ITP
Immune thrombocytopenia comprises § Drug induced § Neonatal alloimmune thrombocytopenia § Post-transfusion purpura § ITP § Acute ITP § Secondary ITP
Incidence 6/100,000
Pathophysiology § Immunne dysregulation § Accelerated platelet destruction § Abnormalities in megakaryocyte growth and development § Poorly compensated thrombopoiesis § TPO is produced by the liver and binds to its receptor c-MPL on platelet membrane. At high platelet counts, TPO is internalised by platelets. In ITP, low TPO levels are found. § Acute ITP usually occurs in children following viral illness or immunisaton, the majority do not require treatment and 80% resolve within 6 months. (20% go on to develop chronic ITP) § Secondary ITP occur in patients with other immune disorders (eg SLE or CLL), viral illneses or bacterial (H. pylori)
Adult ITP § Clinical features § Predominantly occurs in women of childbearing age § Insidious onset, with no preceding viral or other illnesses
History § Mucocutaneous bleeding (rather than coagulation type haematomas) § Recent transfusion (PTP) § Alcohol / liver disease § FH – inherited thrombocytopenia § Marrow infiltration § Type 2B VWD § Drugs § Viruses (HIV) § Other AI disease § Malignancy
Investigation Blood film § To exclude other causes (acute / chronic leukaemia; MDS; megaloblastic anaemia; MAHA; inherited thrombocytopenias and pseudothrombocytopenia)
Bone marrow § Contentious (unless over 60 and in those in whom splenectomy is being considered) o May also be considered if refractory to first line treatment / relapse after CR § In one study 61 of 66 patients had marrows consistent with ITP; 4 had hypocellular aspirates and one had giant metamyelocytes and neutrophil hypersegmentation.
Antiplatelet assays § Direct platelet immunofluorescence test (PIFT) is used to investigate referred samples for the presence of platelet associated immunoglobulin (PAIg) (indirect testing against normal platelets of little use) § Can be detected in most patients with ITP but not very specific (esp when septic) § Assays for GP IIb/IIIa and Ib/IX (most commonly identified antigenic targets)are less sensitive (50-60%) but more specific (90%) § Can be useful in distinguishing immune from non immune in complex cases but routine use not justified § Recommended in: § Bone marrow failure with ITP § ITP patients refractory to first and second line treatment – recommended when third line therapy being considered § Drug dependent immune mediated thrombocytopenia (DDITP) – serological investigations are important particularly for Heparin / Quinine and Teicoplanin
TPO assays § Can be useful in distinguishing between reduced production (high level) and increased destruction (normal level) but currently not routinely available.
Reticulated platelets § Measurement of platelet RNA by flow gives measure of platelet maturity. § Role not established yet
Helicobacter pylori infection § Conflicting evidence but some studies suggest that H. pylori infection is associated with ITP and that treatment of the H. Pylori caused remission of ITP. § May be worthwhile performing screening § Urea breath test and antigen detection in stools are the most accurate § serology - but antibody levels only fall slowly § Eradication therapy is successful in about 50% § More likely to respond the shorter the duration of ITP and if not severe § Investigations for other causes: § UE § LFT § Inflammatory markers
§ Clotting screen § AI screen (lupus)
§ Virology (HIV, Hep B/C)
§ Antiphospholipid screen § vWF levels (Type IIB)
Treatment § Risk of fatal haemorrhage 1.6-3.9 % per patient year when the platelet count is <30 § 85% achieve platelet counts >30 and have the same mortality as the general population § 9% with severe ITP have a mortality risk of 4.2 § Recent review found that more patients died of infection than bleeding
Safe platelet counts § Dentistry >10 § Extraction/ regional dental block >30 § Minor surgery >50 § Major surgery >80
Platelet counts >30 require no treatment (unless undergoing surgery)
First line - Prednisolone (1mg /kg) and IVIg (0.4g for 5 d or 1g for 2 d)
1. Prednisolone § 50% response rate § Dose should be tapered at 2-4 weeks § Long term remission only seen in 10-20%
2. IVIg § 75% response rate § Responses only transient – lasting 3-4 weeks § Mechanism largely unknown but is believed to involve blockade of Fc receptors on macrophages § Pooled blood product – cases of Hep C but has excellent safety record
