Haematology

1. Haematology The important bits!

2. Multiple Myeloma A cancer of plasma cells causing bone lesions and immunodeficiency

3. Myeloma • 60 years old • More common in men and Afro-Carribbeans • Malignant proliferation of B-lymphocyte derived plasma cells • Normally many different plasma cells produce different Igs. In myeloma a single clone of plasma cells produce identical Igs which are polyclonal. • Diffuse bone marrow infiltration causing bone destruction • Osteolytic bone lesions • Classification is based on Ig product (i.e. IgG/IgA) • Other Igs are low - immunoparesis • Organ dysfunction and ↑susceptibility to infection • IgG excess is most common

4. Hypercalcaemia presentation and management? Normal bone healing? Presentation • Bone pain – unexplained back ache • Pathological fractures – long bones, ribs, vertebral collapse • Spinal cord/nerve root compression • Bleeding/bruising • Dehydration • Hypercalcaemia – thirst, constipation, nausea and confusion • Fever • CVE • Recurrent infections • Anaemia, neutropenia or thrombocytopenia • Renal impairment (light chain deposition)

5. Investigations • FBC – normocytic, normochromic anaemia • ESR↑, Urea and creatinine↑, calcium↑ • Serum protein electrophoresis - paraproteins • Urine protein electrophoresis - Bence Jones' protein • Free Ig ‘light-chains’ • Bone marrow aspirate +/- trephine biopsy • X-rays for fractures – ‘punched out’ lesions (pepper-pot skull) • After diagnosis – skeletal survey

6. Diagnosis • Monoclonal protein band in serum or urine electrophoresis • Increased plasma cells found on bone marrow biopsy • Evidence of end-organ damage from myeloma • Hypercalcaemia • Renal insufficiency • Anaemia • Bone lesions

7. Management • Chemotherapy: • Young – Aggressive with VAD (vincristine, adriamycin, dexamethason) then autologous stem cell transplant • Elderly – melphalan or cyclophosphamide with prednisolone controls for 1 yr then becomes resistant • Pain management – avoid NSAIDs due to renal failure • Bisphophonates– reduces fractures • Prognosis – median survival 3-4 years; death due to renal failure or infection.

8. Important bits! • Bence Jones proteins • IgG • Light chains cause Renal Failure • Skeletal survey

9. Leukaemia A malignant neoplasm of blood-forming tissues characterised by proliferation of leukocytes leaving the body susceptible to infection

10. Types • ALL – generally in children; majority are B cell • AML – median age of onset 70; auer rods • CLL – most common in western adults • CML – median 40-60 years old (For more information on Leukaemia see Lorna’ presentation in the 2011-2012 folder)

11. Idiopathic Thrombocytopenic Purpura (ITP) An immune reaction found in children and adults associated with a reduction in circulating blood platelets resulting from a variety of factors

12. What is it? • Autoimmune - idiopathic • Anti-platelet autoantibodies (IgG) leading to phagocytic destruction of platelets (60%) and therefore thrombocytopenia • The ‘Harrington-Hallingsworth experiment’ discovered the immune pathogenesis • Children 2-4 years – abrupt onset; Adults 20-50 years – gradual onset (40% <10yrs) • Diagnosis of exclusion

13. Symptoms • Children – following a viral infection (most commonly varicella) • Adults – (20-50 y.o.) Women>Men; associated with other autoimmune diseases • Sometimes no symptoms • Mucosal or skin bleeding – epistaxis, oral bleeding, menorrhagia, petechiae • Platelets <20,000 • Afebrile, no hepatosplenomegaly • Rarely • intracranial bleeding or serious haemorrhage • Lower GI bleeding

14. What are the causes of thrombocytopenia? Investigations • Exclude other causes of thrombocytopenia • Bone marrow disorders usually have particular marrow features • Non-bone marrow causes usually have systemic illness • FBC • Platelet count • Bone marrow examination- only required if atypical features or diagnosis in doubt. • Positive ANA test may be a predictor of chronicity (chronic disease status) in childhood ITP

15. Side-effects of long-term steroid use? Management • Treat if platelet count very low (<20,000) or symptomatic • Prednisolone 1mg/kg/d then slowly reduce once in remission • Splenectomy– refractory ITP • Immunosupression • Cyclophosphamide, azathioprine, vincristine, danazol • Platelet transfusion is not recommended (does not target underlying pathology)

