How do ITP, TTP and HUS differ?
All three present with low platelets, which is why they are asked together. The key question is whether there is microangiopathic haemolysis. A thrombotic microangiopathy (TMA) is the triad of thrombocytopenia, Coombs-negative haemolytic anaemia with schistocytes, and ischaemic end-organ damage. TTP and HUS are TMAs. ITP is not: the smear shows reduced platelets of normal or increased size, with normal red and white cells.
| Feature | ITP | TTP | HUS |
|---|---|---|---|
| Core mechanism | IgG autoantibodies coat platelets; spleen macrophages clear them | ADAMTS13 activity under 10% (autoantibody or inherited): ultra-large VWF multimers cause platelet microthrombi | Endothelial injury by Shiga toxin (typical) or uncontrolled alternative complement (atypical) |
| Smear | Low, sometimes large platelets; RBC and WBC normal | Schistocytes | Schistocytes |
| Haemolysis (LDH up, haptoglobin low, Coombs negative) | Absent | Present | Present (Coombs positive only in pneumococcal HUS) |
| Dominant organ | Mucocutaneous bleeding | Neurological and kidney; renal involvement is relatively rare | Kidney (acute kidney injury) |
| PT / aPTT | Checked to exclude other causes | Normal (coagulation abnormalities uncommon) | Abnormal results suggest DIC |
| Typical patient | Child after viral illness; women 18–45 | Adult over 40, women 2:1 | Child under 5 with bloody diarrhoea |
| Treatment | Steroids, IVIG, TPO agonists, rituximab, splenectomy | Plasma exchange + steroids, rituximab, caplacizumab | Typical: supportive. Atypical: eculizumab |
| Platelet transfusion | For critical bleeding only | Avoid unless major bleeding | Sparingly |
What is ITP and how is it classified?
Immune thrombocytopenia (ITP), formerly idiopathic thrombocytopenic purpura, is mediated by IgG autoantibodies against platelet membrane glycoproteins (including GP IIb/IIIa). Antibody-coated platelets are cleared by tissue macrophages, mainly in the spleen, shortening platelet lifespan. Megakaryocyte-directed T-cell cytotoxicity may also contribute. ASH defines ITP as a platelet count under 100,000/µL with a normal white count and haemoglobin; abnormal WBC or Hb should prompt another diagnosis.
| Phase | Duration |
|---|---|
| Newly diagnosed | Diagnosis to 3 months |
| Persistent | 3 to 12 months |
| Chronic | More than 12 months |
| Refractory | Does not resolve with splenectomy |
| Severe | Platelets under 20,000/µL: warrants treatment |
| Trigger group | Examples |
|---|---|
| Infection | HIV, hepatitis C, CMV, varicella zoster; about 60% of affected children have a viral illness in the preceding month |
| Autoimmune | SLE, antiphospholipid syndrome, Evans syndrome, CVID, autoimmune lymphoproliferative syndrome |
| Drugs | Quinine, heparin, carbamazepine, phenytoin, linezolid, vancomycin, rifampicin, sulfonamides, beta-lactams, abciximab |
| Malignancy | CLL, lymphoma, adenocarcinoma |
| Vaccine | Small risk within 6 weeks of MMR |
| Endocrine | Hypothyroidism, Addison disease |
Children: peak at 2–5 years and in adolescence; usually acute after a viral illness and self-limiting, with most recovering within 3 months; about 25% in the United States become persistent or chronic. Adults: more often chronic; women predominate at 18–45 years (estrogen effect), with peak incidence around 60 years, after which men and women are affected about equally.
How is ITP diagnosed?
ITP is a diagnosis of exclusion. Most patients have mucocutaneous bleeding (petechiae, bruising, epistaxis, gum bleeding); a few are asymptomatic. Major bleeding risk rises with a platelet count under 20,000/µL, older age and prior minor bleeding. Fever, weight loss or lymphadenopathy suggest infection or malignancy rather than ITP.
- Initial tests: CBC with differential, reticulocyte count and peripheral smear. Platelets are usually under 100,000/µL; WBC, Hb and red cell indices are normal; platelets are reduced with normal or increased size. Schistocytes suggest microangiopathic haemolysis; blasts suggest leukaemia or lymphoma.
- Antiplatelet antibody testing is not recommended: high specificity but low sensitivity and it does not correlate with outcome.
- Bone marrow biopsy is no longer routine in typical ITP in adults or children. It is for features of malignancy or marrow failure (lymphadenopathy, splenomegaly, neutropenia, leucocytosis, atypical lymphocytes, anaemia with bone pain or weight loss) or when immunosuppression fails.
- Secondary causes: HIV and hepatitis C, ANA (positive in 17.5% of ITP; about 12.8% of SLE patients first present as ITP), anti-dsDNA if SLE criteria are met, H. pylori testing when epigastric pain suggests peptic ulcer, immunoglobulin levels if immunodeficiency is suspected, PT and aPTT in moderate or severe thrombocytopenia.
How is ITP treated?
