstruction of the major hepatic veins

Often prothrombotic or tumor-related

Hepatic vein imaging is decisive

Slide 52 · Differential II: SOS versus cardiac congestion

Sinusoidal obstruction syndrome

Primary endothelial injury / small-vessel obstruction

Temporal association with drugs or HCT

Terminal venular edema/fibrosis

Cardiac passive congestion

Elevated systemic venous pressure from right heart failure

Centrilobular sinusoidal congestion

Correlate with cardiopulmonary disease

Slide 53 · Differential III: Hepatic syndromes after HCT

Conditions to consider

Drug-induced hepatocellular injury

Infection or sepsis-related cholestasis

Hepatic graft-versus-host disease

Cardiac failure / portal vascular disorders

Features favoring SOS

Compatible endothelial-toxic exposure

Weight gain and tender hepatomegaly

Ascites plus evolving jaundice

Concordant imaging or histology

Slide 54 · Compare the level of hepatic vascular obstruction

Disorder

Predominant anatomical level

Useful discriminator

Portal vein thrombosis

Inflow through portal venous tree

Portal venous thrombus on imaging

SOS/VOD

Sinusoids and terminal venules

Toxic exposure; Microvascular lesion

Budd–Chiari

Major hepatic veins/outflow

Major-vein occlusion

Cardiac congestion

Systemic venous pressure elevation

Right-sided cardiac disease

Slide 55 · Severity is a dynamic clinical assessment

EBMT severity grades range from mild to very severe.

Grading incorporates symptom tempo, bilirubin kinetics, aminotransferases, weight gain, and renal function.

Multiorgan dysfunction places patients in a very severe category.

Reassess severity as the syndrome evolves rather than relying solely on presentation.

Slide 56 · Escalation from local liver injury to organ dysfunction

Venular blockade

Severe hepatic congestion

Persistent fluid shift

Ascites and circulatory changes

Systemic involvement

Kidney and pulmonary dysfunction

Very severe disease

Multiorgan dysfunction

Organ failure marks high-risk disease and requires urgent specialist management.

Slide 57 · Monitoring priorities in suspected SOS/VOD

Record daily weight and fluid balance during the vulnerable post-HCT interval.

Follow abdominal findings, bilirubin trajectory, renal function, and platelet support.

Repeat vascular imaging when symptoms evolve or the first study is inconclusive.

Escalate rapidly if respiratory or renal dysfunction appears.

Slide 58 · Supportive management addresses complications

Balance fluid status while avoiding intravascular depletion.

Limit avoidable hepatotoxic and nephrotoxic exposures.

Manage ascites, coagulopathy, and organ failure with the transplant team.

Severe cases require early disease-directed therapy in addition to supportive care.

Slide 59 · Defibrotide: Contemporary disease-directed therapy

EBMT guidance recommends prompt defibrotide for severe or very severe SOS/VOD.

Its early use is also recommended by EBMT in moderate disease.

Mild cases receive close surveillance and supportive care, with escalation if worsening.

Defibrotide carries bleeding-related precautions; Treatment is specialist-led.

Slide 60 · Prevention: Distinguish established from uncertain

Risk reduction supported by EBMT

Modify conditioning where feasible

Identify baseline hepatic risk

Ursodeoxycholic acid prophylaxis in adult HCT

Track high-risk patients closely

Important limitation

Routine prophylactic defibrotide has mixed trial evidence

2024 EBMT notes a large trial without benefit

Preventive drug strategies are not interchangeable with treatment

Slide 61 · Interpret older statements against newer evidence

Early suggestions concerning anticoagulants and ursodeoxycholate after HCT.

EBMT 2024 supports ursodeoxycholic acid for adult prophylaxis and defibrotide for indicated treatment.

Routine anticoagulation should not be presented as established SOS treatment.

Diagnostic and therapeutic claims must be dated and linked to their source.

Slide 62 · Teaching vignette: Early clinical suspicion

Recent HCT → tender hepatomegaly, increasing weight and ascites, with evolving bilirubin

Question: Which hepatic microvascular process should be considered?

What additional diagnostic and differential information is necessary?

Slide 63 · Vignette reasoning: Localize the lesion

The timing and fluid-retention pattern make SOS/VOD a key differential.

Assess bilirubin, daily weight, platelet support, ultrasound/elastography, and hepatic vein patency.

Exclude competing causes such as sepsis-related cholestasis, GVHD, and cardiac congestion.

Assess severity immediately; Do not wait for biopsy in a deteriorating patient.

Slide 64 · Teaching vignette: Pathology interpretation

Biopsy shows zone 3 hemorrhage with a narrowed, edematous terminal venule.

Question: Why does this finding favor SOS over isolated passive congestion?

What could a connective-tissue stain establish in a later lesion?

Slide 65 · Vignette reasoning: Distinguish cause from effect

Centrilobular hemorrhage is a downstream effect of impeded venous flow.

Primary endothelial and terminal venular lesions are more informative than congestion alone.

Trichrome may reveal narrowing or obliteration by collagen during organization.

Clinical toxic-exposure context remains necessary because histologic findings may overlap.

Slide 66 · High-yield synthesis: Injury to syndrome

Endothelial toxin

Sinusoidal cell injury

Microvascular lesion

Detachment, venular edema

Parenchymal effect

Zone 3 congestion/necrosis

Clinical syndrome

Painful liver, ascites, jaundice

When recovery is incomplete, venular collagen may produce persistent obliteration.

Slide 67 · References and further reading

Robbins, Cotran & Kumar. Pathologic Basis of Disease, 11th ed. Chapter 18, “Sinusoidal Obstruction Syndrome.”

Carreras E, et al. Hepatic Complications. EBMT Handbook, 8th ed., Chapter 49 (2024).

EASL Clinical Practice Guidelines on vascular diseases of the liver. Journal of Hepatology (2025).

LiverTox: Sinusoidal Obstruction Syndrome (Veno-occlusive Disease). NIDDK (2019).