Haematological Disease Flashcards

Question

What is the management of hereditary spherocytosis?

Answer 1

• Neonates o Supportive +/- red blood cell transfusion o Folic acid supplementation ▪ As they have a raised folate requirement secondary to increased RBC production o Consider phototherapy or exchange transfusion if the baby also has jaundice • Infants, children and adults o Supportive care +/- red blood cell transfusion o Folic acid supplementation (2-5 mg oral OD) o Splenectomy may be considered with a pre-operative vaccination regimen for encapsulated bacteria (*H. influenzae*, meningitis C and *S. pneumoniae*) ▪ Considered if poor growth or troublesome symptoms of anaemia o Cholecystectomy may be performed because gallstones are common in HS o Pneumococcal prophylaxis (oral penicillin) • Aplastic crisis caused by parvovirus B19 requires blood transfusions

Answer 2

1 in 2000 live births

Answer 3

AR HbS forms as a result of a point mutation in codon 6 of the beta globes gene which causes a change in the amino acid encoded from glutamic acid to valine.

Answer 4

tropical Africa or the Caribbean, Central India, Middle East

Answer 5

o Sickle cell anaemia(HbSS) ▪ Homozygous for HbS ▪ Have small amounts of HbF and no HbA ▪ Most severe form o HbSC disease ▪ Inherited HbS from one parent and HbC from the other ▪ HbC mutation is amino acid change from lysine to glutamate at 6th position of beta globin chain ▪ No HbA o Sickle beta-thalassemia ▪ Inherited HbS from one parent and beta-thalassemia trait from the other ▪ Most patients make no HbA hence have symptoms similar to SCA ▪ In these patients, a mutation of the beta gene blocks production of the normal beta globin chain (beta 0) or reduces its production (beta+) o Carrier(sickle trait) ▪ Inherited HbS from one parent and a normal beta-globin gene from the other ▪ Approx. 40% of Hb will be HbS ▪ Asymptomatic

Answer 6

o HbS polymerises within red blood cells forming rigid tubular spiral bodies which deform the RBCs into a sickle shape o These cells have a reduced life span and are prone to haemolysis, contributing to anaemia ▪ As this haemolysis happens within the vasculature, it is called intravascular haemolysis ▪ Recycling of the haem leads to high levels of unconjugated bilirubin→jaundice o They can also get stuck in microcirculation resulting in vaso-occlusion and hence ischaemia of an organ o This is exacerbated by low oxygen tension, dehydration and cold o Severity can vary based on how much HbF the patient is able to produce (this has some genetic variation) ▪ HbF consists of two alpha and two gamma globin chains so does not include the mutated beta globins o To counteract the anaemia, bone marrows increases number of reticulocytes produced ▪ This can lead to new bone formation and medullary cavities of the skull can expand outward causing enlarged cheeks and ‘hair-on-end’ appearance on skull X-ray ▪ Extramedullary haematopoiesis can also occur – usually in liver RBCs can over time clog up the spleen leading to infarction and splenic sequestration ▪ Over time, this can lead to an auto-splenectomy (when spleen scars up with fibrosis)→spleen becomes non-functional ▪ Encapsulated bacteria are normally opsonised and phagocytosed by macrophages in the spleen→become susceptible to these

Answer 7

Manifests as HbF synthesis reduces ~ 6 months of age Anaemia o All have moderate anaemia (Hb 60-100g/L) with clinically detectable jaundice from chronic haemolysis • Infection o Susceptible to infection from encapsulated organisms e.g. pneumococci, H influenzae, N meningitidis, Salmonella sp. o Increased risk of osteomyelitis due to Salmonella • Painful vaso-occlusive crises o Cause pain in many organs of the body o Acute crises can be precipitated by cold, dehydration, excessive exercise or stress, hypoxia or infection o In late infancy, often presents as hand-foot syndrome ▪ Dactylitis with swelling and pain of the fingers and/or feet from vaso- occlusion o Acute chest syndrome ▪ Severe form of crises which can lead to severe hypoxia and can require mechanical ventilation and emergency transfusion o Avascular necrosis of femoral head • Acute anaemia o Sudden drop in Hb due to ▪ Haemolytic crises ▪ Aplastic crises • Parvovirus infection causes temporary cessation of RBC production ▪ Sequestration crises • Sudden splenic or hepatic enlargement, abdominal pain and circulatory collapse from accumulation of sickled cells in spleen • Priapism o Due to vasoocclusion o Requires prompt treatment with transfusion as it can lead to fibrosis of the corpora cavernosum and erectile impotence • Splenomegaly o Common in young children but less frequent in older children

