Medicine chapters
Immune thrombocytopenia and von Willebrand disease
Immune thrombocytopenic purpura (antibody destruction of platelets) and von Willebrand disease (the commonest inherited bleeding disorder), including why desmopressin, factor VIII concentrate and FFP are used.
- ITP: IgG autoantibodies (often against GPIIb/IIIa) coat platelets, which the spleen destroys; result is isolated thrombocytopenia with a normal film otherwise and normal or increased megakaryocytes. Children: post-viral and self-limiting; adults: chronic, young women.
- ITP treatment: children usually observe; adults treat if bleeding or count very low with prednisolone first, IVIG for a rapid rise, then TPO agonists, rituximab or splenectomy; platelet transfusion only for life-threatening bleeding.
- von Willebrand disease: commonest inherited bleeding disorder (mostly autosomal dominant); mucosal bleeding, long bleeding time, often long APTT (low factor VIII), abnormal ristocetin test; treat mild type 1 with desmopressin, severe forms with vWF-containing factor VIII concentrate.
On this page
Overview
Both conditions cause primary haemostasis problems: bleeding into skin and mucosa (petechiae, purpura, gum bleeding, epistaxis, heavy periods) rather than into joints and muscles.
- Immune thrombocytopenia (ITP): platelet number is low because antibodies destroy them.
- von Willebrand disease (vWD): platelet number is normal but platelets cannot stick to damaged vessel walls, and factor VIII is low.
Immune thrombocytopenic purpura (ITP)
Aetiology and pathogenesis
- IgG autoantibodies against platelet membrane glycoproteins, usually GPIIb/IIIa (sometimes GPIb).
- Antibodies are made mainly in the spleen; coated platelets are removed by splenic macrophages (via Fc receptors).
- Antibodies can also impair platelet production by megakaryocytes.
- It is the commonest cause of isolated thrombocytopenia in otherwise well children and adults.
Primary ITP: no cause found.
Secondary ITP: SLE and other autoimmune disease, CLL and lymphoma, HIV, hepatitis C, H. pylori, drugs, and with autoimmune haemolysis (Evans syndrome).
Childhood versus adult ITP
| Feature | Children | Adults |
|---|---|---|
| Age/sex | Usually 2-6 years; either sex | Mainly young women |
| Onset | Acute, often a few weeks after a viral infection or vaccination | Gradual, insidious |
| Course | Self-limiting in most; chronic ITP unusual | Usually chronic, relapsing |
| Associations | Varicella, measles, other viruses | SLE, thyroid disease, AIHA, CLL, HIV |
| Treatment | Usually none (observe) | Often needed |
Presentation
- Petechiae, purpura and easy bruising; gum bleeding, epistaxis, menorrhagia.
- The patient is otherwise well; examination is normal except for bleeding.
- Splenomegaly is rare; a big spleen suggests another diagnosis (leukaemia, lymphoma, hypersplenism).
- Serious bleeding (e.g. intracranial) is rare and occurs only with very low counts.
- In pregnancy, maternal IgG can cross the placenta and cause short-lived thrombocytopenia in the newborn.
Diagnosis
ITP is a diagnosis of exclusion:
| Test | Finding |
|---|---|
| Full blood count | Isolated thrombocytopenia; Hb and white cells normal (unless bleeding) |
| Blood film | Few platelets, some large (young) platelets; no blasts, fragments or other abnormalities; excludes pseudothrombocytopenia (clumping in EDTA) |
| PT, APTT, fibrinogen | Normal |
| Bleeding time | Prolonged (not usually needed) |
| Bone marrow | Normal or increased megakaryocytes; only if atypical features, age over 60 or before splenectomy |
| Antiplatelet antibodies | Found in many but not needed for diagnosis |
| Others | HIV, hepatitis C, H. pylori, ANA, thyroid tests, pregnancy test as appropriate |
Splenomegaly, anaemia, abnormal white cells or fragmented red cells do not fit ITP. Think leukaemia, aplastic anaemia, TTP or DIC.
Treatment
Children: most need no treatment; avoid contact sports and NSAIDs/aspirin. Treat only significant bleeding with steroids or IVIG.
