Thrombotic Microangiopathy

The contract between this chapter and the reader.

1. 1. Define the TMA syndrome and its endothelial mechanism.
2. 2. Recognise the triad (MAHA, thrombocytopenia, organ injury).
3. 3. Distinguish TTP, STEC-HUS, atypical HUS, and secondary TMA.
4. 4. Diagnose TTP (ADAMTS13) and treat it urgently.
5. 5. Recognise and manage STEC-HUS.
6. 6. Diagnose and treat atypical HUS (complement).
7. 7. Identify and manage secondary TMA.
8. 8. Apply the cause-based treatment framework.
9. 9. Understand the prognosis.

A sixty-second reading. Each bullet stands alone.

• Thrombotic microangiopathy is a syndrome of microvascular thrombosis from endothelial injury.
• It is recognised by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and organ injury.
• The kidney is prominently involved, with acute kidney injury, hypertension, and an active sediment.
• The causes are distinguished because their treatments differ sharply.
• TTP is caused by severe ADAMTS13 deficiency and is treated urgently with plasma exchange.
• STEC-HUS follows Shiga-toxin-producing E. coli infection and is usually managed supportively.
• Atypical HUS is caused by complement dysregulation and is treated with a complement inhibitor.
• Secondary TMA results from drugs, pregnancy, malignancy, infection, or transplantation.
• ADAMTS13 activity, stool Shiga toxin, and complement studies distinguish the causes.
• TTP must be distinguished from atypical HUS urgently because the treatments differ.
• Plasma exchange is started urgently when TTP is suspected, without waiting for the ADAMTS13 result.
• Complement inhibition has transformed atypical HUS.
• Secondary TMA is managed by removing or treating its cause.

The medical core. An expert should agree thrombotic microangiopathy is fully covered here.

Why it matters at the bedside

Thrombotic microangiopathy is a syndrome, not a single disease — and the whole game is finding out which cause you are dealing with, because the treatments could not be more different. Miss TTP and the patient can die for want of plasma exchange; miss atypical HUS and you withhold a transformative complement inhibitor. Recognise the triad, then name the cause.

What TMA is: the syndrome and the endothelium

• Thrombotic microangiopathy is the disease of the injured endothelium — the third glomerular cell of the first chapter. Endothelial injury triggers platelet-fibrin thrombi in the microvasculature, which shear passing red cells and consume platelets. The renal histology shows fibrin thrombi, endothelial swelling, fragmented red cells, and (chronically) double contours — the morphologic face of a syndrome that is fundamentally vascular.

Recognising the triad

• TMA is recognised clinically by a triad: microangiopathic hemolytic anemia (MAHA — schistocytes on the film, a high LDH, a low haptoglobin, a negative direct antiglobulin test), thrombocytopenia (platelets consumed in the thrombi), and organ injury — with the kidney prominently affected (acute kidney injury, hypertension, an active sediment). The triad is the entry point; the cause is the destination.

The causes and why distinguishing them matters

• The TMA syndrome has several causes whose treatments diverge sharply, so identifying the cause is the central task. The major categories are TTP (ADAMTS13 deficiency), STEC-HUS (Shiga toxin), atypical HUS (complement dysregulation), and secondary TMA (drugs, pregnancy, malignancy, infection, transplantation). The same clinical triad demands completely different treatment depending on which of these it is.

TTP

• Thrombotic thrombocytopenic purpura is caused by severe deficiency of ADAMTS13 — the enzyme that cleaves von Willebrand factor — whether congenital or, more often, from an autoantibody. Uncleaved large von Willebrand factor multimers trap platelets into microthrombi. Neurologic features are prominent and renal involvement may be relatively mild. It is a medical emergency: untreated TTP is frequently fatal, and urgent plasma exchange is life-saving.

STEC-HUS

• Shiga-toxin-producing E. coli haemolytic uraemic syndrome — ‘typical’ HUS — follows an infection (classically a bloody diarrhoeal illness, often in children); the Shiga toxin injures the endothelium directly, producing a renal-predominant TMA. It is largely managed supportively and is usually self-limiting, with antibiotics approached cautiously as they may worsen toxin release in some settings.

Atypical HUS

• Atypical HUS is the complement-driven TMA — dysregulation of the alternative complement pathway (gene variants or autoantibodies, the same biology as C3 glomerulopathy but expressed as TMA) — producing a renal-predominant microangiopathy that, without treatment, is progressive and relapsing. Its management has been transformed by complement inhibition (eculizumab, ravulizumab), with plasma exchange sometimes used initially.

