Category Archives: Haem/Oncology

Sickle cell disease

Autosomal recessive genetic disorder caused by a single nucleotide mutation of the haemoglobin ß-unit, from glutamic acid to valine. The resulting mutant haemoglobin S (HbS) is prone to distortion in cooler or hypoxic conditions, turning into a sickle shape. This damages the erythrocyte causing haemolysis.

The gene is more common among Africans and is occasionally seen in races from the Middle East and South Asia. Its existence is due to protection from malaria seen in sickle cell trait (the heterozygote form), due to shortened red cell lifespan.

You can of course get combinations of sickle cell with other genetic haemoglobin disorders.

Triggers for sickling include cold environment, acidosis, hypoxia and hyperviscosity eg dehydration. Blood flow in capillaries is impaired by the damaged red cells, which leads to a vicious cycle of increased tissue acidosis and hypoxia. Infarction may occur.

Diagnosis

Can be diagnosed even in newborns by hemoglobin electrophoresis.

Screening programmes exist in some countries, so that prophylactic oral penicillin can get started early, preventing sepsis.

Clinical

Presents in infancy or early childhood. The neonate with its high proportion of Haemoglobin F does not get symptoms until there is enough abnormal haemoglobin A produced for red cells to start to sickle.

Acute Crisis

  • Pain
  • Chest syndrome
  • Aplastic crisis
  • Gut crisis
  • Stroke
  • Priapism
  • Sepsis (may precipitate crisis or complicate it)

Pain

Pain can be widespread, but particularly involves bones, the spine, the chest.

Acute Chest syndrome

Can mimic pneumonia, with unilateral or bilateral signs of consolidation, pleuritic pain, and hypoxia. Pain is in chest wall, thoracic spine and upper abdomen. Leads to hypoventilation, causing vicious cycle of atelectasis and subsequently worse sickling. High mortality, so low threshold of suspicion.

  • Hypoxia should be managed aggressively, with respiratory support if necessary.
  • Antibiotics in infection contributing.
  • Avoid diuretics – signs may suggest pulmonary oedema, but likely to exacerbate hyperviscosity.

Aplastic Crisis

Usually secondary to Erythrovirus B19 (formerly known as parvovirus B19) infection, which can trigger transient bone marrow arrest. So sudden drop in haemoglobin with an absence of reticulocytes. Classic “slapped cheek” appearance may never become apparent. Can affect multiple members of a family simultaneously. Differential is spleen sequestration.

Abdominal crisis

Manifest as anorexia, abdominal pain, distension. Usually not diarrhoea or vomiting. Usually not rebound. Bowel sounds usually quiet.

  • Girdle or Mesenteric syndrome – ileus with vomiting. Associated with liver enlargement and bilateral basal consolidation.
  • Differential includes appendicitis, biliary colic or cholecystitis, ischaemic colitis.

Stroke

Typically affects middle cerebral artery territory but may affect any region of the brain; may be transient or permanent. Seizures may occur. Predictive factors are:

  • Previous TIA/stroke
  • Chest syndrome
  • Hypertension
  • Family history of SCD related stroke
  • Low HbF and/or low total haemoglobin
  • Doppler velocities >200cm/sec in children

Differential is meningitis, subarachnoid haemorrhage (associated with multiple intracranial aneurysms).

Sequestration syndromes

  • Splenic sequestration – Seen in infants and young children. Precipitated by fever or dehydration. Symptoms are:
    • Abdominal pain/distension
    • Rapidly expanding spleen (may or may not be painful)
    • Shock, pallor due to drop in haemoglobin (but high reticulocytes cf aplastic crisis)
  • Management is by fluid resuscitation with blood (type specific/O negative if necessary).
  • Hepatic sequestration: similar to splenic, although less shock, and possibly jaundice along with enlarging liver.
  • Priapism: =sustained painful erection. Potentially leads to peripheral gangrene, else cavernosal fibrosis and hence impotence. A urological emergency. Management:
    1. Warm bath, hydration, analgesia
    2. Catheterize if unable to urinate
    3. Sedation eg diazepam
    4. Aspiration + irrigation – ideally within 4-6hrs of onset. Else shunt.
    5. Top-up transfusion may be considered if unstable with other sickle related problems (aiming for Hb 10-12g/dl).
  • Sepsis. Children are relatively immunocompromised due to functional hyposplenism from recurrent spleen infarction. This increases susceptibility to capsulated organisms eg pneumococcus, salmonella, haemophilus.
    • Yersinia is a particular risk in children on desferrioxamine. Causes diarrhoea.