Adults: patients with counts above 30 × 10⁹/L and no bleeding usually need no treatment (unless surgery is planned).
| Line | Treatment | Notes |
|---|---|---|
| First | Oral prednisolone (about 1 mg/kg) | About two-thirds respond; relapse common on tapering |
| First (rapid) | IV immunoglobulin (IVIG) | Fastest rise; effect lasts only weeks; used before surgery, in pregnancy or for serious bleeding; blocks macrophage Fc receptors |
| Second | Thrombopoietin receptor agonists (eltrombopag, romiplostim) | Increase platelet production |
| Second | Rituximab (anti-CD20) | Reduces antibody production |
| Second | Splenectomy | Removes the main site of destruction and antibody production; most respond; give pneumococcal, Hib and meningococcal vaccines beforehand |
| Emergency | Platelet transfusion (+ IVIG, IV methylprednisolone) | Only for life-threatening bleeding (e.g. intracranial), since transfused platelets are also destroyed |
IVIG gives the quickest rise in platelet count; steroids are the usual first-line drug.
Platelet transfusion is not routine in ITP; the antibodies destroy transfused platelets quickly. It is reserved for life-threatening haemorrhage.
Von Willebrand disease (vWD)
What von Willebrand factor does
von Willebrand factor (vWF) is made by endothelial cells (stored in Weibel-Palade bodies) and megakaryocytes. It has two jobs:
- Glues platelets to damaged vessel wall: it binds subendothelial collagen and platelet GPIb (platelet adhesion).
- Carries and protects factor VIII in plasma, preventing its early breakdown.
So lack of vWF gives a double defect: poor platelet adhesion and low factor VIII.
Genetics and types
- The commonest inherited bleeding disorder; the vWF gene is on chromosome 12, so both sexes are affected.
| Type | Defect | Inheritance | Severity |
|---|---|---|---|
| Type 1 | Partial quantitative deficiency (commonest) | Autosomal dominant | Mild |
| Type 2 | Qualitative (abnormal vWF; subtypes 2A, 2B, 2M, 2N) | Usually autosomal dominant | Mild-moderate |
| Type 3 | Almost complete absence of vWF | Autosomal recessive | Severe; factor VIII very low |
Presentation
- Mucocutaneous bleeding: easy bruising, epistaxis, gum bleeding, menorrhagia (often the first clue in young women), bleeding after dental extraction or surgery.
- Haemarthrosis is rare (except sometimes in type 3).
- Often a family history in both men and women.
Tests for diagnosis
| Test | Result in vWD |
|---|---|
| Platelet count | Normal (mildly low in type 2B) |
| Bleeding time / PFA-100 closure time | Prolonged |
| PT | Normal |
| APTT | Normal or prolonged (from low factor VIII) |
| vWF antigen | Low (types 1 and 3) |
| vWF activity (ristocetin cofactor) | Low |
| Factor VIII | Low or normal |
| Ristocetin-induced platelet aggregation | Reduced (increased in type 2B) |
| vWF multimer analysis | To classify type 2 |
Ristocetin makes vWF bind platelet GPIb. Platelets from a vWD patient aggregate poorly with ristocetin; adding normal plasma (with vWF) corrects it. In Bernard-Soulier syndrome (GPIb missing) the ristocetin test is also abnormal but is not corrected by normal plasma, and platelets are large and fewer.
Treatment
- Avoid aspirin and NSAIDs; local measures; tranexamic acid (antifibrinolytic) for mucosal bleeding, dental work and menorrhagia; hormonal treatment for heavy periods.
- Desmopressin for type 1 (and some type 2).
- Plasma-derived factor VIII concentrate that contains vWF (or recombinant vWF) for type 3, severe bleeding, major surgery or when desmopressin fails.
- Cryoprecipitate or FFP only if concentrates are not available.
