Thrombotic Microangiopathies

Slide 1 · Thrombotic Microangiopathies

Renal mechanisms, morphology, and clinicopathologic interpretation

TTP • Shiga toxin–HUS • Complement-mediated TMA

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Define the shared pathologic lesion in thrombotic microangiopathy (TMA).

Contrast the causal pathways of Shiga toxin–HUS, complement-mediated TMA, and TTP.

Identify acute and chronic renal vascular and glomerular lesions.

Connect morphology to the clinical pattern and etiologic investigation.

Slide 3 · TMA: A syndrome defined by microvascular thrombi

Microvascular lumen

Occluding thrombi

Schematic — not a histologic specimen

Slide 4 · The lesion is shared; The triggers differ

Endothelial injury

Excess platelet aggregation

Occlusive microvascular thrombi

Slide 5 · From thrombi to the clinical syndrome

Microvascular thrombi

Platelet consumption + red-cell injury

Organ ischemia / dysfunction

Slide 6 · Why red cells are injured

Microvascular lumen

Erythrocyte injury

Schematic — not a histologic specimen

Slide 7 · Why the platelet count falls

Platelet activation

Platelet-rich microthrombi

Consumptive thrombocytopenia

Slide 8 · Why ischemia follows microvascular occlusion

Capillary / arteriolar occlusion

Reduced blood delivery

Tissue injury and dysfunction

Slide 9 · TMA affects capillaries and arterioles

Capillary thrombi

Glomerular tuft (idealized)

Schematic — not a histologic specimen

Slide 10 · Etiologic classification is more useful than symptoms alone

Shiga toxin–HUS

Shiga toxin–producing enteric bacteria

Complement-mediated TMA

Defective complement regulation or regulator antibodies

TTP

Deficient ADAMTS13 activity

Secondary TMA associations

Vascular, autoimmune, gestational or toxic injury

Slide 11 · Two dominant pathogenic entry points

Endothelial injury

(HUS pathways)

Excess platelet activation

(TTP pathway)

Thrombosis → ischemia

Slide 12 · Endothelial injury promotes thrombosis

Endothelial damage / activation

Platelet recruitment

Microvascular occlusion

Slide 13 · Platelet aggregation can initiate thrombosis

ADAMTS13 deficiency

Very large vWF multimers

Platelet-rich microthrombi

Slide 14 · HUS and TTP converge on the same injury pattern

HUS / endothelial route

TTP / vWF route

Shared microangiopathic morphology

Slide 15 · TMA and disseminated intravascular coagulation are distinct

TTP / HUS

DIC

Primary platelet/endothelial pathway

Systemic coagulation activation

Microvascular thrombi

Microvascular thrombi

PT / PTT usually normal

Coagulation tests often abnormal

Slide 16 · Clinical overlap does not eliminate etiologic differences

The traditional TTP pentad is not present in every patient.

HUS can include fever and neurologic manifestations.

Clinical distribution suggests a subtype; Mechanism establishes a more reliable distinction.

Slide 17 · Shiga toxin–mediated HUS: The initiating exposure

Enteric infection

Shiga-like toxin

Endothelial injury → renal TMA

Slide 18 · Typical HUS is linked to enteric infection

The offending bacteria produce toxins resembling Shiga toxin.

Contaminated food may transmit the infection.

The gastrointestinal illness may precede renal and hematologic findings.

Slide 19 · A clinical sequence: Intestine to kidney

Gastrointestinal infection

Circulating bacterial toxin

Renal endothelial response

TMA / renal dysfunction

Slide 20 · Shiga-like toxin: An endothelial injury model

Shiga-like toxin

Endothelial activation / injury

Microvascular thrombosis

Slide 21 · Changes in endothelial mediators

Increased leukocyte adhesion molecule expression.

Endothelin may increase, while nitric oxide production may decrease.

Such changes can favor vasoconstriction and platelet activation.

Slide 22 · Vasoconstriction can amplify endothelial injury

Endothelial mediator imbalance

Vasoconstriction

Reduced renal perfusion

Slide 23 · Shiga toxin and factor H: A proposed link

Shiga-like toxin

Possible factor H interference

Potential complement amplification

Slide 24 · Typical HUS: Clinical sequence

Bloody diarrheal illness

Interval of several days

Hemolysis + thrombocytopenia + AKI

Slide 25 · Recovery does not always imply no renal sequelae

Many survivors of less severe typical HUS regain renal function within weeks.

Some experience persistent renal damage despite surviving the acute illness.

