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PA27.{11,15} | Vascular Diseases & Thrombotic Microangiopathies — SDL Guide (Part 3)

Thrombotic Thrombocytopenic Purpura (TTP)

A four-panel educational diagram explains TTP pathogenesis from ADAMTS13 deficiency, resulting platelet-rich microthrombi, clinical pentad, causes, and distinction from HUS. — **Panel A:** Endothelial cell, Weibel-Palade bodies, ultra-large vWF multimers, ADAMTS13 cleavage, smaller vWF fragments, ADAMTS13 deficiency, platelet adhesion, platelet-rich microthrombus, small vessel lumen. **Panel B:** MAHA with schistocytes and low Hb, severe thrombocytopenia, neurological symptoms from cerebral microthrombi, fever, renal impairment less severe than HUS. **Panel C:** Acquired TTP with IgG autoantibody against ADAMTS13, hereditary TTP or Upshaw-Schulman syndrome with ADAMTS13 gene mutation, reduced vWF cleavage. **Panel D:** TTP with CNS-predominant microthrombi and severe thrombocytopenia, HUS with kidney-predominant injury and more severe renal failure.

TTP is the most dangerous of the thrombotic microangiopathies, with historically ~90% mortality if untreated.

Pathogenesis — the ADAMTS13 story:
• Von Willebrand factor (vWF) is released as ultra-large multimers (ULvWF) from endothelial Weibel-Palade bodies; these are pro-thrombotic
• ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) — a plasma metalloprotease — normally cleaves ULvWF into smaller, less sticky monomers
• ADAMTS13 deficiency → ULvWF accumulates → platelet aggregation on endothelial surfaces → widespread platelet-rich microthrombi

Type	Mechanism
Acquired TTP (most common)	Autoantibody (IgG) against ADAMTS13 — inhibits cleavage activity
Hereditary TTP (Upshaw-Schulman)	ADAMTS13 gene mutation — rare, recurrent

Clinical pentad of TTP (memorise):
1. MAHA (schistocytes, low Hb)
2. Thrombocytopenia (<30,000/μL — typically severe)
3. Neurological symptoms (fluctuating — confusion, seizures, focal deficits; from cerebral microthrombi)
4. Fever
5. Renal impairment (less severe than HUS — kidneys are not the primary target)

TTP vs HUS — key distinguishing features:

Feature	TTP	HUS (typical)
Age	Adults (any age)	Children <5
Prodrome	None (acquired)	Bloody diarrhoea
Neurological features	Prominent	Absent/mild
Renal failure	Mild-moderate	Severe (main feature)
ADAMTS13	Severely low (<10%)	Normal
Platelet count	Very low (<30K)	Low (<80K)
Treatment	Plasma exchange (PLEX)	Supportive; eculizumab for aHUS

Treatment of acquired TTP:
• Plasma exchange (PLEX/plasmapheresis) — removes anti-ADAMTS13 antibodies AND replaces ADAMTS13 enzyme. Dramatically reduces mortality from ~90% to <20%.
• Caplacizumab (anti-vWF nanobody) — newer adjunct
• Rituximab for refractory/relapsing cases

Side-by-side comparison of typical HUS and TTP showing renal Shiga toxin-Gb3 endothelial injury, shared MAHA and thrombocytopenia, and ADAMTS13 deficiency causing platelet-rich thrombi with brain-predominant disease. — **Panel A:** Typical HUS pathway with Shiga toxin, Gb3 receptor on glomerular endothelium, endothelial injury, glomerular platelet-fibrin microthrombi, and kidney-predominant involvement.. **Panel B:** Shared thrombotic microangiopathy features including schistocytes / MAHA, thrombocytopenia, and platelet-rich microthrombi.. **Panel C:** TTP pathway with ADAMTS13 deficiency or inhibitor, ULvWF multimer accumulation, platelet-rich thrombus formation, and brain-predominant involvement..

SELF-CHECK

A 34-year-old woman presents with confusion, fever, petechiae, and MAHA. ADAMTS13 activity is 4% (reference >67%). Shiga-toxin stool PCR is negative. Which treatment is the MOST critical immediate intervention?

