Thrombotic Microangiopathies Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome

Slide 1 · Thrombotic microangiopathies

Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

Mechanisms • morphology • clinicopathologic reasoning

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Recognize the shared consequences of small-vessel platelet-rich thrombosis.

Explain how ADAMTS13 deficiency initiates TTP.

Distinguish Shiga toxin–associated from complement-mediated HUS.

Interpret the renal morphology and major clinicopathologic differentials.

Slide 3 · TMA is a clinicopathologic syndrome

Shared vascular lesion

Microvascular thrombi link hemolysis, platelet consumption, tissue ischemia, and organ dysfunction.

Slide 4 · The shared thrombotic microangiopathy cascade

Initiating disorder

Microvascular platelet-rich thrombi

RBC injury + platelet consumption

Ischemic organ dysfunction

Slide 5 · Why microthrombi have systemic consequences

Schematic: Capillary obstruction links thrombosis and hemolysis

Platelet-rich

Thrombus

Flow direction →

RBC fragmentation under shear

Native schematic • not a histologic image

Slide 6 · Microangiopathic hemolytic anemia is mechanical

Microvascular lesions narrow the vessel lumen.

Passing erythrocytes are subjected to abnormal shear stress.

Fragmentation produces intravascular hemolysis and red-cell fragments.

The mechanism is distinct from immune-mediated erythrocyte destruction.

Slide 7 · Fragmented erythrocytes in TMA

Before microvascular passage

After high-shear obstruction

Schistocytes / helmet forms

Conceptual cell silhouettes; Not a blood film

Slide 8 · Why platelet counts fall in TMA

Excessive platelet activation

Formation of platelet microaggregates

Peripheral platelet consumption

Thrombocytopenia

Slide 9 · Organ dysfunction reflects thrombus distribution

Microvascular occlusion deprives downstream tissue of perfusion.

Renal microvasculature is a major target in HUS.

Neurologic involvement is often prominent in TTP.

The distribution and severity of thrombosis vary between patients.

Slide 10 · TMA: The shared clinical and laboratory picture

Feature

Clinicopathologic explanation

Thrombocytopenia

Platelet consumption into microthrombi

Hemolytic anemia

Red-cell fragmentation within narrowed small vessels

Renal dysfunction

Microvascular ischemic injury

Neurologic symptoms

Microvascular dysfunction in nervous tissue

Slide 11 · The historical TTP pentad

Fever

Thrombocytopenia and microangiopathic hemolytic anemia

Transient neurologic deficits

Renal dysfunction or failure

Slide 12 · Why the historical pentad is insufficient

Many patients diagnosed with TTP do not exhibit all five classical features.

Some patients with HUS develop neurologic dysfunction or fever.

Diagnostic distinction is better based on initiating pathogenesis.

Do not exclude TTP merely because the complete pentad is absent.

Slide 13 · Typical clinical emphasis is not absolute

TTP

• Neurologic dysfunction often dominates

• Renal injury can occur

• Thrombocytopenia is often more pronounced

HUS

• Acute renal dysfunction often dominates

• Neurologic symptoms can occur

• Frequently affects children in typical infection-associated HUS

Clinical overlap makes etiology central.

Slide 14 · TMA and disseminated intravascular coagulation

TMA

• Primarily platelet/endothelial mechanisms

• Coagulation cascade is not the dominant driver

• PT and PTT are usually normal

DIC

• Systemic coagulation activation

• Widespread fibrin-rich microthrombosis

• Clotting factors may be consumed

Both can produce fragmented erythrocytes and organ ischemia.

Slide 15 · Why PT and PTT often remain normal

TTP and HUS do not begin with widespread activation of the coagulation cascade.

Platelet aggregation and endothelial injury dominate the pathogenic events.

Routine PT and PTT are consequently usually normal.

Coagulation results support—but do not alone establish—the differential.