Later renal function should not be inferred solely from early recovery.

Slide 26 · Complement-mediated TMA: Loss of regulation

Complement dysregulation

Endothelial injury

Platelet activation / renal TMA

Slide 27 · Normal complement regulators protect vascular surfaces

Alternative-pathway activity

Factor H / Factor I / CD46 restraint

Protected endothelial surface

Slide 28 · Factor H protects against uncontrolled complement

Impaired factor H

Excess alternative-pathway activation

Renal endothelial injury

Slide 29 · Factor I and CD46: Additional regulatory defects

Regulatory protein

Role in disease

Factor I

Inherited dysregulation can permit complement activity

CD46

Membrane-associated protective regulation

Factor H

C3 convertase control

Slide 30 · Complement components may also be implicated

Complement pathway abnormality

Poorly controlled activation

Endothelial thrombogenic injury

Slide 31 · Inherited susceptibility may require a second insult

Inherited susceptibility

Superimposed trigger

Clinical complement-mediated TMA

Slide 32 · Acquired antibodies can impair complement protection

Complement-mediated TMA

Acquired TTP

Antibodies to complement regulators

Antibodies inhibiting ADAMTS13

Excess complement activation

Very large vWF multimers

Predominantly endothelial trigger

Predominantly platelet trigger

Slide 33 · Not all HUS-like TMAs are complement disorders

Immune / thrombotic

Antiphospholipid antibodies

Pregnancy

Pregnancy or postpartum complications

Renal vascular

Systemic sclerosis; Severe hypertension

Exposures

Chemotherapeutic / immunosuppressive drugs; Radiation

Slide 34 · Antiphospholipid syndrome can trigger renal TMA

Antiphospholipid antibodies are associated with endothelial and thrombotic disease.

Renal microangiopathy may resemble HUS/TTP microscopically.

The causative clinical setting is important for etiologic assignment.

Slide 35 · Pregnancy and postpartum TMA

Pregnancy-related complications are recognized settings for TMA.

Postpartum renal failure can represent a microangiopathic process.

Some affected patients may have underlying complement regulatory defects.

Slide 36 · Systemic sclerosis and severe hypertension

Wall thickening

Narrowed lumen

Schematic — not a histologic specimen

Slide 37 · Drugs and radiation may damage the endothelium

Chemotherapeutic and immunosuppressive agents are reported associations.

Radiation exposure is another recognized endothelial insult.

Evaluation of exposure is part of etiologic interpretation.

Slide 38 · Complement-mediated and secondary TMA may persist

Persistent causal factor

Recurrent endothelial damage

Progressive chronic renal lesions

Slide 39 · TTP: Deficiency of ADAMTS13

ADAMTS13 deficiency

Large vWF multimers persist

Platelet-rich thrombi

Slide 40 · Normal ADAMTS13 restrains vWF multimer size

Intact vWF multimer

ADAMTS13 proteolysis

Schematic — molecular relationships simplified

Slide 41 · Excessively large vWF multimers recruit platelets

Uncleaved very large vWF

Platelet recruitment + aggregation

Schematic — molecular relationships simplified

Slide 42 · Acquired TTP is most often antibody-mediated

Inhibitory antibodies

Low functional ADAMTS13

Platelet microthrombi

Slide 43 · Inherited TTP arises from ADAMTS13 mutations

Inherited enzyme deficiency

Additional trigger

Episodic TTP

Slide 44 · TTP commonly has prominent neurologic involvement

TTP tendency

HUS tendency

Neurologic findings often prominent

Renal dysfunction often prominent

Thrombocytopenia often marked

Thrombocytopenia may be less pronounced

Severe kidney failure less typical

Acute renal failure characteristic

Slide 45 · The classic TTP pentad is a historical description

Fever

Neurologic abnormalities

Microangiopathic hemolytic anemia

Thrombocytopenia and renal dysfunction

Slide 46 · Do not require the complete pentad

Many affected patients lack one or more components of the classic pentad.

HUS may also produce neurologic manifestations or fever.

Reasoning should prioritize TMA recognition and the underlying etiology.

