or ITP for short.

80% of children with ITP will recover spontaneously within 6–8 weeks.

Diagnosis

Diagnosis by exclusion. Can occur at any age, but in neonates maternal ITP or alloimmune thrombocytopenia more likely.

In acute ITP:

• Short history: purpura/bruising appear over 24–48 hr.
• Platelet count usually less than 10–20/fl but may be 0 (with few symptoms or signs!)
• Children with counts above 20 rarely show any symptoms cf other causes.

May follow an acute viral infection or within 6 weeks of immunisation esp MMR (1 in 24 000 risk).

(The CSM recommend that children who develop MMR associated ITP should have serology checked and a second dose given if not fully immune – rubella associated ITP is a bigger problem than MMR associated ITP!).

ITP associated with Varicella needs special caution: occasionally more complex coagulation disorders viz antibodies against proteins S +/or C.

Differential diagnosis

A chronic history, with symptoms developing over weeks or months, is possible in ITP but suggests something else. Beware non-accidental injury (NAI) and meningococcal disease – children with infection usually have other features and non-accidental injury does not present with generalized purpura.

• (a) In a young child (within a few weeks or months of birth)
  1. Wiskott Aldrich syndrome
  2. Bernard Soulier syndrome
  3. Other unspecified congenital or hereditary thrombocytopenias
• (b) In older children
  1. Evolving Fanconi anaemia
  2. von Willebrand’s disease type IIB
  3. Serious marrow disorders
  4. Acute leukaemia (NB especially Down syndrome)
  5. Aplastic anaemia (eg parvovirus)

Special diagnostic considerations in older children

• Children over the age of 10 more likely to have a chronic course.
• Consider other autoimmune diseases esp systemic lupus erythematosus (SLE) and antiphospholipid syndrome

Investigations

• Full blood count and film.
• Coagulation screening. Only necessary if there is a possibility of meningococcal infection, other features suggestive of an inherited bleeding disorder, or a suspicion of NAI.
• (Antiplatelet antibodies do not assist in the diagnosis)
• Bone marrow aspiration. Normal bone marrow excludes some causes of thrombocytopenia but does not explain peripheral destruction. Consider if therapy is considered (esp steroids), in the presence of atypical clinical features or if no response to treatment.

Management: general measures

Classify clinically and not by platelet count, because even with severe thrombocytopenia (less than 10 /fl) clinical symptoms usually “mild”. Equally, pronounced skin purpura and bruising, however extensive, do not indicate a serious bleeding risk on their own and serious complications are probably rarer than sometimes quoted.

• Two UK national surveys of children with ITP have demonstrated that only 4% of children with ITP have serious symptoms such as severe epistaxis or GI bleeding.
• Several studies have confirmed that the incidence of intracranial haemorrhage (ICH) is 0.1–0.5% (cf 1- 3% as widely quoted) – only 2 UK cases, complete recovery in both.
• Impossible to predict which children will develop an ICH – ?other predisposing factors eg underlying vascular anomaly. ICH has occurred in children who have been treated.
• The severity of bleeding at any given time, esp at presentation, does not predict the risk of subsequent episodes of serious bleeding.
• Children who continue to be severely thrombocytopenic with significant bleeding symptoms are very rare – refer to a specialist centre for management.

Treatment: Watch and Wait policy

• More than 80% of children with acute ITP will not have significant bleeding symptoms and will not need treatment to raise count. It is essential that the parents, and child where able, have an explanation that this is usually a self-limiting benign disorder.
• Hospital admission should be reserved for children with clinically important bleeding (severe epistaxis, i.e. lasting more than 30 min with heavy bleeding, GI bleeding, etc.).
• Advise parents to watch for other signs of bleeding and give contact name and 24 h telephone number; as far as possible, avoid contact sports or activities with high risk of trauma or head injury. Other activities can be continued as normal, and the child should be encouraged to continue schooling on the basis that ITP is a disorder that may last some weeks or months.
• Repeat count within the first 7-10 d to check that there is no evidence of a serious marrow disorder emerging, eg aplasia.
• Otherwise repeat platelet counts only when clinically indicated by a change of symptoms (beware excessive family focus on numbers). While purpura still present, count is likely to be less than 20 /fl.
• Minimise interference with schooling – deal with lifestyle limitation issues. “Most parents and patients can live quite comfortably with petechiae and low platelets awaiting spontaneous remission, providing their physician can!” (Dickerhoff, 1994).

Specific treatment to raise the platelet count

Several therapies raise the count faster than no treatment. However, all have significant side effects and none alters the underlying pathology nor increases the chance of complete remission. These strategies are appropriate for children with severe bleeding symptoms.

