Thrombotic thrombocytopenic purpura (TTP)

Definition

Thrombotic thrombocytopenic purpura (TTP, Moschcowitz syndrome) is an acute, life-threatening thrombotic microangiopathy (TMA) caused by severe deficiency of the von Willebrand factor-cleaving protease ADAMTS13 (activity below 10 %). Its hallmark is the triad of Coombs-negative microangiopathic hemolytic anemia with schistocytes, thrombocytopenia and ischemic organ damage, mainly affecting the brain, heart, kidneys and gut.

Classification

• Immune-mediated TTP (iTTP): more than 90 % of cases; autoantibodies against ADAMTS13 (mostly IgG) inhibit the enzyme or accelerate its clearance; typically presents in adulthood.
• Congenital TTP (cTTP, Upshaw-Schulman syndrome): about 5 % of cases, prevalence 0.5–2 per million; autosomal recessive (homozygous or compound heterozygous) mutations in the ADAMTS13 gene; onset often in infancy or childhood or first in pregnancy.

Aetiopathogenesis

ADAMTS13 cleaves ultra-large von Willebrand factor multimers released by the endothelium. If the enzyme is lacking, these multimers persist and spontaneously bind platelets. When a trigger is added (e.g. infection, pregnancy), platelet- and von Willebrand factor-rich microthrombi form at the arteriocapillary junctions of many organs. They consume platelets and shear passing red cells (mechanical, intravascular hemolysis).

The microthrombi are platelet-rich; unlike in DIC, plasmatic coagulation remains largely normal. Risk factors for iTTP are female sex and pregnancy; in US cohorts the risk was about sevenfold higher in Black people.

Clinical features

Onset may be insidious with mild complaints or acute and severe; symptoms are often non-specific.

• Thrombocytopenia (virtually always): petechiae, purpura, bruising, mucosal and retinal bleeding – often only mild
• Hemolytic anemia (virtually always): pallor, weakness, fatigue, exertional dyspnea, jaundice
• Neurological symptoms (about 61 %, severe in about 31 %), often transient and fluctuating: headache, confusion, visual disturbance, aphasia, dysarthria, hemiparesis, seizures, coma
• Kidney (about 40 %): rising creatinine, proteinuria, microscopic hematuria; acute kidney failure in only about 10 %; the kidney is more often involved in cTTP
• Gastrointestinal (about 35 %): abdominal pain, nausea, vomiting, diarrhea, pancreatitis
• Heart: troponin rise, arrhythmias, angina pectoris, myocardial infarction up to sudden cardiac death
• non-specific arthralgia, myalgia, fever

Histology

Blood smear

The key finding is schistocytes (fragmented red cells): helmet cells, triangular and bizarrely deformed red cell fragments, together with polychromasia reflecting reticulocytosis and a marked reduction in platelets. The number of schistocytes varies widely; if in doubt, the smear is reassessed the following day.

Diagnosis

• Blood count and smear: thrombocytopenia, anemia, schistocytes
• Signs of hemolysis: LDH and indirect bilirubin raised, haptoglobin low to undetectable, reticulocytes raised
• Direct Coombs test usually negative
• Coagulation (prothrombin time/INR, aPTT, fibrinogen, D-dimer) largely normal – distinction from DIC
• Organ assessment: creatinine, urinalysis, troponin, NT-proBNP, liver tests, lipase; brain imaging with neurological signs
• ADAMTS13 activity (key finding; below 10 % confirms TTP) and anti-ADAMTS13 antibodies; only citrate blood drawn before any blood products are given is informative, as EDTA inhibits the enzyme
• Genetics with absent antibodies, onset in childhood or pregnancy, relapses or a positive family history

PLASMIC score

In confirmed microangiopathic hemolysis with thrombocytopenia, it estimates the probability of severe ADAMTS13 deficiency while the result is pending. 1 point each:

• platelets below 30 G/l
• hemolysis: reticulocytes above 2.5 % or indirect bilirubin above 2 mg/dl or undetectable haptoglobin
• no active cancer
• not a transplant recipient
• MCV below 90 fl
• INR below 1.5
• creatinine below 2 mg/dl

0–4 points: low (0–4 %), 5 points: intermediate (5–24 %), 6–7 points: high probability (62–82 %).

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Further reading (open access)

1. Onkopedia-Leitlinie (DGHO): Thrombotische Mikroangiopathie (TMA)
2. MSD Manual Professional: Thrombotic Thrombocytopenic Purpura (TTP)

Cross-references