Slide 47 · ADAMTS13 is a mechanistic discriminator

TTP

Atypical / complement TMA

Deficient ADAMTS13

ADAMTS13 generally preserved

Platelet-vWF initiation

Endothelial/complement initiation

Neurologic tendency

Renal tendency

Slide 48 · Acute renal TMA: Gross manifestations

Subcapsular petechiae / ischemia

Simplified kidney outline

Schematic — not a gross specimen

Slide 49 · Glomerular capillaries may be occluded by thrombi

Capillary thrombi

Glomerular tuft (idealized)

Schematic — not a histologic specimen

Slide 50 · Acute mesangial injury: Mesangiolysis

Mesangial matrix disruption

Mesangial damage

Glomerular tuft (idealized)

Schematic — not a histologic specimen

Slide 51 · Small arteries and arterioles also thrombose

Microvascular lumen

Occluding thrombi

Schematic — not a histologic specimen

Slide 52 · The acute pattern links structure to function

Glomerular + arteriolar occlusion

Reduced cortical perfusion

Renal dysfunction / necrosis

Slide 53 · Chronic renal TMA reflects repeated injury and repair

Repeated endothelial injury

Remodeling and fibrosis

Chronic renal ischemia

Slide 54 · Glomerular “double contours” mark chronic injury

Duplicated capillary wall

Glomerular tuft (idealized)

Schematic — not a histologic specimen

Slide 55 · Why basement membrane duplication develops

Persistent endothelial injury

Repair / basement membrane remodeling

Duplicated capillary wall contours

Slide 56 · Chronic arteries develop luminal narrowing

Wall thickening

Narrowed lumen

Schematic — not a histologic specimen

Slide 57 · Chronic arterioles may show hyalinosis

Wall thickening

Hyaline wall change

Schematic — not a histologic specimen

Slide 58 · Renal cortical necrosis is an ischemic endpoint

Cortical ischemic necrosis

Simplified kidney outline

Schematic — not a gross specimen

Slide 59 · Acute and chronic morphology differ by timing

Acute dominant lesions

Chronic dominant lesions

Capillary / arteriolar thrombi

Capillary-wall duplication

Mesangiolysis

Arterial mural thickening

Petechiae or cortical necrosis

Scarring, hyalinosis, hypoperfusion

Slide 60 · Renal morphology does not identify TMA subtype

What histology demonstrates

What histology alone cannot prove

Microvascular thrombotic injury

Shiga toxin exposure

Acute versus chronic changes

ADAMTS13 deficiency

Cortical ischemic consequences

Complement-regulatory mutation

Slide 61 · Distinguish TMA from a coagulopathic process

TMA is a pathologic pattern, not a single laboratory diagnosis.

The clinically important differential includes disseminated intravascular coagulation.

That systemic coagulation cascade activation is not central in HUS/TTP.

Slide 62 · A unified etiologic investigation starts with context

Immune / thrombotic

Antiphospholipid antibodies

Pregnancy

Pregnancy or postpartum complications

Renal vascular

Systemic sclerosis; Severe hypertension

Exposures

Chemotherapeutic / immunosuppressive drugs; Radiation

Slide 63 · Case: Post-diarrheal renal TMA

A patient develops bloody diarrhea after gastrointestinal illness.

Several days later, hemolysis, thrombocytopenia, and acute renal dysfunction appear.

Which upstream mechanism is most consistent with this sequence?

Discuss: Infer the initiating mechanism before revealing the answer.

Slide 64 · Case: Platelet-driven microangiopathy

A patient has MAHA, marked thrombocytopenia, and neurologic dysfunction.

Investigation supports deficient ADAMTS13 function.

What molecular interaction explains the small-vessel thrombi?

Discuss: Infer the initiating mechanism before revealing the answer.

Slide 65 · Case: Recurrent renal microangiopathy

A patient has recurrent episodes of TMA with dominant renal injury.

An inherited complement-regulatory protein defect is identified.

What shared tissue event links genotype to kidney dysfunction?

Discuss: Infer the initiating mechanism before revealing the answer.

Slide 66 · Three etiologic routes, one renal lesion

Shiga toxin–HUS

Endothelial toxin injury

Complement-mediated TMA

Insufficient complement regulation

TTP

ADAMTS13 deficiency

Platelet-containing microthrombi and renal ischemia

Slide 67 · Take-home: Interpret TMA by mechanism and chronicity

Recognize microvascular thrombosis with hemolysis, platelet consumption, and ischemia.

Distinguish endothelial pathways from ADAMTS13/vWF platelet-driven TTP.

In the kidney, separate acute occlusive lesions from chronic vascular remodeling.

Do not assign an etiology from renal morphology alone.

Slide 68 · Selected source

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026).

Renal thrombotic microangiopathy is discussed in “The Kidney.”

The hematologic pathogenetic context is discussed in “Red Blood Cell and Bleeding Disorders.”