Immune Thrombocytopenia (ITP) (BSH 2003, ash 2019)

note

My notes are based mostly on the BSH and ASH clinical guidelines. The International Working Group (IWG) on ITP also published guidelines in 2019 - they are exhaustive in reviewing the evidence, and can be found here.

definitions

Primary ITP: Acquired immune-mediated disorder characterized by a plt count <100 & absence of any obvious initiating or underlying disorder

It can be:

  • Newly Diagnosed

  • Persistent: 3-12 months

  • Chronic: >12 months

 

Intro

  

Adults – insidious onset, no clear cause, chronic process. 3 per 100,000 per year

Vs

Children – short lived, 2/3 recover in <6 months, 2/3 have a preceding infection

 

Differential

  • Secondary ITP: Hep C, HIV, Infection, SLE, MMR vaccine, Lymphoproliferative disorders

  • Liver disease

  • B12/Folate deficiency

  • Thyroid disease: Hyper —> reduced survival, Hypo —> reduced production

  • Drugs: Antibiotics, Alcohol, Quinine, Environmental toxins

  • BM disorders: AA, MDS, MF, Leukaemia

  • Post-Transfusion Purpura

  • Inherited thrombocytopenias

 

Investigations

 

Standard panel

H. pylori, FBC, Retic, Film, Immunoglobulins, G&S, DAT, HIV, Hep C

ANA: If positive predicts a chronic course in children

TSH + Thyroid antibodies: 10% of ITP patients develop hypothyroidism

Pregnancy Test

 

When to consider BM biopsy

Age >60

Atypical history/examination

Prior to splenectomy

 

Tests Not Required

Antiplatelet antibodies: Glycoprotein-specific antibodies – not specific

Antiphospholipid antibodies: Positive in 40% but does not predict response to treatment

 

Treatment Overview

 

1st Line:

Steroids, IVIg, Anti-D

(Risk of bleeding in patients taking antiplatelets at time of diagnosis? Ollier 2022 - all events occurred at plt <20)

2nd Line:

Rituximab, Splenectomy, TPO agonists, Steroid-sparing immunosuppressants

Beyond 2nd Line:

TPO agonists, Syk inhibitor or toxic treatments (Campath, HSCT, Chemotherapy)

 

Management of Adult ITP

 

Tailored to patient, no fixed protocol

Haemorrhagic death is rare – 0.01 cases / adult patient / year

1.5-1.8% risk of intracranial haemorrhage

Treatment very rarely required if platelet count >50, or even >30

 

There are no head-to-head trials to enable recommendation of one Rx over another.

But note TPO agonists have gone through proper RCT’s unlike older therapies

 

Supportive Care

Tranexamic Acid, Mirena coil / OCP

Patient support groups

 

Steroids

10-60% respond

Pred 0.5-2mg/kg/day until response, then taper and stop by 4 weeks

Dex 40mg/day for four days and stop

Methylpred if oral route not an option

 

IV Immunoglobulins

Dose: 1g/kg as a single infusion

Quicker time to response than steroids.

 

IV Anti-D

50-75 micrograms/kg as a single dose

Suitable for Rh D+, non-splenectomised patients

Thought to work by coating Rh D+ cells leading to their preferential destruction by the spleen, sparing the platelets.

SE: DIC, Renal failure, Intravascular haemolysis

 

Splenectomy

80% respond, 66% for >5 years. Unmatched by other therapies

10% complication rate with laparoscopic approach. Aim plt >20 prior to surgery.

Vaccination:

  • Hib/Men C, Polyvalent Pneumococcal, Men B, Men ACWY, Annual ‘flu

 

Rituximab

40% respond, 20% for 3-5 years

375mg/m2 weekly for four weeks. May be more effective combined with dex

Given to >1 million patients worldwide with good tolerability

 

TPO Agonists

As of 2023, approved by NICE only for chronic ITP not responding to first line treatments

60-90% response rate but requires maintenance therapy. 1-2 weeks to first effect

Avatrombopag: 20-40mg PO daily (or less frequent). Taken with food. NICE approved Dec 2022. (Study 301)

Romiplostim: 1-10 microg/kg SC weekly

Eltrombopag: 25-75mg PO daily. 2 hours apart from food, 4 hours from calcium-foods

SE: small number of reports of increased marrow reticulin.

Stopping treatment: A proportion of pts that stop TPO-RA’s may remain in remission (Blood 2023)

Spleen Tyrosine Kinase (Syk) Inhibitors

Fostamatinib 100-150mg twice daily

MOA: Syk expressed in B cells, T cells, macrophages and platelets. In macrophages, Syk is involved in the activation pathway that leads to phagocytosis of antibody-coated platelets. Syk is also involved in antibody formation. Fostamatinib is a competitive inhibitor of the Syk catalytic domain.

SE: Diarrhoea, Hypertension, Nausea

NICE approved 2022 for pts who have already received (or are not suitable for) a TPO agonist

Based on FIT1 and FIT2 trials, fostamatinib vs placebo. Stable Response rate = 18% vs 2%.

Future Therapies?

BTK inhibitors - e.g. Rilzabrutinib. NEJM 2022 Ph1/2 trial. 40% platelet count response.

FcRn inhibitors - e.g. efgartimod. Fc receptor recycles immunoglobulin. Inhibition of this leads to depletion of immunoglobulin. ADVANCE IV Ph 3 trial. 22% sustained platelet count response vs 5% in placebo arm. No difference in bleeding events.

Management in pregnancy

See here.

 

Management of Childhood ITP

 

Remember diagnosis of exclusion, continue to re-visit over time

After 3-6 months consider:

  • BMAT, Immunoglobulins, ANA, APL Ab, HIV, H. pylori, Hep C

 

General

97% clinically asymptomatic

If bleeding, grade severity 1-4. Treat if grade 3 or 4.

Watch and Wait management should still be consented for

Avoid contact sports, continue all other activities

 

Supportive Care

Tranexamic Acid

OCP

 

Treatment

To raise plt count

  • IVIg – rapid rise in >80% of patients

  • IV Anti-D – Small dose, gives transient rise

  • Steroids

Emergencies

  • Platelet transfusion with IV Steroids + IVIg

Second lines

  • As per adults. No TPO studies in children yet.