Treatment depends on bleeding, platelet count and risk, not on the count alone. ASH 2019 guidance, as summarised in StatPearls, is below.
| Situation | Approach |
|---|---|
| Adult, new, platelets under 30,000/µL, no or minor bleeding | Corticosteroids over observation: prednisone 0.5–2 mg/kg/day or dexamethasone 40 mg daily for 4 days. Avoid prednisone for more than 6 weeks including taper |
| Adult, new, platelets 30,000/µL or more, no or minor bleeding | Observation (consider steroids if near threshold, anticoagulants or antiplatelets, planned procedure, age over 60) |
| Child, no or mild bleeding | Observe regardless of count; 50–70% recover in 3–6 months. If non-life-threatening mucosal bleeding or poor quality of life: prednisone 2–4 mg/kg/day (max 120 mg) for 5–7 days. IVIG or anti-D are not preferred over observation |
| Steroids unsuitable | IVIG, or anti-D (RhD-positive only; boxed warning for haemolysis) |
| Critical bleeding (intracranial, intraocular, retroperitoneal, compartment syndrome, instability) | ICU. Platelet transfusion (1 apheresis or 4–6 pooled units), IVIG 1 g/kg (repeat next day if platelets under 50,000/µL), methylprednisolone 1 g IV daily for 3 days or dexamethasone 40 mg IV daily for 4 days, tranexamic acid |
| Second line (steroid-dependent, no response by 3 months, or chronic) | TPO receptor agonists (eltrombopag, romiplostim, avatrombopag), rituximab, splenectomy. In children: TPO-RA first, then rituximab |
What causes TTP and what does ADAMTS13 do?
ADAMTS13 is a plasma protease that cleaves ultra-large von Willebrand factor (VWF) multimers into smaller, less sticky forms. When activity is severely deficient, ultra-large multimers bind platelets spontaneously, forming platelet-rich microthrombi in small arterioles and capillaries. Platelets are consumed (thrombocytopenia), red cells are sheared as they pass through occluded vessels (schistocytes), and ischaemia damages the brain and kidney. TTP is defined by ADAMTS13 activity under 10%.
| Type | Mechanism | Notes |
|---|---|---|
| Acquired (immune) TTP | Autoantibodies against ADAMTS13 | More common. Triggers: antiplatelet drugs, immunosuppressants, HIV, estrogen-containing contraceptives, pregnancy |
| Congenital TTP | ADAMTS13 gene mutations | Often silent until a trigger such as infection or pregnancy; can present in children |
TTP is rare (1–13 per million), most often after age 40, and female-to-male about 2:1. Untreated mortality is about 90%, falling to 10–15% with treatment; about 80% respond to initial therapy. Histology shows platelet thrombi in small vessels without large-vessel thrombosis, endothelial swelling, and a normal bone marrow with increased erythropoiesis and thrombopoiesis.
How is TTP recognised, and what is the PLASMIC score?
The classic pentad is fever, thrombocytopenia, microangiopathic haemolytic anaemia, renal dysfunction and neurological dysfunction, but fewer than 5% have all five (Oklahoma registry). Presentation is variable: gastrointestinal symptoms (69%), weakness (63%), bleeding or purpura (54%), major neurological findings (41%), minor neurological findings (26%), fever (10%). Neurological symptoms dominate: headache, confusion, seizures, focal deficits. A raised troponin is a bad prognostic sign.
- Laboratory proof of haemolysis: schistocytes, high LDH, high indirect bilirubin, high reticulocyte count, low or absent haptoglobin.
- Normal WBC and normal coagulation profile (uncommon coagulopathy) separates TTP from DIC.
- ADAMTS13 activity under 10% confirms TTP in a patient with haemolysis and thrombocytopenia, but it can also be low in severe sepsis and systemic cancer. Activity under 20% after recovery is a relapse, even without thrombocytopenia.
| Item | Point if |
|---|---|
| Platelet count | Under 30 × 109/L (30,000/µL) |
| Haemolysis | Reticulocytes over 2.5%, undetectable haptoglobin or indirect bilirubin over 2 mg/dL |
| No active cancer | Yes |
| Solid-organ or stem-cell transplant | None |
| MCV | Under 90 fL |
| INR | Under 1.5 |
| Creatinine | Under 2.0 mg/dL |
Interpretation: 0–4 low, 5 intermediate, 6–7 high risk of severe ADAMTS13 deficiency. A score of 5 or more has sensitivity about 99% and specificity about 57%; at 6 or more sensitivity falls to about 85% and specificity rises to about 89%. Because of the high negative predictive value, it is a screening tool, and a score of 5 or more should be treated empirically unless there is an obvious alternative cause. Notice that the score rewards normal creatinine, normal INR and normocytic or smaller red cells, which are what make TTP different from HUS and DIC.
How is TTP treated?