Second line
Splenectomy § 60% achieve a normal platelet count § Platelet count should be >30 preop (treat with pred / IVIg pre op) § Donor random platelets can be given intraoperatively once the splenic artery has been clamped § 2% mortality on case series § Response to splenectomy can be predicted using indium-labelled platelets – if destruction was splenic then >90% response rate to splenectomy – if elsewhere <10% responded § Accessory splenic tissues may cause patients to fail to respond (seen on imaging in 12% of those who fail to respond) or to relapse
Prevention of infection post splenectomy
1. Vaccinations (should be given 2 weeks pre surgery) § Pneumococcal vaccine (revaccination every 5 years) § Hib (no need for booster) § Meningococcal C (no need for booster) § Annual influenza vaccine recommended
2. Pen V / erythromicin
Refractory disease = failure to maintain platelet >30 after 6-12 months of standard therapy
Second line therapy 1. High dose corticosteroids § Dexamethsone 40mg 4d repeated every 28d for 6 cycles § Methylprednisolone e.g. 30mg/kg for 3d then 20mg/kg for 4d the 5, 2, 1 mg/kg for a week each § Small studies showing good response rates but transient responses
2. Anti-D § Only used in RhD positive patients who do not have a splenectomy § Elevates the platelet count in around 80% § Mechanism – causes haemolysis with the red cells being preferentially taken up by the reticuloendothelial system. § Can cause severe haemolysis § Check Hb and DAT § If transfusion required, use RhD negative red cells
3. Vinca alkaloids § Cause a transient increase in platelet count lasting 1-3 weeks § 50% respond but only 10% sustained
4. Danazol § 60% response rate § Down regulates Fc receptors on splenic macrophages § When given for more than 1 year induced remissions lasting for years after discontinuation
5. Immunosuppressants § Azathioprine (60% response rate but slow – several months) § Cyclosporine A o Use limited by side effect profile § Cyclophosphamide
6. Dapsone § 50% response rate in a small study
Third line treatment 1. IFN-alpha Not currently recommended, case report of a fatality 2. Anti-CD20 antibody – rituximab 3. Campath-1H (CD52) 4. MMF 5. Protein A immunoadsorption 6. Combination chemotherapy (eg CVP)!
Emergency treatment § Platelet transfusion § Methylpred § IVIg
Rituximab § 3 large cohorts of adults who had failed multiple therapies § 50% had a PR or CR and 33% had durable remissions § Prospective multicentre study in children § 31% achieved a sustained plt count >50 § Mechanism § Elimination of B lymphocytes, but doesn’t explain very rapid responses § B-cells opsonized with anti CD20 cause Fc receptor blockade
Platelet growth Factors § Romiplostim § TPO peptide mimetic § Binds at the endogenous TPO-binding site § Weekly subcutaneous administration § Adverse events of increased marrow reticulin § Continuing in an extended open label trial for continued surveillance of efficacy and safety in ITP § Also in trial for MDS and chemo related thrombocytopenia § Approved by the FDA for chronic ITP § Eltrombopag § TPO non-peptide mimetic § Binds at the intramembrane portion of the TPO receptor § Daily oral administration § Eltrombopag is a new, orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis. It interacts with the transmembrane domain of the thrombopoietin receptor inducing proliferation and differentiation of megakaryocytes. § Randomised placebo controlled study of 118 adults with chronic ITP and platelet counts <30 x109/l who had had relapses or were refractory to at least one standard ITP treatment. Primary end point was a platelet count >50 x109/l at day 43. § In the Eltrombopag groups receiving 30, 50, and 75 mg per day, the primary end point was achieved in 28%, 70%, and 81%, whilst in the placebo group only 11% reached the primary end point. Median platelet counts for eltrombopag were 26 x109/l in 30mg group, 128 x109/l in 50mg group and 183 x109/l, compared to 16 x109/l in placebo group. § By day 15, >80% responses were seen for 50 or 75 mg Eltrombopag. Incidence and severity of adverse events were similar in the placebo and Eltrombopag groups. § Eltrombopag seems effective at increasing platelet counts in a dose-dependent manner in patients with relapsed or refractory ITP. § It has also been used with good effect in HCV patients, increasing the platelet count to adequate levels to enable anti-viral treatment.
