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Perth Haematology :: Dr Steven Ward

Inherited Platelet Disorders



Inherited Platelet Disorders

 

Platelets help prevent bleeding. They take part in the clotting (coagulation) system.

  • Adhere to sites of vascular injury - plug any defects in the vessel wall.
  • generate biological mediators – signals to other cells to aid haemostasis.
  • secrete their granule contents – factors involved in coagulation
  • serve as a surface for clotting to occur upon.

 

Platelet effects lead to bruising and bleeding. Mainly muco-cutaneous bleeding with petechiae, ecchymosis and surgical or traumatic bleeding.

 

The Inherited Platelet defects are a group of rare conditions.

 

Platelet Membrane Defects

Disorder

Defect

 

Inheritence

Clinical

Rx

Glanzmann’s Thrombasthenia

GpIIb/IIIa (CD41)

binding fibrinogen

plat agg

Autosomal Recessive

Life-long muco-cutaneous bleeding

Platelets (beware immunisation to GpIIb/IIIa)

rFVIIa

Bernard-Soulier Syndrome

GpIb/V/IX mutation

Principle vWF receptor – plats cannot adhere to vasc subendoth.

Giant plats.

Sl plats

Autosomal Recessive

Mostly asymptomatic

Platelets DDAVAP rFVIIIa

Pseudo (platelet type) vWD

GpIb mutation

Platelets hypersensitive to vWF. Sl plats

Inc agg with ristocetin. Loss of vWF HMW multimers

Autosomal Dominant

Mucosal bleeding

Platelets [Not vWF conc]

ADP-receptor deficiency

P2Y12

plat agg to ADP, and aggreg rapidly reverses

Autosomal Recessive

Mild bleeding at surgery / trauma

Platelets

Collagen Receptor Defect

Gp1a/IIa and GpVI

 

 

 

 

 

 

Platelet Granule Disorders

Platelet Storage Pool Defect: a term for a number of defects in number and contents of platelet dense (delta) granules and alpha-granules. Autosomal Recessive.

Dense granule defic:  Pro-aggregatory factors: ADP, serotonin, Ca.

Grey plat syndrome (alpha gran):  mild plat dysfunction. (Haemostatic protein: PF4, PDGF, Fibronectin, vWF, FV, FXIII, Fibrinogen)

Also acquired: MPD, MDS, Acute leuk, SLE, cardiac bypass.

 

 

Hereditary Macrothrombocytopenias

  • Heterogeneous group
  • Autosomal Dominant
  • mild /moderate thrombocytopenia and large plats.
  • Variable platelet dysfunction.

 

May-Heggelin anomaly: Very large platelets; leucocyte inclusions; normal plat function.  MYH9 mutation (myosin heavy chain)

Fechtner syndrome: nephritis, deafness, cataracts, granulocyte inclusions.

Sebastian syndrome: same WCC and plate abn as Fechtner but no organ involvement. Near normal plat function.

Epstein  syndrome: Nephritis, deafness, no granulocyte inclusions, platelet dysfunction

 

 

Mediterranean macrothrombocytopathy: Greek, Italian, thrombocytopenia, large plats. Some are carriers of Bernard-Soulier; mild or no bleeding. Good platelet mass.

 

Platelet signalling disorders

Not well characterised. G-protein subunit defects.

 

Platelet coagulant function

Plats also imp in 2y haemostasis – plasma coagulation – occurs on platelet surface;  PS and PE on inner surface, PC outer leaflet; in plat activn PE and PS appear on outer surface – faster coagulation – thrombin generation.   Scott syndrome: platelets do not support prothrominase assembly and thrombin generation. N plat adhesion, agg, secretion. Not express PS.  

Source of FV.

 

 

 

Platelet aggregation studies

 

Tests the ability of certain agonists (stimulants) to produce platelet clumping or aggregation.

Patterns of abnormality can help identify the type of platelet defect.

 

Common defect patterns:

Disorder

Defect

Plat count

Blood Film

ADP 2uM

ADP 5-10uM

Collagen 1ug/mL

AA 100uM

Adrenaline 10UM

Risto 1.2mg/ml

Aspirin/NSAID

 

Inhibit COX

N

N

1Y wave no 2y wave

1y
no 2y

absent

Absent

N

ADP antagonists (clopidogrel)

Inhib ADP receptor

N

N

Absent

Absent

N

N

N

N

Glanzmanns’s Thrombasthenia

GpIIb/IIIa receptor

N

N

Absent

Absent

Absent

Absent

Absent

N

Bernard Soulier Syndrome

GpIb-V-IX receptor

Giant plats

ę plat

N

N

N

N

N

Absent

vWD

 

N/

N

N

N

N

N

N

Gray Platelet Syndrome

α-granule defic

Gray plats

N/

N/

N/

N

N

N

Dense Granule Deficiency

δ-granules

N

N

N

Absent

N

No 2y wave

? 1Y only

VWD Type IIb

VWF protein

 

N

N

N

N

N

N  
0.5 risto

Platelet type vWD

Mutn GpIb receptor

 

N

N

N

N

N

N  
0.5 risto

Renal Failure

Acquired SPD

N/

 

N

N/

N/

N/

Liver Disease

 

N/

 

1Y only

1Y only

?

1Y only

N/

Afibrinogenaemia

 

 

 

Absent

Absent

Absent

 

Absent

 

Strong agonists: collagen, thrombin, TXA2 – directly induce plat agg, TX synthesis and plat gran secretion.

Weak agonists: ADP, Adren: Induce platn agg without secretion. (biphasic curve)

 

Agonists:

Agonist

Conc

Comment

ADP

LD:1–5 uM

HD 10uM

ADP binds ADP receptor on plat. Shape change – 1y agg. 2y wave = ADP from plat storage grans. LD –> 1y only. 2y wave inhib by aspirin and NSAIDs.

Clopidogrel inhibs P2Y1 receptor

Collagen

1, 4ug/mL

Collagen binds GpVI and GpIa/IIa inducing granule release, TX and GPIIb/IIIa activn. Lag phase.

Ristocetin

LD: 0.5mg/mL

HD: 1.5-5mg/mL

Ristocetin (not LD) cuases plats agglutination (not agg) via vWF abd GP1b-IX-V complex.

Adrenaline

5,10uM

Adrenaline blinds a2 recepotor on plat -- Ca release. Similar to ADP agg. 1y , 2y wave with ADP released from grans. 2y wave inhib by aspirin,. NSAIDs.  Variation in a receptor density – reduced agg.

Arachadonic Acid

500ug/mL

AA is precursor to TXA2. Via cyclo-oxygenase and thromboxane synthase.  TX is potent plat activator