itp and ttp in gp practice - igazi foundation · – unnecessary in patients with typical features...

Willem van Schalkwyk Haematology Pathologist

ITP and TTP in GP practice

Immune thrombocytopenia (ITP)

• Acquired immune-mediated disorder. • Definition:

• Platelet count <100 x 109/L. • Absence of obvious initiation or underlying cause.

Blood, 2010;115: 168-186

Trigger

Production of antibodies and / or immune complexes that attach to platelets

- Infection - Immunization - Toxin - ?

Destruction of “sensitized” platelets by phagocytes in the reticuloendothelial system (spleen)

+/- inhibition of megakaryopoiesis

Thrombocytopenia

Pathophysiology of ITP

• Primary ITP: – Absence of other causes/disorders that may be associated with ITP.

• Secondary ITP: Underlying disease or to drug exposure.

– HIV, HCV, H Pylori – Auto-immune/immunodeficiency disorders – Lymphoproliferative neoplasms – Recent vaccination – Post transfusion purpura – Drugs

Blood, 2009;113: 2386-2393

Classification

• Usually follows a chronic course. • +/-15% Of patients remit within 1 year. • Muco-cutaneous bleeding most common.

– Petechiae, purpura, epistaxis and gum bleeding.

• Rarely GIT bleeding and intracranial bleeding. • Risk of major bleed increases with:

– Platelet count < 30 x 109/L. – Age >60 years. – Other comorbidities.

Clinical presentation in adults

• No “gold standard” test. • Presumptive diagnosis is made when history, physical examination,

FBC and smear do not suggest other etiologies for the thrombocytopenia.

• Distinction between primary and secondary ITP.

Diagnostic work-up

1. Necessary evaluation: – History:

• Isolated bleeding symptoms consistent with thrombocytopenia without constitutional symptoms. • Review medication usage.

– Physical examination: • Bleeding symptoms in the absence of hepatosplenomegaly, lymphadenopathy, or stigmata of

congenital conditions. – FBC:

• Isolated thrombocytopenia. • Anaemia only if due to significant bleeding. • Normal red cell indices, white cell and differential counts.

– Peripheral blood smear: • Platelets normal to large in size. • Red and white cell morphology normal.

Diagnostic work-up

2. Additional investigations: – Direct coombs test – HIV, HCV – H Pylori – Antinuclear antibodies – Immunoglobulin levels (IgM, IgG and IgA) in children. – Pregnancy test in woman of childbearing age.

3. Bone marrow evaluation: – Unnecessary in patients with typical features of ITP. – Presence of abnormalities in the history, physical examination, or the FBC and smear

should be further investigated before a diagnosis of ITP is made.

Diagnostic work-up

• Therapeutic goals of initial therapy: – Rapidly obtaining a safe platelet count. – Prevent or stop haemorrhage. – To ensure an acceptable quality of life. – Minimize treatment-related toxicity.

• Assessment of disease status:

– Consider treatment for patients with platelet count <30 x 109/L. – Severity of bleeding? – Additional risk factors for bleeding (antithrombotic agents or high risk occupation). – Is a surgical procedure anticipated?

Blood (2010), vol 115, no 2: 168-186

Management in adult patients

• First-line therapy:

Blood (2010), vol 115, no 2: 168-186


• Emergency treatments: – Patients needing surgical procedures. – High-risk of bleeding. – Active CNS or GIT haemorrhage.

Combining corticosteroids with IVIg. Platelet transfusions +/- IVIg. Antifibrinolytics (tranexamic acid). Emergency splenectomy.


• Durable response in 10 – 30% of patients after first line therapy. • Second line treatment:

– Goal: to attain a sustained increase of the platelet count that is considered hemostatic for the individual patient.

• Splenectomy • Rituximab • Thrombopoietin receptor agonists

American Society of Hematology Educationbook 2013: 276-282


• Peak age of presentation between 5 and 6 years. • 50-60% have a preceding febrile illness:

– Rubella – Varicella – Mumps – Rubeola – EBV – Immunization with measles-mumps-rubella vaccine.

• Bleeding manifestations vary from little/none to purpura, petechiae, epistaxis.

• Clinically significant bleeding seen in only 3% of children. • Spontaneous resolution within 6 months (often within 6 weeks) in the

majority of children.

Clinical presentation and natural history of ITP in children

• To treat or not to treat? • To perform a bone marrow aspirate or not? • To hospitalize or not?

Management of ITP in children

• “Watch and wait” policy: – No significant bleeding symptoms. – No abnormalities on peripheral smear or physical examination. – Parents advised to watch for signs of bleeding and contact details of clinician. – Weekly outpatient visits.

• Hospitalization:

– Reserved for those with clinically significant bleeding.