Answer 8

o Short stature and delayed puberty o STROKE and cognitive problems ▪ 1 in 10 children with SCD have a stroke ▪ Can have subtle issues like poor concentration o Adenotonsillar hypertrophy ▪ Causes sleep apnoea syndrome leading to nocturnal hypoxaemia which can lead to vaso-occlusive crises or stroke o Cardiac enlargement from chronic anaemia o Heart failure from uncorrected anaemia o Renal dysfunction o Pigment gallstones due to increased bile pigment production o Leg ulcers (uncommon in children) o Psychosocial issues

Answer 9

Screened for in newborn blood spot screen FBC o Anaemia o High reticulocytes • Blood film o Sickle cells o Nucleated RBCs o Howell-Jolly bodies due to hyposplenism Protein electrophoresis If presenting with acute chest syndrome take ABCDE approach o FBC o CXR o Oxygen saturation o ABG o Blood cultures

Answer 10

o Immunisation against encapsulated organisms (e.g. *S. pneumoniae* and *H. influenzae* type B) o Daily oral penicillin o Daily oral folic acid o Vaso-occlusive crises should be minimised by avoiding exposure to cold, dehydration, excessive exercise, undue stress or hypoxia

Answer 11

o Oral and IV analgesia o Good hydration o Infection should be treated with antibiotics o Oxygen (if reduced saturation) o **Exchange transfusion** is indicated for acute chest syndrome, priapism and stroke

Answer 12

o Children who have recurrent hospital admission for acute chest syndrome or vaso-occlusive crises could benefit from **hydroxycarbamide** (stimulates HbF production) o Monitor for white blood cell suppression (side-effect of hydroxycarbamide) Splenectomy with immunisation against encapsulated organisms o Bone marrow transplant may be considered in severe cases

Answer 13

o Can cause premature death due to complications o 50% of patients with the most severe form of sickle cell disease will die \< 40 years

Answer 14

*Inherited microcytic anaemia caused by mutations of the beta-globin gene leading to decreased or absent synthesis of beta globin*

Answer 15

Higher prevalence In those from Indian subcontinent, Mediterranean and Middle East

Answer 16

o Beta-thalassemia major (also called transfusion dependent thalassaemia) ▪ Most severe form ▪ HbA cannot be produced due to abnormal beta globin gene - patients inherit 2 copies of abmnormal beta globin from each parent o Beta-thalassemia intermedia (non transfusion dependent thalassaemia) ▪ Milder form of variable severity ▪ A small amount of HbA and/or large amount of HbF produced

Answer 17

o When there’s a beta-globin chain deficiency, free alpha chains accumulate within RBCs and clump together to form intracellular inclusions which damage the cell membrane o This leads to haemolysis (RBCs breakdown in bone marrow or are destroyed by spleen) o Haemolysis leads to * High unconjugated bilirubin and jaundice * The excess iron from haemolysis leads to secondary haemochromatosis * Hypoxia o The hypoxia leads to extramedullary haematopoiesis

Answer 18

• Severe anaemia + jaundice o Transfusion dependent o From 3 months to 6 months of age (until this point HbF is produced and this process uses up the alpha chains) o Fatigue, shortness of breath, pallor, fatigues easily * Faltering growth/growth failure * Extramedullary haemopoiesis o Prevented by regular transfusions o If no transfusions→hepatosplenomegaly and bone marrow expansion (causes maxillary overgrowth and skull bossing described as chipmunk faces) ▪ Skull Xray shows ‘hair-on-end’ appearance rarely seen in high income countries

Answer 19

• FBC o Microcyticanaemia • Peripheral blood smear o Microcytic, hypochromic RBCs o Target cells • Haemoglobin electrophoresis o Low HbA o Increases in HbF and HbA2

Answer 20

* Beta-thalassemia major is FATAL without regular blood transfusions * The transfusions aim to maintain the Hb concentration \> 95-100 g/L to reduce growth failure and prevent bone deformation * Repeated blood transfusion can cause iron overload * This can lead to cardiac failure, liver cirrhosis, diabetes, infertility and growthfailure * To prevent this, all patients are treated with iron chelation * Chelators include SC desferrioxamine or oral deferasirox * Good compliance with transfusion and chelation is associated with a high probability of surviving beyond 40 years * Bone marrow transplantation is the only cure for beta-thalassemia major * However, this is reserved for children with an HLA-identical sibling