Rationale for desmopressin, factor VIII replacement and FFP
| Product | Why it works | When used | Limitations |
|---|---|---|---|
| Desmopressin (DDAVP) | Synthetic vasopressin analogue (V2 agonist) that releases stored vWF and factor VIII from Weibel-Palade bodies of endothelium; raises both levels 3-5 fold | Type 1 vWD, mild haemophilia A; IV, subcutaneous or intranasal | Needs the patient to have stored normal vWF: fails in type 3; avoid in type 2B (worsens thrombocytopenia); tachyphylaxis with repeat doses; water retention → hyponatraemia (restrict fluids, care in children); useless in haemophilia B |
| vWF-containing factor VIII concentrate | Directly replaces both vWF and factor VIII in a small, virus-inactivated volume | Type 3, type 2 not responding, severe bleeding, major surgery | Cost; availability |
| Cryoprecipitate | Rich in factor VIII, vWF, fibrinogen (and factor XIII) | Backup if concentrates unavailable | Not virus-inactivated; pooled donors |
| Fresh frozen plasma (FFP) | Contains all coagulation factors including vWF and factor VIII | Last resort if nothing else | Factor content per mL is low, so large volumes are needed to raise levels → fluid overload; infection and transfusion-reaction risk |
Pure recombinant factor VIII (as used in haemophilia A) has no vWF and is short-lived in vWD; a vWF-containing concentrate is needed.
Desmopressin squeezes out the stores; it cannot help if the stores are empty (type 3) or faulty in a harmful way (type 2B).
In Pakistan, factor concentrates may be hard to get, so cryoprecipitate and FFP are often used in practice. Know their content and limits; follow local transfusion guidance.
ITP versus vWD versus haemophilia
| Feature | ITP | vWD | Haemophilia A |
|---|---|---|---|
| Platelet count | Low | Normal | Normal |
| Bleeding time | Long | Long | Normal |
| PT | Normal | Normal | Normal |
| APTT | Normal | Normal or long | Long |
| Factor VIII | Normal | Low/normal | Very low |
| Bleeding pattern | Mucocutaneous | Mucocutaneous | Joints, muscles |
| Inheritance | Acquired | AD (mostly) | X-linked recessive |
Expect: a child with petechiae a few weeks after a viral illness and isolated low platelets (ITP, observe); a young woman with chronic ITP (steroids, then IVIG, TPO agonists, rituximab, splenectomy); GPIIb/IIIa as the target; normal or increased megakaryocytes; splenectomy as the definitive option; why platelet transfusion is avoided. For vWD: commonest inherited bleeding disorder, mucosal bleeding and menorrhagia, prolonged bleeding time with a normal or long APTT and normal PT, abnormal ristocetin test, and how desmopressin, vWF-containing factor VIII concentrate, cryoprecipitate and FFP work.
Quick revision
- ITP: IgG to GPIIb/IIIa; spleen destroys platelets; isolated thrombocytopenia.
- Children: post-viral, self-limiting, usually observe. Adults: young women, chronic.
- No splenomegaly; PT/APTT normal; marrow megakaryocytes normal or up.
- Prednisolone first; IVIG for fastest rise; then TPO agonists, rituximab, splenectomy.
- Platelet transfusion only for life-threatening bleeding.
- vWD: commonest inherited bleeding disorder; type 1 AD; type 3 AR and severe.
- vWD: long bleeding time, normal PT, normal/long APTT, low vWF and VIII, abnormal ristocetin.
- Desmopressin releases vWF + VIII from Weibel-Palade bodies; fails in type 3, avoid in 2B, hyponatraemia.
- Severe vWD: vWF-containing factor VIII concentrate; cryo or FFP only as backup.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Pathoma: Fundamentals of Pathology).
FAQ
Why is the spleen important in ITP?
It makes much of the antiplatelet antibody and its macrophages destroy the antibody-coated platelets, so splenectomy can cure many patients.
Does ITP cause an enlarged spleen?
No; splenomegaly is rare in ITP and should prompt a search for another cause such as leukaemia or lymphoma.
Why is the APTT sometimes prolonged in von Willebrand disease?
von Willebrand factor protects factor VIII in the circulation, so when vWF is low, factor VIII is broken down faster and the APTT lengthens.
Why does desmopressin not work in type 3 von Willebrand disease?
Desmopressin only releases vWF already stored in endothelial cells; in type 3 there is virtually no vWF to release.
Why is FFP a poor choice for von Willebrand disease?
FFP contains vWF and factor VIII at low concentration, so large volumes are needed to raise levels, risking fluid overload and transfusion reactions.