Slide 16 · Etiologic classification of TMA

Entity

Principal initiating abnormality

TTP

ADAMTS13 deficiency: autoantibodies or inherited mutation

Shiga toxin–associated HUS

Bacterial toxin-associated endothelial injury

Complement-mediated HUS

Excessive alternative complement activation

Other secondary TMAs

Drug, radiation, infection, autoimmunity, pregnancy or vascular disease associations

Slide 17 · Three major pathogenic routes to microthrombosis

TTP

ADAMTS13 deficiency

Unusually large vWF multimers

Platelet aggregation

Typical HUS

Shiga-like toxin exposure

Endothelial injury / activation

Platelet activation

Complement-mediated HUS

Alternative complement dysregulation

Endothelial injury

Platelet activation

Slide 18 · TTP: The defining molecular defect

ADAMTS13 deficiency

Failure to process very-high-molecular-weight von Willebrand factor permits pathogenic platelet aggregation.

Slide 19 · Von Willebrand factor supports normal hemostasis

VWF mediates platelet adhesion to exposed subendothelial matrix.

Circulating vWF is organized into multimers of different sizes.

Very-large multimers have high capacity to recruit platelets.

Physiologic proteolysis limits persistence of unusually large multimers.

Slide 20 · ADAMTS13 normally trims vWF multimers

Normal ADAMTS13 cleaves very-large vWF multimers

ADAMTS13

Smaller vWF

Fragments

Native mechanism schematic

Slide 21 · ADAMTS13 deficiency preserves large vWF multimers

Deficient ADAMTS13: Unusually large vWF multimers persist

Spontaneous platelet activation

And aggregation

Native mechanism schematic

Slide 22 · TTP pathogenesis from enzyme deficiency to injury

Reduced ADAMTS13 activity

Accumulation of very-large vWF multimers

Spontaneous platelet activation / aggregation

Occlusive microvascular thrombi

Slide 23 · Acquired versus inherited TTP

Acquired TTP

• Inhibitory autoantibodies against ADAMTS13

• Metalloprotease activity is impaired

• Plasma exchange removes inhibitory antibody

Inherited TTP

• Inactivating ADAMTS13 variants

• Enzyme deficiency is constitutive

• Additional triggers may precipitate attacks

Slide 24 · Acquired TTP: An antibody-mediated protease defect

Autoantibodies inhibit ADAMTS13 metalloprotease activity.

Persisting high-molecular-weight vWF multimers activate platelets.

Plasma exchange addresses both the inhibitor and deficient enzyme.

This is not a disorder of primary clotting-factor deficiency.

Slide 25 · Inherited TTP: Deficiency does not guarantee an attack

ADAMTS13-inactivating mutations are less common than acquired inhibitors.

Symptoms may be episodic, with onset delayed until adolescence.

Additional endothelial injury or prothrombotic states may precipitate clinical disease.

The genotype creates susceptibility; A trigger influences expression.

Slide 26 · A two-component model of clinical TTP

Predisposing ADAMTS13 deficiency

Additional endothelial or prothrombotic trigger

Marked microvascular platelet aggregation

Acute clinical TTP

Slide 27 · TTP: Neurologic and renal involvement

Occlusive microthrombi develop in systemic arterioles.

Central nervous system dysfunction is a prominent feature.

Severe renal injury is less common than in HUS.

Clinical findings follow the distribution of involved microvascular beds.

Slide 28 · Recognizing a possible TTP presentation

Concurrent thrombocytopenia and microangiopathic hemolysis are a critical signal.

Fever, transient neurologic changes, or renal abnormalities may accompany the syndrome.

Absence of some classical manifestations does not exclude TTP.

Urgent evaluation is essential because delays can be fatal.

Slide 29 · Why plasma exchange is effective in acquired TTP

Remove inhibitory antibodies

Replace plasma ADAMTS13 activity

Reduce propagation of vWF-mediated thrombosis

Slide 30 · TTP: Treatment illustrates causation

Plasma exchange removes antibodies inhibiting ADAMTS13.

Replacement plasma supplies functioning ADAMTS13.

Successful treatment in more than 80% of patients.

The therapeutic response reinforces the pathogenic role of the enzyme defect.

Slide 31 · HUS: The dominant pathogenic setting

Endothelial injury

Unlike TTP, typical and complement-mediated HUS generally begin with endothelial injury, followed by platelet activation.