Recommendation: If a child has mucous membrane bleeding and more extensive cutaneous symptoms, high dose prednisolone 4 mg/kg/d is effective (Grade A recommendation, Level Ib evidence). It can be given as a very short course (maximum 4 d). There are no direct comparisons of low dose (1–2 mg/kg/d) with high dose therapy. If lower doses of 1–2 mg/kg/d are used the treatment should be given for no longer than 14 days, irrespective of response.

Other steroid regimens:

• High dose methyl prednisolone (HDMP). This has been used as an alternative to IVIg because it is cheaper and effective.
• Pulsed high dose dexamethasone. This treatment appears to be less effective in children than in adults in producing long-term remission, but may be useful as a temporary measure.

Intravenous immunoglobulin is effective and seems to work more quickly cf steroids (mean 2 days to achieve plt count of 50 cf 4 days). Works by binding to spleen receptors, reducing platelet destruction. Expensive and invasive, reserve for emergency treatment of patients who do not remit or respond to steroids and who have active bleeding. It is an appropriate treatment to enable essential surgery or dental extractions. IVIg is a pooled blood product, the risks of which must be explained to patients. It has significant side effects (75% of children, esp severe headache).

Recommendation: IVIg can raise the platelet count rapidly, but should be reserved for emergency treatment of serious bleeding symptoms or in children undergoing procedures likely to induce blood loss. It is effective given as a single dose of 0.8 g /kg (Evidence level Ib, Grade A recommendation). Lower doses are also effective, and fewer side effects are seen, in younger children; but usually it is used for emergencies where a higher dose eg 1g/kg may be more appropriate.

Anti-D immunoglobulin is less expensive than IVIg and can be given to Rh (D) positive individuals as a short infusion, and is therefore amenable to outpatient therapy. It is as effective as IVIg in children when given at sufficient dosage (45–50 lg /kg). The mechanism of action is not fully understood. Like IVIg, anti-D is a pooled blood product; some degree of haemolysis is commonly seen, occasionally severe and is associated with renal failure. Lower dose treatment is less effective at raising the platelet count than IVIg.

Use of platelet transfusions

Life-threatening haemorrhage is the only indication for platelet transfusion in ITP, a destructive platelet disorder where transfusions of normal doses are unlikely to be effective. In a life-threatening situation (such as the rare ICH) larger than normal doses are required with monitoring of the increment as a guide, and other modalities such as high dose IV steroids and IVIg should be given at the same time to maximise the chances of raising the count and stopping the haemorrhage.

Chronic ITP in childhood

The management of children with continuing thrombocytopenia is essentially the same as for acute ITP. Many children settle with an adequate platelet count (i.e. more than 20 /fl) and have no symptoms unless injured. In children under 10 years of age at diagnosis spontaneous remission is likely to occur eventually eg within 15 years; expectant management can continue.

Children more than 10 years of age at diagnosis, esp girls, are more likely to sustain a chronic course but tends to attenuate over time.

Most children need no specific therapy to raise the count unless injured or requiring surgery or dental extraction. Particular problems may arise for girls at the onset of menstruation. It is advisable for the family to carry a card, letter or medical bracelet with details of the disorder in case of emergency eg trauma.

Children with counts persistently below 10 /fl are likely to have some symptoms, e.g. easy bruising or odd petechiae. Very rare, and are difficult to manage – refer such chronic severe ITP (CSITP) cases to paediatric haematologists with a special interest.

A significant group of children with ITP have counts of 10–30 /fl, and although they have no serious bleeding, are nevertheless troubled by purpura esp physical appearance, secondary school. Lifestyle issues and restrictions on sporting activities become more important and should be taken into account in considering therapy. Intermittent treatment with IVIg can be given to cover activity holidays after appropriate discussion of the risks.

Splenectomy is often considered, but it is ineffective in around 25% of cases, and most chronic cases remit spontaneously. It does bump the platelet count up with fewer symptoms but it is clear that the relapse rate with longer follow-up is high. Given that the risk of dying from ITP in childhood is extremely low (less than 1 in 500), that the mortality associated with splenectomy is 1.4 to 2.7% and that the risk of over-whelming sepsis probably persists for life, splenectomy is only justified in exceptional circumstances eg life-threatening bleeding.

The ITP Support Association

The basic coagulation screen is PT, APTT and Fibrinogen.