Management

  • Analgesia, aiming to get rapid symptom control with IV bolus doses of opiates eg morphine, diamorphine ideally within 30 minutes of admission, followed by infusion or regular oral doses. Paracetamol and non-steroidal anti-inflammatories may be synnergistic.
  • Oxygen, esp for acute chest syndrome. Debatable if effective for other problems.
  • Hydration, even hyperhydration eg 150% normal daily requirements, IV if necessary. Impairment of renal concentrating power may contribute to dehydration.
  • Warm environment
  • Identification and treatment of infection. Give treatment doses of penicillin (else erythromycin) even if no specific agent identified.
    • Treat with IV antibiotics if severe symptoms/signs
    • Add macrolide eg clarithromycin if chest symptoms
    • Treat empirically for Yersinia with ciprofloxacin if diarrhoea on desferrioxamine.
  • Folic acid (should be on already)

Transfusion

Although anaemia is common in SCD, repeated transfusions lead to the possible complications of:

  • Allo-immunization
  • Iron overload

Hence top up transfusion is only used for acute symptomatic anaemia eg cardiac failure, severe sequestration or pre-operatively. Do not transfuse above Hb 11g/dl. Regular transfusions have a prophylactic role – see on-going treatment below.

Hyperhaemolysis is a life threatening complication of red cell transfusion in sickle cell disease. Can be acute (within 7 days of transfusion) or delayed. Affects not just transfused but autologous cells so Hb can drop below previous level. Fever, haemogobinuria as usual; negative DAT, reticulocytopenia seen (cf parvo). Cover subsequent transfusion with IVIG and steroids; use erythropoietin to maintain. For elective surgery, prophylactic postop CPAP has been used without transfusion. Risk factors poorly defined.

Exchange transfusion

Undertaken to rapidly reduce the percentage of sickle cells in the circulation where life-threatening eg severe chest syndrome, stroke, multi-organ failure. The aim is to reduce %HbS to <20%. Complications are common eg fluid overload, transfusion reaction.

Other Treatments

  1. Pneumococcal prophylaxis is essential for all children. Polysaccharide vaccine should be offered with repeat doses as per Green book.
  2. Folic acid
  3. Hepatitis B immunization
  4. Splenectomy for recurrent splenic sequestration.

On-going treatment

Consider for:

  • Recurrent or stuttering priapism (etilefrine orally is another option here)
  • Stroke/TIA
  • Chronic organ damage eg renal failure
  • Failure to thrive
  • Intractable crises

Options:

  • Regular transfusions. The aim is to keep %HbS <25%. Compared with exchange transfusion, regular transfusions are just as good at reducing complications, are less challenging in terms of vascular access, involve less donor exposure, but cause more iron accumulation.
  • Hydroxyurea. Reduces frequency of crises and transfusion requirements, improves growth. Trials ongoing. Long term risks need to be clarified (toxicity, mutagenicity, teratogenicity).
  • Bone marrow transplant

Iron overload and chelation therapy

Iron overload can be monitored by means of Ferritin levels. Chelation therapy should commence at ferritin levels of 1000mcg/l, with desferrioxamine (desferal) the chelator of choice. Treatment should include vitamin C. Ophthalmological, audiological and cardiological review is necessary.

Anaemia

Like many things, low red cell count can be problem of production, loss or destruction.

So causes include:

  • Bone marrow failure or infiltration (leukaemia, Fanconi’s, Blackfan Diamond, erythrovirus/parvovirus)
  • Nose bleeds, gastrointestinal losses eg Meckel’s, gastritis, heavy periods
  • Haemolysis eg G6PD deficiency, hypersplenism, autoimmune
  • Iron, folate or B12 deficiency

In children, one of the most common causes is excessive milk consumption, which appears to lead to a low level colitis. Pica is often the presenting problem.

Investigations

  • Blood film – Howell Jolly bodies if hypersplenism. Leucoerythroblastic reaction (with immature red cells, as well as immature white cells) can be due to malignancy but can also be due to infection and haemolysis. Spherocytes or other abnormal forms may suggest a hereditary haemolytic condition. Sickle cells in sickle cell disease.
  • Low MCV suggests lack of iron, but may also be due to thalassaemia.
  • Reticulocyte count – indicates on going red cell production, may be high if recovering from low production
  • White cell count and platelets – if low too, suggests bone marrow failure but parvovirus can knock off all cell lines too.
  • Coagulation – deranged coagulation with low platelets suggests disseminated intravascular coagulation (DIC), usually due to sepsis, but can also reflect haemophagocytosis syndrome (due to sepsis or rheumatological disease)
  • Renal function – haemolytic uraemic syndrome (usually with diarrhoea and bloody stools, but not always)

Iron is found in red meat, pulses, green leafy vegetables, wholemeal bread, nuts, dried fruit, fortified breakfast cereals.