Secondary TMA

• A large group of secondary TMAs is provoked by an identifiable insult: drugs (calcineurin inhibitors, gemcitabine, quinine, VEGF inhibitors), pregnancy (HELLP, severe pre-eclampsia), malignancy, infection, autoimmune disease, severe hypertension, and transplantation (the transplant volume). The treatment is to remove or treat the cause — stop the offending drug, deliver in pregnancy-related TMA, treat the malignancy — and these are not primarily complement- or ADAMTS13-driven.

The diagnostic workup

• Once the triad is recognised, the workup assigns the cause: ADAMTS13 activity (severely low confirms TTP), stool studies for Shiga toxin/STEC, complement studies and genetics for atypical HUS, and a review for drugs, pregnancy, malignancy, and autoimmune disease for secondary TMA. The most urgent discrimination is TTP versus atypical HUS, because their treatments — plasma exchange versus a complement inhibitor — are entirely different.

The cause-based treatment framework

• Treatment follows the cause directly. TTP — urgent plasma exchange (removing the autoantibody and replenishing ADAMTS13), with steroids and increasingly rituximab and caplacizumab; crucially, plasma exchange is started on clinical suspicion, without waiting for the ADAMTS13 result, because delay kills. STEC-HUS — supportive care. Atypical HUS — a complement inhibitor. Secondary TMA — remove or treat the cause. The framework is: recognise the syndrome, name the cause, give the cause-specific treatment.

Prognosis

• Prognosis tracks the cause and the speed of treatment. TTP is fatal if untreated but does well with prompt plasma exchange; atypical HUS is progressive and relapsing without complement inhibition but transformed by it (and recurs after transplantation, reflecting its complement biology); STEC-HUS usually recovers; and secondary TMA depends on whether its cause can be removed or treated. In every case, the outcome is decided by getting the cause right, quickly.

Five fully-built tables.

Table A — The TMA syndrome

Table B — The causes

Table C — Distinguishing tests

Table D — Treatment by cause

Table E — TTP vs atypical HUS vs STEC-HUS

Visualise & Map

Causal chains, each ending in a named action.

Chain 1 — The injured endothelium

Endothelial injury → platelet-fibrin microthrombi → sheared red cells and consumed platelets with organ ischemia → the TMA triad → ACTION: recognise the syndrome and identify the cause.

Chain 2 — The missing enzyme

Severe ADAMTS13 deficiency → uncleaved large von Willebrand factor multimers → platelet microthrombi → TTP → ACTION: start urgent plasma exchange.

Chain 3 — The unchecked complement

Alternative-pathway complement dysregulation → endothelial complement attack → renal-predominant TMA → atypical HUS → ACTION: give a complement inhibitor.

Chain 4 — The toxin

Shiga toxin from E. coli → direct endothelial injury → renal-predominant HUS after a diarrhoeal illness → STEC-HUS → ACTION: manage supportively.

Chain 5 — The provoking insult

A drug, pregnancy, malignancy, or transplant → endothelial injury → secondary TMA → ACTION: remove or treat the underlying cause.

Numbered rules. These numbers are the cross-reference handle for the cases and flowcharts.

Clinical Reasoning

Five cases. Each stops you at a decision before it answers it.

Every mechanism from Level 3 earns a bedside consequence and an action.

Exhaustive. Every rule in the chapter is here.

Safety & Evidence

Panel A — Red flags

Panel B — NEVER DO

Anti-patterns clinicians fall into. Each becomes a Level 22 distractor.

The grade reflects strength of evidence, not importance.

Patient Decisions

Outcomes as natural frequencies. Figures are representative; the direction of effect is given where precise numbers are uncertain.

Apply & Test

Copy-paste chart notes that map to the real decisions in this chapter.

Template 1 — TMA syndrome workup note

• Triad: MAHA (schistocytes, LDH, haptoglobin); thrombocytopenia; organ injury ___.
• ADAMTS13 sent (TTP); plasma exchange started empirically if TTP suspected ___.
• Stool Shiga toxin / STEC: ___.
• Complement studies / genetics (atypical HUS): ___.
• Secondary review: drugs, pregnancy, malignancy, transplant ___.

Template 2 — Cause-specific treatment note

• Cause assigned: TTP / STEC-HUS / atypical HUS / secondary ___.
• TTP: plasma exchange + steroids ± rituximab / caplacizumab ___.
• Atypical HUS: complement inhibitor ___.
• STEC-HUS: supportive ___.
• Secondary: cause removed/treated; transplant recurrence note (aHUS) ___.

Pre-rounds compression. Rules only.

Active recall. At least one card per objective.

Micro-teaching for rounds. Two scenarios, five steps each.

Nine items, each anchored in this chapter. At least one per objective.