• PT – liver disease, warfarin, DIC
• APTT – haemophilia, heparin, DIC, anticoagulant eg lupus anticoagulant
• Fibrinogen – congenital hypofibrinogenaemia, DIC

A prolonged APTT which corrects (at least partially) on mixing with normal plasma is deficient in clotting factors. If correction is not possible, then must be an anticoagulant.

The more advanced coagulation tests are:

• Diluted Russel Viper Venom Time (DRVVT)
• Kaolin Clotting Time (KCT)

Basic thrombophilia screen is:

• Protein C/S
• Anti-thrombin III
• Prothrombin mutations
• Factor V Leiden mutation
• Homocysteine

Protein C and S can be transiently low with acute thrombosis. Levels also affected by warfarin but not by LMWH.

Factor V Leiden

Most common inherited thromophilia in Europe. Co factor for factor X. Autosomal dominant so variable penetrance. Rare in East Asian and African.

Anti-Phospholipid Syndrome

Antiphospholipid antibodies are a mixed bag:

• Lupus anticoagulant – total misnomer, as it is PRO-thrombotic and only occasionally associated with lupus! Anticoagulant only in vitro. Overall, found in 1-5% of normal population, though in low titre, usually IgM and transient. Persistent positivity is strongly associated with venous thrombosis and stroke and fetal loss.
• Anticardiolipin is more associated with pregnancy morbidity than with thrombosis, and is less predictive than LA.
• Anti beta2 glycoprotein 1 (beta2Gp1) antibodies are less well established as an independent risk factor but are cumulative with the other 2.

An autoimmune disorder of recurrent thrombosis and pregnancy loss! Migraine, livedo, raynauds, unexplained persistent thrombocytopenia can be clues. Not well defined in children, usually heralds SLE and is probably much the same thing.

There is no one antiphospholipid syndrome, despite the name! All have persistent antiphospholipid antibodies (of one sort or another) plus 1 or more clinical criteria:

1. thrombosis
2. pregnancy related morbidity:
   • unexplained IUD beyond 10/40 with normal morphology
   • preterm (<34/40) due to pre-eclampsia/placental insuff
   • 3+ unexplained consecutive miscarriages

For lab, must test positive on 2 occasions, 12+/52 apart. Testing is affected by warfarin and heparin.

Antiphospholipid syndrome occurs in isolation in more than 50%. 30% of SLE patients get it. A catastrophic clinical presentation can occur with multiorgan involvement (pulmonary haemorrhage, ARDS, cerebral/adrenal infarction, Budd-Chiari), microangiopathic thrombocytopenia, haemolysis similar to TTP/HUS/DIC (Rx anticoagulation, high dose steroids, plasma exchange, IVIG).

Acute treatment is with IV or subcut heparin, followed by warfarin (target INR 2-3). Aspirin may be added if problematic. Hydroxychloroquine should probably always be used. Avoid smoking, oestrogens, cocaine… Plasma exchange and Rituximab may be used in life-threatening cases.

The antibodies act by inducing adhesion molecules from endothelial cells, upregulating tissue factor, activating platelets and the complement cascade generally.  [Current Opinion in Hematology. 13(5):366-75, 2006]

[BMJ 2010:340;1125]

Presents with mucous membrane bleeding (eg epistaxis, ecchymoses, menorrhagia, and excessive bleeding with surgical or other invasive procedures esp post adenotonsillectomy). Not usually petechiae (more commonly associated with platelet function defects) but may be seen esp if aspirin/NSAID has been taken. Not usually haematomas (more characteristic of hemophilia) but may be seen if severe vWD. Menorrhagia is a frequent presentation in women.

vWD has been reported in association with hemorrhagic telangiectasia (Osler-Weber-Rendu) syndrome; so consider telangiectasias contributing eg recurrent epistaxis or gastrointestinal bleeding.

Diagnosis may be missed esp in mild vWD, because vWF levels are influenced by factors such as age, inflammation, stress, pregnancy, hormonal cycles, hypo- or hyperthyroidism, and various medications. Hence stress and inflammation due to illness (eg ruptured appendix) may reduce symptoms, whereas minor surgery in the nonstressed patient may be associated with severe bleeding! Family history should be positive, as VWD is mostly inherited in autosomal dominant fashion.

Although men and women are affected equally, women may be recognized more often because of menorrhagia and excessive bleeding with childbirth.

vWF binds platelets in plug formation. It is also a carrier for Factor VIII – without it factor VIII is lost from the circulation. Subtypes:

• Type 1 is the commonest and the mildest – simple deficiency.
• Type 2 is mutant vWF, so doesn’t work well. Type 2B binds platelets spontaneously leading to thrombocytopenia.
• Type 3 is total absence, factor VIII usually low (3-5% of normal) – severe, very rare (usually autosomal recessive).