Answer 21

o Iron deposition ▪ Heart→cardiomyopathy ▪ Liver→cirrhosis ▪ Pancreas→diabetes ▪ Pituitary gland→delayed growth and sexual maturation ▪ Skin→hyperpigmentation o Antibody formation (10%) ▪ Allo-antibodies to transfused RBCs in the patient make finding compatible blood very difficult o Infection (very rare now) ▪ Hepatitis A, B, C ▪ HIV ▪ Malaria ▪ Prions o Venous ▪ Often traumatic in young children ▪ Central venous access device, e.g. Portocath, may be required but these predispose to infection

Answer 22

Prenatal diagnosis o Prenatal diagnosis via chorionic villus sampling and genetic counselling should be offered to parents who are heterozygous for beta thalassaemia

Answer 23

Heterozygotes are asymptomatic A blood film will show microcytic hypochromic red cells o This can lead to confusion between beta-thalassaemia trait and iron deficiency anaemia o However, beta-thalassaemia trait has NOT got a low ferritin Anaemia may be mild or absent RBC is usually increased MOST IMPORTANT DIAGNOSTIC FEATURE: Raised HbA2 (~5%) on high performance liquid chromatography (HPLC)

Answer 24

o Aka Hb Barts hydrops fetalis o Mostsevereform o Caused by deletion of all four alpha-globin genes o NO HbA can be produced o Presents in mid-trimester with fetal hydrops (oedema and ascites) due to foetal anaemia o ALWAYS fatal *in utero* or within hours of delivery o Diagnosis is made by high-performance liquid chromatography which shows only Hb Barts

Answer 25

o Occurs when THREE of the alpha-globin genes are deleted o Affected children have mild-moderate anaemia o Some patients may be transfusion-dependent

Answer 26

o Deletion of one or two alpha-globin genes o Usually asymptomatic o Red cells may be microcytic and hypochromic

Answer 27

* Reduced red blood cell production * Haemolytic anaemia (increased red cell destruction) * Blood Loss * Anaemia of Prematurity

Answer 28

o TWO main causes (both are rare): ▪ Congenital infection with parvovirus B19 ▪ Congenital red cell aplasia (Diamond-Blackfan anaemia) o Hb is low o Red cells look normal o Reticulocyte count is low o Bilirubin is normal

Answer 29

o Either due to antibodies destroying red cells or due to an intrinsic abnormality of the red cell o Main causes: ▪ Immune (haemolytic disease of the newborn) ▪ Red cell membrane disorders (e.g. hereditary spherocytosis) ▪ Red cell enzyme disorders (e.g. G6PD deficiency) ▪ Abnormal haemoglobins (e.g. alpha-thalassaemia major) o Increased reticulocyte count (as red blood cell output is increased in an attempt to compensate for increased destruction) o Increased unconjugated bilirubin o Haemolytic disease of the newborn (immune haemolytic anaemia) is due to antibodies against blood group antigens o Mostimportantantibodies: ▪ Anti-D (rhesus) • This occurs if the mother is RhD-negative but the baby is RhD positive ▪ Anti-A ▪ Anti-B ▪ Anti-Kell o This can be diagnosed using Coombs test ▪ NOTE: it is only positive in antibody-mediated o MOST COMMON causes of non-immune haemolytic anaemia in neonates: ▪ G6PD deficiency ▪ Hereditary spherocytosis

Answer 30

o Main causes: ▪ Feto-maternal haemorrhage (occult bleeding into the mother) ▪ Twin-to-twin transfusion ▪ Blood loss around the time of delivery (e.g. placental abruption) o Diagnostic clues: ▪ Severe anaemia ▪ Raised reticulocyte count ▪ Normal bilirubin

Answer 31

o Main causes: ▪ Inadequate EPO production ▪ Reduced red cell lifespan ▪ Frequent blood sampling whilst in hospital ▪ Iron or folic acid deficiency