A. Plasma exchange (plasmapheresis) to replace ADAMTS13 and remove inhibitor antibodies

B. Platelet transfusion to raise count above 50,000/μL

C. Eculizumab infusion to block terminal complement

D. Haemodialysis for acute kidney injury

Reveal Answer

Answer: A. Plasma exchange (plasmapheresis) to replace ADAMTS13 and remove inhibitor antibodies

This presentation — adult, no diarrhoea, prominent neurological features, very low ADAMTS13 (<10%) — is acquired TTP. Plasma exchange (PLEX) is the cornerstone emergency treatment: it simultaneously removes the autoantibody inhibiting ADAMTS13 and replenishes functional ADAMTS13 enzyme, reducing TTP mortality from ~90% to <20%. Platelet transfusion is CONTRAINDICATED in TTP — it adds fuel to microthrombus formation and has caused deaths. Eculizumab is for complement-mediated aHUS, not TTP. Haemodialysis may be needed but is not the primary TTP intervention.

DIC, Scleroderma Renal Crisis, Cortical Necrosis, and Renal Infarction

A multi-panel renal pathology diagram comparing DIC, scleroderma renal crisis, bilateral cortical necrosis, and renal infarction with gross and microscopic vascular features. — **Panel A:** Kidney cortex, medulla, glomerular capillaries, arterioles, fibrin microthrombi, platelet consumption, vascular narrowing, cortical ischemia, coagulation activation, intimal proliferation.. **Panel B:** Glomerulus, glomerular capillary loops, fibrin thrombi, platelets, red blood cells, cortical ischemia, thrombosis, bleeding, common causes: sepsis, obstetric catastrophe, malignancy, transfusion, snake bite.. **Panel C:** Interlobular artery, onion-skin intimal hyperplasia, narrowed lumen, adventitial fibrosis, fibrinoid necrosis of arteriole, severe hypertension, acute kidney injury, MAHA, elevated renin, ACE inhibitor: captopril.. **Panel D:** Renal cortex, pale yellow cortical necrosis, preserved medulla, spared juxtamedullary strip, cortical vessel thrombosis, dystrophic cortical calcification, oliguria or anuria, obstetric associations: abruptio placentae, placenta praevia, eclampsia, septic abortion.. **Panel E:** Renal artery branches, embolus, occluded interlobar or arcuate artery, wedge-shaped pale infarct, cortex, medulla, apex of infarct toward blocked vessel, embolic source: atrial fibrillation or mural thrombus..

Disseminated Intravascular Coagulation (DIC):
• Diffuse activation of coagulation and fibrinolysis → microvascular fibrin thrombi + consumption of clotting factors/platelets → simultaneous thrombosis and bleeding
• Renal lesions: fibrin thrombi in glomerular capillaries, cortical ischaemia
• Causes: sepsis (most common), obstetric catastrophes, malignancy, massive transfusion, snake bite

Scleroderma (Systemic Sclerosis) Renal Crisis:
• Sudden severe hypertension + AKI in a scleroderma patient
• Pathogenesis: intimal proliferation + adventitial fibrosis in interlobular arteries → concentric onion-skin hyperplasia (morphologically identical to malignant hypertension) + fibrinoid necrosis of arterioles
• Lab: MAHA picture, elevated plasma renin
• Treatment: ACE inhibitors (captopril) — reduce renin-angiotensin activation; dramatically improved prognosis

Bilateral Cortical Necrosis:
• Ischaemic necrosis of the renal cortex (sparing medulla and a thin juxtamedullary strip)
• Mechanism: prolonged vasospasm + DIC → cortical vessel thrombosis
• Classic obstetric association: abruptio placentae, placenta praevia, eclampsia, septic abortion
• Gross: pale/yellowish cortical zone; medulla preserved (medullary vessels have collateral supply)
• May progress to dystrophic cortical calcification (visible on plain X-ray)
• Outcome: oliguria/anuria → CKD or permanent renal failure

Renal Infarction:
• Usually embolic: atrial fibrillation (left atrial thrombus), infective endocarditis (septic emboli), aortic plaque, post-cardiac catheterisation
• Morphology: wedge-shaped coagulative necrosis oriented cortex-to-papilla, with haemorrhagic rim
• Clinical: sudden flank pain, haematuria, elevated LDH; large infarcts → hypertension (renin release from ischaemic juxtaglomerular cells)
• Treatment: anticoagulation; revascularisation only in acute bilateral occlusion

