Platelet Disorders (BCSH 2011)

 

Normal Platelet Function

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Intro

 

Numerical & functional platelet disorders can co-exist with other bleeding disorders and be indistinguishable from one another.

 

Testing of platelet function highly sensitive to pre-analytical variables

-       Collect sample from a fasted, rested subject who has avoided caffeine and smoking

-       Large bore needle with low tourniquet pressure

-       Discard the first 3-5ml and then collect into a 1 in 10 volume of trisodium citrate

-       Keep at room temperature, avoid shaking and test within 4 hours

 

Factors affecting platelet function & test results

-       Drugs

o   antibiotics, antidepressants, beta-blockers, anticoagulants, analgesics

-       Misc

o   Dextrans, radiographic contrast, expectorants

-       Food – fat, garlic, caffeine, turmeric, alcohol, fenugreek, onion, ginger, ginseng

-       Temperature, pH

-       Platelet count above or below 200-400

-       FGN concentration

-       Sample prep and handling

-       Acquired defects – uraemia, liver disease

 

Platelet Function Analyser (PFA-100)

 

A measure of global platelet function

Used at the screening stage alongside PT, APTT, VWF, FVIII

A normal result avoids the need for more difficult, time consuming tests

 

Method:

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Results

 

High negative predictive value

If PFA-100 if normal then primary haemostasis very likely to be intact

            (Exceptions: Storage pool disorders, Primary secretion defects, mild type 1 VWD)

 

‘Non-Closure’ is typical of Glanzmann, Bernard-Soulier and Platelet-Type VWD

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Light Transmission Aggregometry (LTA)

 

Method

 

Light passing through the sample is recorded as agonists are added to platelet-rich plasma and stirred at 37oC.

Confusingly, results may be charted against optical density or light transmission à produces opposite curves.

Analytical Variables – see introduction

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A few specific cases

-       Hydroxycarbamide – abnormal ADP and Adrenaline

-       A small percentage of normal population show reduced response to adrenaline

 

Results:

Typical graphs when plotted using light transmission:

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Other Tests

 

Flow cytometry for plt receptor densities

-       Glanzmanns, Bernard-Soulier, Scott Syn

Nucleotide release assays

-       Storage pool and release defects

Whole Blood Aggregometry

-       Rarely used, unclear correlation with LTA results

Alpha Granule proteins

Electron Microscopy

Genetic Diagnosis

 

Congenital Platelet Disorders

 

Glanzmann Thrombasthenia (GT)

 

Autosomal recessive – ITGA2B & ITGB3 gene mutations (& >100 others)

Deficiency or functional deficiency of the GpIIb/IIIa receptor

GpIIb/IIIa mediates the aggregation of activated platelets by VWF, FGN and other proteins

 

Presentation

-       Usually <5 y.o.

-       Purpura, epistaxis, gum bleeding (but major neonatal complications are rare)

-       May present later in adolescence as severe menorrhagia

-       Associated with angiodysplasia and GI bleeding

 

Natural history

-       Severity of bleeding diminishes with age

-       Except severe risk of bleeding in labour remains

 

Investigation

-       Normal platelet count & size

-       PFA-100 non-closure

-       LTA – no response except for partial aggregation with ristocetin

-       Flow cytometry for GpIIb and GpIIIa receptor density

 

Bernard-Soulier Syndrome (BSS)

 

Autosomal recessive

Deficiency or absence of GpIb/IX/V complex

GpIb/IX/V complex is a receptor for VWF à deficiency results in defective plt adhesion

 

Presentation

-       Usually presents in childhood

-       Epistaxis, easy bruising, gum bleeding

-       Sometimes 1st diagnosed in pregnancy, or confused with ITP

 

Investigation

-       Macrothrombocytopenia (count anywhere from 30 to normal)

-       PFA-100 non-closure

-       LTA – no response to ristocetin

-       Flow cytometry for GpIb-alpha receptor density

 

Grey Platelet Syndrome

 

<100 cases worldwide

Storage pool disorder - Absence of alpha granules

Associated with myelofibrosis

 

Investigations

-       Macrothrombocytopenia of typical grey appearances

-       PFA-100 normal

-       Absence of alpha-granules on electron microcopy

 

Chediak-Higashi

 

Autosomal recessive – CHS gene mutation

Platelet granule abnormality

 

Presentation

-       Associated with albinism

-       Infection + lymphoproliferative disease often results in death in 1st decade of life

Investigation

-       Normal platelet count

-       Peroxidase-positive cytoplasmic granules in neutrophils

 

Hermansky-Pudlak

 

Puerto Rican ethnicity (1 in 1800, compared to 0.5 per million worldwide)

Delta granule deficiency

 

Presentation

-       Albinsim, pulmonary fibrosis, colitis

-       Early death due to fibrosis

Investigation

-       Normal platelet count

-       Absent 2o wave on LTA

-       Electron microscopy

 

Wiskott-Aldrich Syndrome

 

X-linked, WAS mutation à WASP protein deficiency

 

Presentation

-       Severe immunodeficiency, eczema

 

CATCH-22 Syndrome

 

Deletion on chromosome deletion à deletes 30-50 genes, including the Gp1b gene

 

Multi-system disorder, CATCH only some of the features

-       Cleft lip

-       Abnormal facies

-       Thymus

-       Cardiac abnormalities

-       Hypocalcaemia

 

Management of Congenital Platelet Disorders

 

General Guidance

 

Manage at a specialist haemophilia centre with 24-hour access to care

Lifestyle

-       Avoid contact sports

-       Avoid aspirin / NSAIDs

Vaccinate for Hepatitis A & B, and monitor LFTs

Often iron deficient, replace as required

Manage pregnancy with a pre-written plan and MDT consultation.

 

Specifics to consider

 

Tranexamic Acid

Desmopressin – for plt storage pool disorders

Platelet transfusion

rFVIIa – licensed for use in Glanzmanns

Stem cell transplant

 

summary

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