• Beware of children with: – < 6 Months or age and adolescents. – History of systemic symptoms (chronic fevers, bone pain). – Abnormalities on the initial FBC that are not early explained (neutropenia, raised MCV). – Clinically significant hepatosplenomegaly / adenopathy. – Failure to respond to standard “front-line” ITP therapies.

Atypical features of childhood ITP

• Beware of children with: – < 6 Months or age and adolescents. – History of systemic symptoms (chronic fevers, bone pain). – Abnormalities on the initial FBC that are not early explained (neutropenia, raised MCV). – Clinically significant hepatosplenomegaly / adenopathy. – Failure to respond to standard “front-line” ITP therapies.

Consider bone marrow biopsy

Atypical features of childhood ITP

• Initiate treatment only for clinically significant bleeding. • First-line treatment options to raise platelet count:

– Corticosteroids: short courses. – IVIg: if a more rapid increase in platelet count is required. – Anti-D : if corticosteroids contra-indicated.

• Goal: elevate platelet count to a level where risk of severe bleeding is minimized.


• <10% Of cases will present with persistent severe thrombocytopenia after 6 months.

• Second line treatment options for children with persistent or chronic ITP: – Dexamethasone – High-dose methylprednisolone – Splenectomy – Rituximab


• Aggressive form of thrombotic micro-angiopathy. • Deficiency of vWF cleavage protein ADAMTS13. • Multi-organ dysfunction as a consequence of widespread microvascular

ischemia.

• Important diagnosis to make: – Untreated mortality 90% – Half of deaths occur within 24hrs from presentation.

Thrombotic Thrombocytopenic Purpura (TTP)

Pathophysiology of TTP

Deficiency in ADAMTS 13

Congenital Acquired

(auto-antibody

mediated) Secondary Idiopathic

Infections: HIV Drugs: Quinine, Ticlopidine, Clopidogrel, Simvastatin,

Trimethoprim Chemotherapy: Cisplatin, Mitomycin C, Cyclosporin Malignancy Connective tissue disorders: SLE. Pregnancy Bone marrow transplant Cardiac surgery

Classification of TTP

• Fever • Neurological symptoms (confusion, visual disturbance, seizures, focal

neurological sings and coma). • Renal dysfunction • Thrombocytopenia • Red cell fragmentation

Clinical presentation

• Confirmation of diagnosis of TTP: • FBC: and smear

– Marked anaemia and thrombocytopenia – Red cell fragments

• Other investigations: – Reticulocyte count, LDH, haptoglobin, unconjugated bilirubin. – DIC screen normal – U&E, serum creatinine

• Decrease in ADAMTS13 enzyme activity (<10%). • Detection of auto-antibodies against ADAMTS13.

Diagnostic work-up

• Identify secondary causes: – HIV, hep B &C serology – Pregnancy test – Auto-immune screen (ANA, RF, Lupus Anticoagulant) – Imaging and investigations to exclude malignancy as directed by clinical history and

examination.

Diagnostic work-up

• Differential diagnosis: – DIC – Pregnancy-associated: Eclampsia, HELLP – Malignant hypertention – Haemolytic uraemic syndrome – Vasculitis – Infections: meningococcus – Catastrophic antiphospholipid syndrome

Diagnostic work-up

• Patients clinically unstable with rapid deterioration. • Resuscitation and stabilization of critical organ dysfunction. • Plasma exchange / plasma infusion most important acute intervention.

Initiate without delay in any patient with suspected TTP.

Management of TTP

• Plasma exchange: – Removal of autoantibody. – Supplementation of ADAMTS13 in exchange plasma. – Replacement fluid: cryoprecipitate-poor plasma, FFP or solvent/detergent-treated pooled

plasma.

• Immunosuppression: – Corticosteroids:

• Methylprednisolone (1g/day for three days) • Oral Prednisolone (1mg/kg/day)

– Rituximab

• Plasma infusion: – Temporary measure if delay in plasma exchange.

Management of TTP

• May be the initial presenting features of HIV disease. • Virological suppression important: ADAMTS13 activity increases as CD4

count recovers and HIV viral load falls. • Novitzky et al (2004):

– Response to plasma infusion significantly better and faster than HIV negative cohort. – Relevant for patients who present to regional hospital that may not have apheresis

facilities. – Prednisone 1mg/kg plus cryoprecipitate-poor FFP 30 ml/kg/day.

HIV-associated TTP

British Journal of Haematology, 128, 373-379

• Recombinant ADAMTS13. • Anti-vWF nanobody: blocking vWF interaction with platelets.

Future directions

• Significant advances in the understanding of the pathological basis of TTP. • Improvement in outcomes. • TTP still has a high mortality rate. • Room for improvement in numerous areas of patient care. • Centralized management of patients in order to concentrate expertise and

experience.

Conclusion

Journal of Blood Medicine 2014: 5, 15-23

itp and ttp in gp practice - igazi foundation · – unnecessary in patients with typical features...

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