Answer 32

• Prevention o **Anti-D immunoglobulin** * Given at 28 and 34 weeks and at birth can be given as a single dose (1500IU) between 28 and 30 weeks • Baby: o **Resuscitation** * A to E approach particularly if preterm, anaemic or hydropic o **Exchange transfusion** Indicated if: * • Bilirubin rapidly rising (\>8-10 μmol/l/hr) despite adequate phototherapy * • Severe hyperbilirubinaemia insufficiently responsive to phototherapy and supportive care * • Significant anaemia (Hb \<100 g/l) o **Phototherapy** * Do not delay if baby thought to clinically have significant jaundice * Transcutaneous bilirubin measurement can be taken to confirm/ if unsure o **IVIG** Only for immune haemolysis o Follow-up Check for late anaemia at 4-6 weeks • Consider folate supplementation to protect against this Hearing screen • Parent: o Should be counselled on recurrence of HDN in subsequent pregnancies

Answer 33

Most common severe inherited coagulation disorder inherited with an X-linked recessive inheritance pattern, resulting from the deficiency of a coagulation factor

Answer 34

o Haemophilia A: deficiency of clotting factor VIII ▪ 1 in 5000 male births o Haemophilia B: deficiency of clotting factor IX ▪ 1 in 30,000 male births

Answer 35

⅔ of newly diagnosed infants have a FH of haemophilia and ⅓ sporadic.

Answer 36

* Can be graded as severe, moderate or mild depending on how much of the factor is produced * **Severe** disease involves recurrent spontaneous bleeding into joints and muscles → Can lead to crippling arthritis if not treated * Many of these children have large bruises from trivial pressure → may lead to the suspicion of NAI * Most present in first year of life when they start to walk, and fall over - develop muscle and joint bleeds * 40% of cases present in neonatal period with intracranial haemorrhage, bleeding post- circumcision or prolonged bleeding from heel prick and venepuncture sites

Answer 37

• APTT: usually prolonged o Mixing study will show APTT corrected (suggesting clotting factor deficiency) Factor VIII and IX assay FBC usually normal PT normal

Answer 38

* Recombinant factor 8 concentrate for haemophilia A * Recombinant factor 9 concentrate for haemophilia B * Acute bleeds are treated with factor concentrates and * anti-fibrinolytics (e.g. amniocaproic acid, tranexamic acid) * NOTE: these should be given by prompt IV infusion whenever there is any bleeding * Analgesia and physiotherapy may be required for deep bleeds into muscles and joints * Orthopaedic and pain team review may also be necessary * In patients with haemophilia, the following should be AVOIDED (NAI) * IM injections * Aspirin * NSAIDs * Replacement therapy should be given at HOME to avoid delay in treatment * Prophylactic factor 8 is given to all children with severe haemophilia A to further reduce the risk of chronic joint damage * Desmopressin (DDAVP) may be useful in mild haemophilia A as it stimulates the endogenous release of factor 8 and vWF.

Answer 39

*Inherited bleeding disorder due to either a qualitative or quantitative abnormality of von Willebrand factor*

Answer 40

AD - multiple different mutations implicated

Answer 41

o Type 1 (60-80%) usually mild and not diagnosed until puberty or adulthood o Type 2 and 3 have more severe symptoms

Answer 42

* Bruising * Excessive, prolonged bleeding after surgery * Mucosal bleeding such as epistaxis and menorrhagia * Soft tissue bleeding such as large haematomas and haemarthroses are uncommon (unlike haemophilia)

Answer 43

PT: within reference range in VWD APTT may be mildly prolonged FBC usually normal vWF antigen \< 0.30 IU/mL vWF assay \< 0.30 IU/mL

Answer 44

Depends on type and severity Type 1 vWD can be treated with DDAVP o NOTE: it should be used with caution in children \< 1 year old, because it can cause hyponatraemia and may precipitate seizures More severe types of vWD have to be treated with plasma-derived factor 8 concentrate Things to AVOID in vWD: o IM injections o Aspirin o NSAIDs

Answer 45

*Autoimmune haematological disorder characterised by isolated thrombocytopenia in the absence of an identifiable cause*

Answer 46

Most common cause of thrombocytopenia in children (4 per 100,000 per year)

Answer 47

o Usually caused by destruction of circulating platelets by antiplatelet IgG autoantibodies o Antibodies are directed against the glycoprotein IIb/IIIa or Ib-V-IX complex o This reduces platelet count o May be accompanied by compensatory increase of megakaryocytes in the bone marrow

Answer 48

* Most children present between 2-10 years * Onset tends to be 1-2 weeks after a viral infection (may also occur after a vaccination) * Typically more acute presentation than in adults * Children develop petechiae, purpura and/or superficial bleeding * May have epistaxis and mucosal bleeding * Intracranial bleeding is a rare but serious complication