Slide 32 · HUS: Major etiologic categories

Category

Biologic trigger

Clinical tendency

Typical / Shiga toxin–associated

Shiga-like toxin–producing enteric bacteria

Often follows bloody diarrhea

Complement-mediated

Alternative pathway dysregulation

Can be episodic and relapsing

Secondary TMA associations

Drugs, systemic disease, pregnancy or radiation

Context-dependent organ injury

Slide 33 · Typical HUS often follows enteric infection

Most cases follow intestinal infection with Shiga-like toxin–producing bacteria.

Escherichia coli O157:H7 is a frequent causative strain.

Shigella dysenteriae and other toxin-producing organisms can also be implicated.

Children and older adults are particularly vulnerable’ account.

Slide 34 · Typical HUS: Clinical sequence

Enteric infection

Gastroenteritis with bloody diarrhea

Shiga-like toxin exposure

Microangiopathy and acute kidney injury

Slide 35 · How bacterial toxin reaches the circulation

Gastroenteritis produces inflamed gastrointestinal mucosa.

The toxin can be absorbed from the affected mucosa.

Systemic exposure precedes endothelial perturbation.

The precise molecular route from toxin exposure to HUS remains incompletely established.

Slide 36 · Proposed endothelial effects of Shiga-like toxin

Endothelial cell activation

More adhesion molecules / endothelin

Reduced nitric oxide; Possible apoptosis

Vasoconstriction and platelet activation

Slide 37 · Endothelin and nitric oxide in a toxin model

Endothelin

• Endothelial activation increases endothelin expression

• Favors vasoconstriction

• Can exacerbate impaired microvascular flow

Nitric oxide

• Endothelial toxin effects may reduce nitric oxide

• Loss of a vasodilatory influence

• May worsen microvascular perfusion

Slide 38 · The proposed Shiga-toxin mechanism has uncertainty

The text describes endothelial activation as a model, not an established complete pathway.

Inflammatory cytokines may enhance toxin-associated endothelial apoptosis.

Possible disruption of factor H and complement control has also been suggested.

These possibilities should not be presented as fully proven mechanisms.

Slide 39 · Typical HUS: Converging consequences

Toxin-associated endothelial dysfunction

Platelet recruitment and microthrombosis

Glomerular / arteriolar vascular injury

Acute renal dysfunction

Slide 40 · Renal injury dominates typical HUS

Small-vessel thrombi compromise the glomerular and arteriolar circulation.

The kidney may develop acute ischemic injury and loss of function.

The clinical syndrome often emerges days after the diarrheal illness.

Neurologic manifestations are possible, despite the classic clinical distinction.

Slide 41 · Typical HUS: Short- and long-term outcomes

Patients with less severe renal failure frequently recover function over weeks.

Survival of the acute episode does not exclude residual renal injury.

Long-term renal function may remain impaired in some survivors.

Persistent renal follow-up rather than assuming complete recovery.

Slide 42 · Complement-mediated HUS

Loss of complement control

Alternative complement activation becomes excessive and injures microvascular endothelium.

Slide 43 · Normal alternative complement control

Alternative pathway activation

Complement regulatory proteins constrain activity

Host endothelial cells remain protected

Slide 44 · Factor H is a major complement regulator

Factor H promotes breakdown of alternative pathway C3 convertase.

This protects host cells from excessive complement activation.

Inherited factor H abnormalities are prominent among complement-mediated HUS causes.

Loss of restraint permits self-tissue microvascular injury.

Slide 45 · Complement-associated proteins named by Robbins

Protein / component

Relevance to complement-mediated HUS

Factor H

Limits alternative pathway activity

Factor I

Regulatory protease; inherited variants described

CD46 (membrane cofactor protein)

Cell-surface complement regulatory protein

C3 and factor B

Alternative pathway components with associated variants

Slide 46 · Inherited complement defects may produce episodic HUS

Genetic susceptibility does not necessarily imply a continuous active syndrome.

Infection or another event may trigger complement overactivation.

Episodes may recur because the underlying defect persists.

Some affected individuals have more than one regulatory-gene variant.