CLINICAL PEARL

The TMA diagnosis hinges on the peripheral blood film. Whenever you see AKI + low platelets, immediately ask: is there a microangiopathic picture? Order a blood film and look for schistocytes. Schistocytes + thrombocytopenia + AKI = TMA until proven otherwise. Then: (1) check for diarrhoeal prodrome (HUS), (2) look for neurological features (TTP), (3) send ADAMTS13, Shiga-toxin PCR, complement levels. Never transfuse platelets empirically in suspected TTP — it worsens microvascular thrombosis.

SELF-CHECK

Bilateral cortical necrosis is most classically associated with which obstetric condition?

A. Hyperemesis gravidarum in the first trimester

B. Abruptio placentae causing profound hypotension and DIC

C. Premature rupture of membranes at 28 weeks

D. Mild pre-eclampsia with proteinuria in the third trimester

Reveal Answer

Answer: B. Abruptio placentae causing profound hypotension and DIC

Bilateral cortical necrosis classically complicates abruptio placentae and other severe obstetric haemorrhagic/thrombotic catastrophes (eclampsia, septic abortion). The combination of profound circulatory shock and DIC triggers cortical vessel vasospasm and thrombosis, leading to selective cortical ischaemia — the medulla is spared by its collateral supply. Hyperemesis, PROM, and mild pre-eclampsia are not associated with this lesion.

Integrative Summary: Framework for Vascular Renal Disease

A three-panel renal vascular disease framework links vessel calibre and lesion type to major diagnoses and clinical patterns. — **Panel A:** Renal artery stenosis, interlobular artery onion-skin hyperplasia, afferent arteriole hyaline arteriolosclerosis, afferent arteriole fibrinoid necrosis, glomerular capillary fibrin/platelet thrombi. **Panel B:** Large artery stenosis causing renovascular hypertension; interlobular artery onion-skin hyperplasia in malignant HTN and scleroderma; afferent arteriole hyaline change in benign nephrosclerosis; afferent arteriole fibrinoid necrosis in malignant HTN and TMA; glomerular capillary thrombi in HUS, TTP, and DIC. **Panel C:** Benign nephrosclerosis clinical pattern, malignant nephrosclerosis clinical pattern, typical HUS clinical pattern, TTP clinical pattern.

Step 1 — Vessel calibre and lesion character:

Vessel	Lesion	Disease
Large artery	Stenosis (atherosclerosis/FMD)	Renovascular hypertension
Interlobular artery	Onion-skin hyperplasia	Malignant HTN, scleroderma
Afferent arteriole	Hyaline change	Benign nephrosclerosis
Afferent arteriole	Fibrinoid necrosis	Malignant HTN, TMA
Glomerular capillary	Fibrin/platelet thrombi	TMA (HUS, TTP, DIC)

Step 2 — Clinical pattern matching:
• Slowly shrinking kidneys + mild proteinuria + long HTN history → Benign nephrosclerosis
• Acute hypertensive emergency + haematuria + AKI + flea-bitten kidney → Malignant nephrosclerosis
• Child + bloody diarrhoea + MAHA triad → Typical HUS (Shiga-toxin; supportive Rx)
• Adult + neurological + MAHA + ADAMTS13 <10% → TTP (plasma exchange is life-saving; no platelets)
• No diarrhoea + relapsing MAHA + complement mutation → aHUS (eculizumab)
• Obstetric catastrophe + DIC + anuria → Cortical necrosis
• Sudden flank pain + AF or endocarditis → Renal infarction

Laboratory approach to suspected TMA:
1. Peripheral blood film (schistocytes?)
2. FBC (Hb, platelets), reticulocyte count, LDH, bilirubin
3. Coombs test (negative in TMA — not immune-mediated haemolysis)
4. Serum creatinine, urinalysis
5. ADAMTS13 activity and inhibitor
6. Stool Shiga-toxin PCR
7. Complement levels (C3, C4, CH50) and CFH mutation screen (if aHUS suspected)