Polycythaemia

Polycythemia vera very rare in kids but described from age 7 months! More typically age 5-14yrs. 

Haemoglobin range of 15.5 to over 25, with haematocrits from 41-80%.  Yet high values often seen in asymptomatic teenagers. Partly this is because pre-pubertal range is different, but lab can’t know pubertal status so will cut off at an arbitrary age. Our lab gives normal up to 18 for adult males and 16.5 for adult females.

Symptoms are headaches, pruritus, dizziness/syncope.  Serious complications not uncommon, often part of presentation eg Budd-Chiari syndrome, stroke, haemorrhage.  Leukocytosis appears to be associated with higher risk of complications.   Thrombocytosis often seen. 

Molecular studies available. [Ann Hem 2009 PMID PMID: 19468728]

Cobalamin related metabolic disorders

Amino acid homocysteine is converted to methionine (“remethylated”) – cobalamin is involved in some of these processes, folate metabolism also important.

Various disorders.

Variety of presentations, at different ages:

  • Neurological (central and peripheral)
    • Feeding difficulties, apnoea in babies
    • Seizures
    • Subacute combined degeneration of spinal cord (peripheral neuropathy, ataxia, incontinence)
    • Acute and/or chronic encephalopathy – hypotonia, regression
    • Neuropsychiatric problems
  • vascular problems (stroke/embolism)
  • bone marrow (megaloblastic anaemia, cytopenia) – folate related
  • Atypical HUS
  • Glomerulopathy

Investigations

  • High homocysteine, usually
  • Vitamin B12 and folate, for differential
  • Methylmalonic acid (in urine)
  • Acylcarnitine
  • Methionine (usually goes low)

Treatment

Start intramuscular B12 (hydroxocobalamin) as soon as samples collected, to prevent end organ damage.

Betaine should be started if high homocysteine with low methionine found, helps push conversion to methionine.

Homocystinuria

Autosomal recessive condition of high homocysteine in blood and urine, causing similar neurological problems, thrombosis, Marfanoid appearance, downward subluxing lenses.

Needs low methionine diet. Betaine supplements help.

Idiopathic thrombocytopaenic purpura

or ITP for short.

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

Diagnosis

Diagnosis by exclusion, because lots of causes of low platelets. 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. See bruising – 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. Acute leukaemia (NB especially Down syndrome)
    4. Aplastic anaemia (eg parvovirus)
    5. SLE (autoimmune)
    6. HUS/TTP
    7. Vascular problem eg Ehlers Danlos, hereditary haemorrhagic telangiectasia

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.). Tranexamic acid can be useful.
  • 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

Thrombosis

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]

Von Willebrand disease

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).

Hereditary spherocytosis

One of the genetic red blood cell abnormalities that protects against malaria (cf sickle cell), as haemolysis shortens life span and potential for parasite reproduction.

Phenotype (severity) consistent within family, but very different between families. FH may be vague eg splenectomy, jaundice rather than awareness of underlying diagnosis…

Presentation

Anaemia, jaundice and splenomegaly classically. Splenomegaly is usually mild and there is no increased risk of rupture. Neonatal jaundice can be severe but does not predict severe disease! Severe cases (assessed when well, not during crises, only about 5%) can be transfusion dependent in first years of life (erythropoietin helpful) but not usually afterwards.

May present with parvovirus aplastic crisis (not just red cells; white cells and platelets often drop too) – only happens once.

Diagnosis by spherocytes on film, reduced MCV, high reticulocytes (but retics do not go up during aplastic crisis), unconj hyperbilirubinaemia, splenomegaly. There are other causes of spherocytes, and they can be seen in normal neonatal blood films.

Differential is autoimmune haemolytic anaemia, which is associated with acute viral infection (direct Coombs test usually positive). Osmotic fragility test does not distinguish, can be false negative in iron deficiency, and is unreliable in the first few months of life. New EMA dye binding test takes 2 hours and is 92% sensitive. Gene tests don’t add much.

Other problem is gallstones. High reticulocyte count predicts.

Folate probably only necessary for severe cases.

Splenectomy

Most children are asymptomatic, but severe cases can have growth failure, lethargy, heart failure and leg ulcers. Should be delayed until at least 5 yrs, potentially laparascopic and/or partial. Do cholecystectomy at same time if symptomatic. Platelets rise to abnormally high levels after splenectomy, but no apparent increase in thrombosis.

[Arch Dis Child PMID 15321852]

Haemolysis

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.