Diagnosis

Bleeding time is not particularly sensitive or specific. Prothrombin time is normal. APTT may be prolonged, depending on the impact on factor VIII. Ristocetin stimulates platelet aggregation in presence of vWF so is a more sensitive and specific test.

Treatment

Desmopressin (DDAVP) is available in IV form and concentrated intranasal form (not the same as used for enuresis and diabetes insipidus!).

• IV desmopressin = 0.3 mcg/kg in 25-50 mL normal saline over 30 minutes.
• Intranasal desmopressin = 150 mcg (one puff) for under 50 kg and 300 mcg (two puffs) for those over 50 kg.
• Side effects are minimal and include facial flushing, headache, or mild increases in pulse rate or blood pressure that resolve when the infusion is slowed or discontinued. Rare cases of seizures and central nervous system injury that are associated with hyponatremia have been reported.
• In type 2B desmopressin may worsen platelet count.

Several vWF concentrates are available, with different ratios of vWF to Factor VIII – used to cover surgery. Maximal increase in VWF/FVIII occurs at 30 to 60 minutes, so time the infusion as close as possible to the surgical procedure. The response time varies between individuals and tachyphylaxis (ie reduction in effect) may occur with repeated doses of desmopressin. A trial to establish effectiveness (judged by vWF:RCo (Ristocetin) level) may be helpful.

For major surgery, give concentrate every 12 to 24 hours for 2 to 3 days to achieve levels of VWF greater than 40%. In patients who have decreased baseline VWF:RCo, levels should be measured daily and extra doses concentrate should be administered if tachyphylaxis occurs. In patients in whom FVIII:C levels also are decreased, FVIII:C should be monitored and maintained at a hemostatic level as recommended for hemophilia A. In Type 2B give platelets if low count.

Antifibrinolytics eg tranexamic acid are useful esp for oral/nasal mucosal bleeding. Can even be used topically (mouthwash).

ie red cell breakdown.

Intravascular (eg disseminated intravascular coagulation) or Extravascular (eg hypersplenism)?

Immune or non-immune? Do Indirect Coombs (anti-globulin) test.

Differential:

• disseminated intravascular coagulation – eg sepsis.  Sick! Low platelets, low Hb, abnormal clotting, high inflammatory markers.
• Hypersplenism eg G6PD deficiency, storage disorders
• autoimmune haemolysis
• Hereditary spherocytosis
• Paroxysmal cold haemoglobinuria – most common autoimmune haemolytic anaemia in under 3 yrs. Post viral. NB normal platelets, no fragments on film cf HUS. Donath-Lansteiner antibody. ?assoc with renal failure. Plasma exchange helps.

Normal newborn has 90%+ HbF (alpha-gamma chains), dropping with age. In childhood, normal HbF is <2%. HbA2 (alpha-delta instead of alpha-beta) is normally <3.5%, and HbA:HbA2 ratio should be at least 40:1.

Alpha thalassaemia

4 genes for alpha chains. Deletions are extremely common in the Mediterranean, Africa, SE Asia but actually Africans tend to carry the “α-” defect not the “–” defect that predisposes to disease.

• If only 1 abnormal, then no detectable clinical problem.
• If 2 abnormal, then there is usually mild microcytic anaemia, easily confused with iron deficiency.
• If 3 abnormal, then abnormal tetramers form viz Hb Barts (4 deltas) and HbH (4 betas). There is anaemia, Heinz bodies (accumulations of excess beta chains) and splenomegaly.
• If all 4 abnormal, then survival is not possible. The baby is born with hydrops, as the unstable Hb forms do not deliver oxygen appropriately, and death occurs in utero or soon after birth.

Electrophoresis will show high quantities of Hb Barts in thal disease. In the trait form, there are often normal levels of HbA so need to do gene deletions.

Beta thalassaemia

Seen in the Mediterranean, Africa, SE Asia. Just 2 genes, so a heterozygote is a carrier, may have mild microcytic anaemia. In the Mediterranean form, the gene is usually a zero producer, so the disease is more severe than in Africa, where production is reduced but not absent.

Beta thal Major (homozygous) present after 6 months of age with anaemia, frontal bossing, growth failure, hepatosplenomegaly.

In Beta-thal trait, HbA2 is obviously increased eg 3.5-7%, and ratio reduced eg 20:1. The only exception is if there is co-existing severe iron deficiency. In beta-thal disease, you may not see such an increase if there’s lots of HbF around (about half the cases), and increased HbF is not specific; but the clinical picture doesn’t leave much doubt. Inclusions (alpha chains) seen esp post splenectomy. Retic count surprisingly normal due to severe intramedullary erythroblast destruction.