Slide 47 · Complement-mediated HUS: Pathogenesis

Inherited defect or acquired regulatory antibody

Excessive complement activation

Endothelial damage

Microvascular platelet thrombosis

Slide 48 · Acquired complement-mediated HUS

Inhibitory autoantibodies can target complement regulatory proteins.

Regulatory loss resembles the functional effect of pathogenic inherited variants.

Excess complement activation damages microvascular endothelium.

A potential role for immunosuppression when inhibitory antibodies are involved.

Slide 49 · Complement inhibition demonstrates mechanism

Uncontrolled complement activation

Terminal complement pathway engagement

C5 blockade

Prevention of thrombosis in hereditary HUS

Slide 50 · Why complement-mediated HUS can relapse

The initiating regulatory abnormality may be persistent.

Intercurrent illness can act as a trigger in a susceptible host.

Recurrent endothelial injury can cause progressive renal damage.

This clinical pattern differs from a single resolved enteric infection.

Slide 51 · Secondary TMAs: Acquired endothelial insults

Certain chemotherapeutic and immunosuppressive drugs are recognized associations.

Radiation exposure and transplantation settings may precede TMA.

Other infections and autoimmune or lymphoid conditions may be implicated.

Such associations need etiologic evaluation; They are not equivalent to ADAMTS13-deficient TTP.

Slide 52 · Examples of secondary TMA associations

Clinical setting

Examples mentioned in Robbins

Drug exposure

Cyclosporine; chemotherapeutic agents

Other infections

HIV infection; pneumococcal sepsis

Autoimmune / vascular

Antiphospholipid syndrome; systemic sclerosis; severe hypertension

Other contexts

Pregnancy / postpartum; transplantation; radiation

Slide 53 · Pregnancy-associated TMA requires context

Pregnancy and the postpartum period are associated with TMA syndromes.

Postpartum renal failure can develop from one day to months after delivery.

A complement-regulatory variant may be involved in some cases.

The pathogenesis is not settled and clinical prognosis can be serious.

Slide 54 · Acute TMA in glomerular capillaries

Schematic of renal microvascular pathology

Occlusive thrombi in glomerular capillaries

Original conceptual schematic • not a photomicrograph

Slide 55 · Acute glomerular injury: The principal lesions

Glomerular capillary lumens are distended or occluded by thrombi.

Mesangial cell and matrix injury may disrupt the mesangium.

Interlobular arteries and arterioles can also contain occlusive thrombi.

These lesions reduce perfusion and contribute to acute kidney dysfunction.

Slide 56 · Ischemic damage may produce cortical necrosis

Schematic of renal microvascular pathology

Necrotic renal cortex

Medulla spared

Cortical necrosis may be patchy or extensive

Original conceptual schematic • not a photomicrograph

Slide 57 · Gross kidney changes in active TMA

Subcapsular petechiae may be present.

Cortical necrosis can be patchy or diffuse.

Severe ischemia can produce sharply cortex-limited necrosis.

Extent of the vascular lesion influences the severity of renal failure.

Slide 58 · Chronic TMA: Double-contour capillary walls

Schematic of renal microvascular pathology

Basement-membrane duplication (“double contours”)

Original conceptual schematic • not a photomicrograph

Slide 59 · Chronic TMA reflects repeated vascular injury

Glomeruli may shrink and develop conspicuous capillary-wall thickening.

Basement-membrane duplication creates double contours (“tram tracks”).

Arterial intimal cellular/connective tissue layering narrows the lumen.

Arteriolar wall thickening and hyalinosis may accompany chronic disease.

Slide 60 · Acute and chronic renal TMA compared

Acute / active

Chronic / healed or ongoing

Capillary and arteriolar thrombi

Glomerular capillary-wall thickening and double contours

Mesangial disruption

Shrunken and scarred glomeruli

Subcapsular petechiae / cortical necrosis

Intimal proliferation and narrowing

Rapid ischemic dysfunction

Persistent hypoperfusion and renal scarring

Slide 61 · TTP and HUS cannot be classified by morphology alone

The renal lesions overlap substantially between pathogenetic subtypes.

Appearance varies more with acute versus chronic disease than with syndrome label.

Biopsy demonstrates microvascular injury but does not by itself establish its trigger.