Answer 49

* Newly-diagnosed: Duration ≤ 3 months * Persistent ITP: Duration 3-6 months * Chronic ITP: ≥ 6 months

Answer 50

Diagnosis of exclusion In younger children, a congenital cause (e.g. Wiskott-Aldrich syndrome or Bernard-Soulier syndrome) should be considered Keep an eye out for atypical clinical findings such as: o Anaemia o Neutropaenia o Hepatosplenomegaly o Marked lymphadenopathy o NOTE: in the case of abnormal clinical findings, bone marrow examination should be conducted to exclude acute leukaemia or aplastic anaemia • NOTE: bone marrow examination is required before treatment with steroids because the steroid treatment could temporarily mask the diagnosis of acute lymphoblastic leukaemia (ALL)

Answer 51

In 80% of children, the disease is acute, benign and self-limiting It will resolve spontaneously within 6-8 weeks Most children can be managed at home→conservative management with repeat FBC in 5-7 days Treatment is indicated if there is evidence of major bleeding (e.g. intracranial or gastrointestinal) or persistent minor bleeding that affects daily life (e.g. excessive epistaxis) **Life- or Organ-threatening bleeding** o IVIG + corticosteroid + platelet transfusion o Antifibrinolytics may be used **Newly Diagnosed Child** o Asymptomatic or Minor Bleeding ▪ Observation (most will achieve a normal platelet count eventually) ▪ Most manifestations are limited to the skin o Major Bleeding ▪ Corticosteroids ▪ IVIG OR anti-D immunoglobulin **Child with Chronic Disease (Chronic ITP) (20%)** o Mycophenolatemofetil o Rituximab o Eltrombopag (thrombopoietin agonist) o 2nd line: splenectomy o Screen for SLE

Answer 52

Acquired syndrome characterised by activation of coagulation pathways, resulting in formation of intravascular thrombi (via fibrin deposition in microvasculature) and depletion of platelets and coagulation factors

Answer 53

o Severe sepsis or shock due to circulatory collapse e.g. meningococcal septicaemia o Extensive tissue damage from trauma or burns

Answer 54

o In DIC, the process of haemostasis goes into overdrive o Multiple clots form in small and medium-sized vessels serving various organs leading to ischaemia o All this clotting consumes platelets and clotting factors o Without enough platelets, other parts of the body start to bleed even with the slightest damage to the blood vessel walls o The clots are also broken down via fibrinolysis, causing release of fibrin degradation products into the circulation o So there is too much clotting as well as not enough clotting

Answer 55

* Bruising * Purpura * Haemorrhage * Purpura fulminans may occur (a rare syndrome of intravascular thrombosis and haemorrhagic infarction of the skin)

Answer 56

• DIC should be suspected when the following abnormalities coexist: o Thrombocytopaenia o Prolonged PT o Prolonged APTT o Low fibrinogen o Raised fibrinogen degradation products and D-dimers o Microangiopathic haemolytic anaemia o There is also usually a marked reduction in naturally occurring anticoagulants (e.g. protein C, protein S and antithrombin) • There is no single reliable test to diagnose DIC

Answer 57

* Treat underlying cause (usually sepsis) * Supportive care e.g. FFP, cryoprecipitate, platelets * Restoration of physiological coagulation pathways (e.g. using heparin) * Replacement therapy - replacement of platelets and coagulation factors * protein C concentrates may be used, particularly in severe meningococcal septicaemia * chronic DIC may require heparin and tranexamic acid

Answer 58

If there is active bleeding, admit to hospital Consider **non-accidental injury** – red flags: o Bruises are on a child who is not yet independently mobile (crawling, cruising, or walking). o Bruises have indicative features - unusually large, multiple sites or in clusters, similar shape and size, patterned in the shape of a hand print, ligature, stick, tooth, grip, or implement (such as a belt). o Bruises are found in indicative places-any non-bony part of the body or face (including the eyes, ears, cheeks, back, abdomen, buttocks, arms, and genitalia). o Explanation for the bruising is implausible, inadequate, or inconsistent o Delay in presentation. • If no suspicion of NAI: o Consider leukaemia if unexplained petechiae, hepatosplenomegaly, high WBC on FBC o Urgent referral for neuroblastoma if periorbital bruising, palpable abdominal mass o Further investigations to detect underlying cause

Haematological Disease Flashcards

(86 cards)