HIV § Prior to HAART, thrombocytopenia occurred in 15-30% § More prevalent in patients with a CD4 <200, clinical AIDS, IVDUs § Pathology § Increased platelet clearance due to immune complex disease § Anti-platelet glycoprotein antibodies § Anti-HIV antibodies that show antigenic mimicry with platelet glycoprotein antibodies § Direct infection of megakaryocytes results in defective platelet production and mega apoptosis § ITP early on in disease more commonly resembles classical ITP, whereas when it occurs later it is often associated with additional cytopenias § Usually respond to HAART and if necessary to conventional ITP treatment § Long term steroids should be avoided due to the risk of immunosupression, but IVIG and anti-D are effective alternatives
HCV § In the largest series published, 30% of patients diagnosed with chronic ITP had HCV antibodies § Possible pathology § High affinity binding of HCV to platelet membrane which binds to anti-HCV and phagocytosis by ‘innocent bystander’ mechanism § Splenic sequestration secondary to portal hypertension § Immune dysregulation resulting in auto-antibodies to platelet glycoproteins § Controversial results with steroids, and should be avoided if possible as it can increase viral load and worsen liver damage § Anti-D and IVIG seem to be effective and eltrombopag has had promising results § Interferon for HCV is also effective
ITP in Children
Differential diagnosis Neonatal period § Maternal ITP § NAIT § Wiscott Aldrich § Bernard Soulier disease § Unspecified hereditary thrombocytopenias
Childhood § Viral infection (varicella can cause more complex coagulation changes with antibodies to protein C and S) § Post vaccination (MMR – 1:24,000) – should check serological levels prior to second vaccine if this occurs to evaluate need for 2nd dose § Evolving Fanconi anaemia § Von Willebrands type IIB § Leukaemia (esp in Down’s) § Aplastic anaemia
Investigations Film Coag screen (if suspected meningococcus, bleeding disorder or NAI)
Bone marrow § If child requires no treatment shouldn’t do § Indicated if atypical features (ideally pre-prednisolone) or poor response to treatment
Clinical course § Only 4% have serious bleeding such as severe epistaxis or GI bleeding § Intracranial haemorrhage 0.1-0.5%
Treatment § Treatment should be based on clinical symptoms rather than platelet alone § Most would treat if <10 &/or mucosal bleeding § If treatment required, intermittent treatment with IVIG or anti-D may be used whilst awaiting spontaneous remission
1. Conservative (>80% patients – recover spontaneously within 6-8 weeks) § Avoid contact sports § Repeat FBC at 7-10d to check there is no evidence of serious marrow disorder § Otherwise FBC only needs to be repeated if there is a change in symptoms suggesting remission (persisting petechiae indicate that it has not resolved and an FBC is probably not useful). § Parents need to have 24h helpline similar to haemophiliacs § Card / letter in case of emergency – if chronic
2. Corticosteroids § Prednisolone 4mg/kg for 4d or 1-2mg/kg for 14d § Brings platelet count up more rapidly than conservative treatment but slower than IVIg (4d v 16d v 2d in one trial). § Significant long term effects so courses must be <2-3 weeks
3. Intravenous immunoglobulin (1g/kg for 1 or 2 days) § Effective in 80% § Expensive and invasive (can transmit hep C)
4. Anti-D (45-50 mcg/kg) § Similar speed of rise as IVIg § Occasionally severe haemolysis (even causing renal failure)
Chronic ITP in childhood § Counts persistently <10 very rare and should be managed in a specialist centre. § For those with counts <20 § Risk of bleeding 0.5% at 12 months in those with a count <20 § Treatment with IVIg can be given to cover activity holidays § Clinic appointments should be spaced out to allow schooling § Splenectomy but 25% don’t respond – rarely justified – perhaps in chronic severe ITP that has not resolved in 12-24 months
Pregnancy Differential diagnosis § Spurious § Gestational thrombocytopenia § Pre-eclampsia § HELLP § ITP § SLE § Drug related (DDITP) § Antiphospholipid syndrome § Viral (HIV) § DIC § HUS § TTP § Folate deficiency § Congenital platelet disorders § Coincidental bone marrow disease § Hypersplenism
Normal platelet count falls 120-150 not uncommon in third trimester
All women with counts <100 should be screened for Pre-eclampsia, coagulopathy or AI disease
Gestational thrombocytopenia (5-8% of all pregnancies) § Mild thrombocytopenia >80 (rarely can be 50) § Otherwise normal blood counts § Third trimester most common § Normal platelet counts before and after pregnancy § No association with maternal haemorrhage § No association with fetal or neonatal thrombocytopenia
ITP § 1-5 cases per 10,000 deliveries (100x less common than GT) § May get neonatal thrombocytopenia § Need to exclude pre-eclampsia, DIC, SLE, APLS § Bone marrow not recommended
Treatment Platelet counts >20 do not require treatment until term Targets >50 for vaginal delivery / C. section >80 for epidural anaesthesia
Prednisolone 1mg/kg § Few fetal side effects (e.g. adrenal suppression) as 90% metabolised in placenta
IVIg – normal adult dose § Same time-course as non-pregnant § Similar response rates to steroids § No good data on effect on neonatal counts § Caution with anti-D because of fear of inducing fetal haemolysis
If resistant § 1g Methyl pred (with IVIg) § Azathioprine § Splenectomy – now rarely done – difficult after 20 weeks
Management of delivery / new born § No evidence C section is safer § Ventouse should be avoided – forceps as well - if possible § Maternal platelet count does not predict fetal platelet count § Just need platelet count on cord blood – should be done on all § Usually reach nadir at day 2-5, therefore daily FBCs § Avoid fetal blood sampling (more dangerous than neonatal thrombocytopenia itself) and scalp electrodes. § Neonatal platelet count rarely <20 § Should be treated with IVIg 1g/kg § If bleeding then should have platelet transfusion and IVIg § Exclude NAIT
Anaesthetic recommendations § Platelet count for epidural >80 not evidence based and should be evaluated on a case by case basis § NSAIDs should be avoided if the platelet count is <100 § VTE is the commonest cause of maternal mortality therefore if immobilised, undergoing surgical delivery or have thrombophilia esp APLS should have prophylactic clexane when platelet count >50.
Menorrhagia § Tranexamic acid § Oral contraceptives § Mirena coil
ITP support organisation § Factsheets / conventions |
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