PhysiologyTier 1Medical Sciences concept

Platelet disorders - glycoprotein defects (Glanzmann's, Bernard-Soulier) vs von Willebrand disease

Core concept

Primary haemostasis, three sequential steps - each has its own disease
- Adhesion - GPIb-IX-V binds vWF on subendothelial collagen
  - Receptor missing = Bernard-Soulier; ligand missing = von Willebrand disease
- Activation/secretion - ADP, TXA2, thrombin -> granule release
  - Granules missing = storage pool disease (dense = delta; alpha = grey platelet syndrome)
- Aggregation - GPIIb/IIIa (integrin alphaIIb-beta3) binds fibrinogen to crosslink platelets
  - Receptor missing = Glanzmann thrombasthenia
All present as mucocutaneous bleeding - epistaxis, gum bleeding, menorrhagia, petechiae, immediate post-surgical ooze
- Not haemarthrosis or deep muscle bleeds - that is a coagulation factor problem

	Glanzmann	Bernard-Soulier	vWD
Defect	GPIIb/IIIa	GPIb-IX-V	vWF
Inheritance	AR	AR	AD (type 1, 2A/2B/2M/2N); AR type 3
Platelet count	Normal	Low	Normal (low in 2B)
Platelet size	Normal	Giant platelets	Normal
Ristocetin agglutination	Normal	Absent	Reduced (inc at low dose in 2B)
ADP/collagen/adrenaline aggregation	Absent to all	Normal	Normal
Correction by normal plasma	No	No	Yes

Ristocetin is the discriminator - it forces vWF-GPIb binding, so it fails when either partner is missing; adding normal plasma corrects vWD but not Bernard-Soulier
vWF has two jobs - platelet adhesion, and carrying factor VIII
- -> severe vWD gives a long APTT with low FVIII, mimicking mild haemophilia A
- Type 2N - vWF cannot bind FVIII -> looks exactly like haemophilia A but is autosomally inherited (affected women)
- Type 2B - gain of function, binds platelets spontaneously -> thrombocytopenia, worse with DDAVP (DDAVP relatively contraindicated)
vWF is an acute-phase reactant - falsely normal in inflammation, pregnancy, oestrogen, exercise, stress; and is lower in blood group O (~25%)
- Repeat testing on more than one occasion before excluding vWD
Acquired forms are commoner than the inherited ones
- Acquired vWD - aortic stenosis and LVADs (Heyde syndrome: high shear cleaves vWF multimers -> GI angiodysplasia bleeding), myeloproliferative neoplasms, lymphoproliferative disease, hypothyroidism
- Acquired Glanzmann-like state = GPIIb/IIIa inhibitors (abciximab, tirofiban); acquired GPIb blockade = nothing common
Bleeding time is obsolete; PFA-100 closure time is a screen only - normal PFA does not exclude vWD

First-line screening - FBE and film (count, giant platelets), coags, then vWF antigen, vWF activity (GPIbM or ristocetin cofactor), factor VIII
- vWF activity : antigen ratio <0.7 -> qualitative defect (type 2)
Treatment
- DDAVP 0.3 microgram/kg - releases endothelial Weibel-Palade stores; works in type 1 vWD and mild platelet function disorders; ineffective in type 3, avoid in type 2B; fluid restrict - hyponatraemia, tachyphylaxis after 2-3 doses
- vWF/FVIII concentrate - type 3, type 2, major surgery
- Tranexamic acid - mucosal bleeding and menorrhagia in all of them
- Glanzmann and Bernard-Soulier - platelet transfusion, but alloimmunisation to the missing glycoprotein makes it progressively ineffective; rFVIIa is the alternative
Do not give aspirin/NSAIDs to any of these
Menorrhagia is often the presenting feature in women - ~10-20% of women with heavy menstrual bleeding have vWD

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