Mechanistic classification requires clinical and laboratory correlation.

Slide 62 · A clinicopathologic approach to suspected TMA

Recognize MAHA + thrombocytopenia

Assess organ injury and coagulation profile

Seek specific mechanism or exposure

Classify TTP, HUS, or other secondary TMA

Slide 63 · High-yield etiologic discriminators

Possible entity

Mechanistic clue

Clinical pattern

TTP

ADAMTS13 deficiency

Often prominent neurologic manifestations

Typical HUS

Toxin-producing intestinal infection

Often bloody diarrhea → renal injury

Complement-mediated HUS

Complement regulation abnormality

Possible recurrent renal TMA

DIC

Systemic coagulation activation

Clotting-factor consumption; abnormal coagulation profile

Slide 64 · Case 1: TTP-directed reasoning

An adult develops thrombocytopenia, red-cell fragmentation, and transient neurologic deficits. PT and PTT are normal. The full historical pentad is absent.

Which initiating mechanism deserves urgent consideration?

Slide 65 · Case 1: ADAMTS13 deficiency is central

The combination suggests a thrombotic microangiopathy.

Incomplete pentad does not rule out TTP.

ADAMTS13 deficiency, commonly from an inhibitory antibody, explains vWF-mediated platelet aggregation.

Urgency because a delay can be fatal.

Slide 66 · Case 2: Diarrheal prodrome

A child develops bloody diarrhea after a gastrointestinal illness. Several days later there is microangiopathic hemolysis, thrombocytopenia, and acute renal dysfunction.

Which pathogenic category best explains the presentation?

Slide 67 · Case 2: Shiga toxin–associated HUS

The temporally preceding diarrheal illness points toward typical HUS.

Shiga-like toxin-producing E. Coli is a major initiating pathogen.

Endothelial injury favors microvascular thrombosis and acute renal injury.

The detailed toxin-to-HUS pathway remains incompletely established.

Slide 68 · Case 3: Recurrent kidney-predominant TMA

A patient experiences repeated episodes of acute renal dysfunction with microangiopathic hemolysis and thrombocytopenia. There is no consistent antecedent diarrheal infection.

What inherited or acquired pathway warrants consideration?

Slide 69 · Case 3: Complement dysregulation

Recurrent HUS can reflect insufficient regulation of the alternative complement pathway.

Factor H, factor I, CD46, C3, and factor B are implicated.

Inherited regulatory defects or acquired antibodies can produce the phenotype.

Complement-mediated endothelial damage distinguishes this route from TTP.

Slide 70 · What the different therapies teach about causation

Acquired TTP

• Plasma exchange removes ADAMTS13 inhibitors

• Replacement plasma supplies functional enzyme

• The target is a vWF-cleaving enzyme defect

Hereditary complement-mediated HUS

• C5-directed therapy inhibits downstream complement activation

• Effective control of thrombosis supports complement causality

• The target is complement-mediated injury

Mechanism-specific treatment follows accurate etiologic classification.

Slide 71 · Integrating the TTP–HUS spectrum

TTP

ADAMTS13 deficiency

Unusually large vWF multimers

Platelet aggregation

Typical HUS

Shiga-like toxin exposure

Endothelial injury / activation

Platelet activation

Complement-mediated HUS

Alternative complement dysregulation

Endothelial injury

Platelet activation

Slide 72 · Five clinically useful principles

MAHA with thrombocytopenia raises the possibility of TMA.

A missing TTP pentad feature does not exclude disease.

TTP is defined mechanistically by ADAMTS13 deficiency.

Typical HUS follows Shiga toxin exposure; Complement-mediated HUS involves complement dysregulation.

Acute and chronic renal lesions overlap and require clinicopathologic interpretation.

Slide 73 · Selected primary references

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026). Chapter 14, “Red Blood Cell and Bleeding Disorders,” pp. 605–606.

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026). Chapter 20, “The Kidney,” pp. 853–855.

Supporting context: Chapter 14, “Hemolytic anemia due to red cell trauma” and “Disseminated intravascular coagulation.”

Original diagrams in this lecture are explanatory schematics, not clinical specimens.