Treatment is with folate and regular blood transfusion, which then leads to cirrhosis, pigmentation, diabetes etc. Splenectomy reduces transfusion requirements but because of the increased vulnerability to pneumococcal infection this is usually deferred until later childhood.

Deferipone is oral chelating agent, used in Europe but not licensed in US. Acrimonious debate between lead researcher and drug company about research.

An intermediate beta thal exists, where transfusion is only required at times of increased stress.

Combined alpha thalassaemia and sickle cell disease tends to give less anaemia, but more vaso-occlusive crises.

The clinical severity of a patient’s hemophilia is gauged by the baseline clotting factor level, a value that remains fairly constant throughout that person’s life, and is pretty consistent through a family. Around 5% of normal is moderate.

Intramuscular injections should be avoided if at all possible. If they must be given, factor replacement therapy should precede the injection. Parenteral agents should be given intravenously or subcutaneously. Immunizations are administered subcutaneously.

Aspirin is contraindicated due to antiplatelet effect. Avoid NSAIDs if possible, and contraindicated if actively bleeding or being treated for a recent bleeding problem.

Indications for Factor Replacement Therapy

1. Suspected bleeding into a joint or muscle.
2. Any significant injury to the head, neck, mouth or eyes or evidence of bleeding in those areas.
3. Any new or unusual headache, particularly one following trauma.
4. Severe pain or swelling at any site.
5. All open wounds requiring surgical closure, wound adhesive, or steri-strips.
6. History of an accident or trauma that might result in internal bleeding.
7. Necessity of a surgical or invasive procedure.
8. Heavy or persistent bleeding from any site.
9. Gastrointestinal bleeding.
10. Acute fractures, dislocations and sprains.

Treatment

Hemophilia A

The treatment of choice for individuals with factor VIII deficiency is recombinant factor VIII. There are different brands, with different combinations of additives which may or may not be antigenic. Cryoprecipate and fresh frozen plasma are used only if factor cannot be obtained.

• When bleeding is severe, or for a head injury, the appropriate dose of factor VIII is 50 units/kg. This should result in a factor VIII level of 80-100%. Half life is 8-10 hrs so repeat if necessary.
• Mild Hemophilia A (factor VIII greater than 5%) with Non-Life/ Limb Threatening Bleeding may respond to desmopressin (some don’t) – 0.3mcg/kg IV over 30 minutes, else as nasal spray (Stimate, 1 spray in one nostril for individuals <50 kg and 1 spray in each nostril for individuals >50 kg). Otherwise, treatment dose is 15-25u/kg.

Hemophilia B

For individuals with Christmas disease (factor IX deficiency), recombinant factor IX is the treatment of choice. Fresh frozen plasma is only used if factor is unavailable.

• When bleeding is severe, or head injury, the appropriate dose of factor IX is 100-120 units/kg. This should result in a factor IX level of 80-100%, but in Hemophilia B the response is variable so check the level and adjust as necessary.
• Mild – 25-35u/kg, check level

Ideally let patients/parents reconstitute and administer their own factor. Families should have an emergency dose of factor concentrate or DDAVP in their home and to take it with them when they travel, esp if they do not live close to a hospital. Factor replacement should be offered within 1 hour of the patient’s arrival: it should be readily available, the patient should not be left waiting, and treatment should not be deferred pending x-rays or other results. The most experienced IV therapist or phlebotomist available should perform venipuncture – misses and tourniquets may cause painful hematomas which then limit further IV access – use the smallest needle possible unless volume replacement is needed..

Factor replacement must be administered intravenously by IV push over 1-2 minutes. Round the dose up to the closest full vial ie don’t throw away any left overs (excess factor does not create a hypercoaguable state but will prolong the therapeutic half-life of the product administered).

For individuals with inhibitors (antibodies to factor VIII or IX), treatment decisions may be more complicated. The care of inhibitor patients should be urgently discussed with the patient’s hematologist. If an individual with an inhibitor presents in a life- or limb-threatening scenario, the safest immediate action is to prescribe recombinant factor VIIa (rFVIIa, Novoseven) at a dose of 90 mcg/kg or activated prothrombin complex concentrates (FEIBA, Autoplex) at 75-100 units/kg (contraindicated in factor IX patients with a history of inhibitors and anaphylaxis). Hopefully the patient/family can provide information on response to second line therapeutic agents.

[Medical and Scientific Advisory Council (MASAC) of the US National Hemophilia Foundation 2003]