TTP is a medical emergency. Start plasma exchange (PEX) with corticosteroids as soon as TTP is suspected in unexplained haemolytic anaemia with thrombocytopenia and a normal coagulation profile; do not wait for the ADAMTS13 result. PEX removes ultra-large VWF multimers and anti-ADAMTS13 antibodies and replaces the enzyme.
| Therapy | Detail |
|---|---|
| Plasma exchange | One plasma volume (about 40 mL/kg) daily, with plasma as replacement fluid. Stop (without taper) once platelets stay above 150,000/µL for more than 48 hours. Plasma infusion alone is only temporising |
| Corticosteroids | Prednisone 1 mg/kg/day, or methylprednisolone 1,000 mg daily for 3 days in severe illness; continue while PEX continues, then taper |
| Rituximab | Anti-CD20; for refractory or relapsing disease; ISTH 2020 suggests adding it in a first event to reduce relapse, and as prophylaxis if ADAMTS13 stays low in remission |
| Caplacizumab | Anti-VWF A1 humanized antibody fragment; blocks platelet adhesion, rapid onset; given for 30 days after PEX stops until ADAMTS13 recovers above 20%; bleeding risk; does not reduce antibody production |
| Platelet transfusion | Contraindicated unless major bleeding |
| Pregnancy with low ADAMTS13 but no TTP | Prophylactic plasma infusion (ISTH 2020) |
What is HUS and what are typical and atypical forms?
Hemolytic uremic syndrome (HUS) is a TMA with thrombocytopenia, microangiopathic haemolytic anaemia and acute kidney injury. Classification is now by cause. Bloody diarrhoea no longer defines typical HUS, because atypical HUS can have it in up to 30%.
| Type | Share | Cause and key facts |
|---|---|---|
| Typical (STEC-HUS) | 90–95% | Shiga toxin-producing E. coli (O157:H7 classically; non-O157 serotypes now common). Undercooked beef, unpasteurised milk, contaminated food or water; cattle carry it. Toxin binds the Gb3 receptor (abundant in glomerular microvasculature), inhibits protein synthesis and also activates complement. Stx2 is more severe. HUS occurs in 5–15% of STEC infections, peak under 5 years. Bloody diarrhoea starts about day 2–3, with HUS 3–10 days after diarrhoea begins |
| Atypical (aHUS) | 5–10% | Dysregulated alternative complement pathway: about 60% have mutations in CFH (commonest), CFI, MCP, C3 or CFB. Incomplete penetrance, so a second trigger such as infection is often needed |
| Secondary | Variable | S. pneumoniae (5–15% of paediatric HUS; neuraminidase exposes antigens, activating complement; the only Coombs-positive HUS), other infections (S. aureus, EBV, CMV, influenza, HIV, SARS-CoV-2), drugs (quinine, calcineurin inhibitors, chemotherapy), SLE, antiphospholipid syndrome, malignancy, pregnancy, malignant hypertension, cobalamin disorders, DGKE mutations |
- Kidney: oliguria, anuria, proteinuria; up to 50% need dialysis at some point. Untreated aHUS: about 50% become dialysis-dependent, with 25% mortality.
- Extrarenal (about 20%): neurological (stroke, seizures, coma; poor prognosis), cardiac, GI (bowel ischaemia, pancreatitis) and pulmonary involvement.
- Tests: schistocytes, high LDH, low haptoglobin, negative Coombs (except pneumococcal), stool test for Shiga toxin (may be negative once cleared), ADAMTS13 to exclude TTP, complement levels and genetics in suspected aHUS. Histology: double-contoured basement membrane on electron microscopy.
How is HUS treated?
| Form | Management |
|---|---|
| Typical STEC-HUS | Supportive. Early adequate volume resuscitation (under-resuscitation raises the need for dialysis; about half need renal replacement therapy), transfusion as needed, platelet transfusion sparingly. Avoid antimotility drugs and antibiotics (worse outcomes, likely from more toxin exposure) |
| Pneumococcal or Shigella dysenteriae HUS | Early antibiotics improve outcomes |
| Atypical HUS | Eculizumab (anti-C5 monoclonal antibody) first line, started early. Ravulizumab (also anti-C5, half-life about 4 times longer) is an alternative. Plasma exchange is second line or adjunct, and is used when eculizumab is unavailable. Kidney transplant recurrence rates in aHUS are high |
Related reading: bleeding disorders: platelet and coagulation, haemolytic anaemias and acute kidney injury.
What are the common exam traps?
- Platelet transfusion: contraindicated in TTP unless major bleeding; used sparingly in HUS; reasonable in ITP only for critical bleeding.
- Do not wait for ADAMTS13 to start plasma exchange when the story and PLASMIC score fit TTP.
- TTP is neurological, HUS is renal. TTP renal involvement is relatively rare. The full pentad is present in under 5%.
- Normal PT/aPTT in TTP and HUS; abnormal coagulation points to DIC.
- Antibiotics and loperamide worsen STEC-HUS.
- Coombs-positive HUS means pneumococcus.
- Bone marrow is not needed for typical ITP; antiplatelet antibody tests are not recommended.
- Eculizumab and ravulizumab are anti-C5 antibodies for aHUS; caplacizumab is an anti-VWF A1 antibody fragment for TTP; rituximab is anti-CD20.