16. Important bits! • Presents with bleeding but no systemic disease • Exclude other causes of thrombocytopenia (including leukaemia) • Management for adults is Prednisolone or Splenectomy

17. Thrombotic Thrombocytopenic Purpura (TTP) A non-immune reaction of the blood-coagulation system causing extensive microscopic thromboses to form in small blood vessels throughout the body causing kidney and CNS damage

18. Role of vWF in coagulation? Thrombotic Thrombocytopenic Purpura (non-immune reaction) • Rare thrombotic micro-angiopathic haemolytic anaemia (MAHA) • More common in womenand 40s • Low platelet count • Results from inhibition of an enzyme responsible for cleaving large multimers of vWF into smaller units • Ultralarge von willebrand factor (UVWF) • Causes an increased tendency for spontaneous coagulation

19. Aetiology • 2 forms: • Idiopathic - autoimmune • Secondary – patient’s history mentions one of the known features associated with TTP. Mechanisms poorly understood. • Post partum/pregnancy • HIV • Cancer • Chemotherapy • Cocaine • Oral contraceptive pill

20. Symptoms ‘Pentad’ of: • Fever • Fluctuating CNS signs (hallucinations, behavioural, stroke, heahaches) • Microangiopathic haemolytic anaemia (anaemia, jaundice, RBC fragments on blood film) • Thrombocytopenia (low platelets – bleeding/purpura) • Renal failure Haemolytic-uraemic syndrome (HUS) is a closely related disease that shares many similar features but is more common in children

21. Other symptoms… • Purpura • Jaundice • Hypertension • Splenomegaly • Petichial haemorrhage on lower extremities • Anaemia • Haematuria/proteinuria • Arrhythmias, heart failure

22. Investigtions • Blood film – fragmented RBCs • ↓platelets • ↓Hb • ↔ Clotting • LDH levels monitor disease activity

23. Management • Due to the high mortality of TTP presumptive treatment is usually started even when only MAHA and thrombocytopenia are seen • Plasmapheresis/plasma exchange - to replace plasma • Continued for 1-8 weeks before patients cease to consume platelets and begin to normalise Hb • Alternatively FFP can be infused • Splenectomyif not responding to plasma exchange • Haemodialysis if renal failure • Recovery may be complete even if MOF is present.

24. Important bits! • High mortality – treat pre-emptively • ‘Pentad’ of symptoms • Fever • Fluctuating CNS symptoms • MAHA • Thrombocytopenia • Renal failure • Treatment with plasmapheresis

25. Haemochromatosis Iron overload resulting in excess iron deposition in many organs. Complications include cardiomyopathy, chronic liver disease and secondary diabetes.

26. Why are women less severely affected? Haemochromatosis • Autosomal recessive • HFE gene • Hereditary or acquired • Primary iron overload - Failure to regulate Fe absorption by the bowel leading to a progressive increase in body Fe • Accumulation • initially liver, then pancreas, heart, skin and other organs • Leads to liver fibrosis and to ↑risk hepatoma due to the production of ROS • Symptoms in middle age

27. Signs of chronic liver disease? Causes of hepatomegaly? When do iron requirements go up? What is ferritin? What is Transferrin? Where is iron normally stored? Clinical features • Asymptomatic early on – then tiredness and arthralgia • Skin pigmentation – slate grey or bronze; ‘bronzed diabetes’ • Hepatic dysfunction – hepatomegaly/hepatitis • Diabetes(T1DM • Gonadal dysfunction – hypogonadism (from pituitary ↓/cirrhosis) • Other endocrine dysfunction – hypothyroid, hypoparathyroid, adrenal insufficiency • Abdominal pain • Cardiac dysfunction – arrhythmias and cardiomyopathy • Chodrocalcinosis – arthropathy

28. Investigations • LFTs – show non-specific hepatitis • Iron indices: • Serum ferritin levels ↑ • Iron ↑ • Transferrin saturation levels >80% • Liver biopsy – also to stage fibrosis • T2 MRI – to assess Fe overload in heart, liver, etc • Genetic analysis - HFE gene • HbA1c levels will be falsely low as venesection reduces the amount of time available for Hb glycosylation

29. Management • Regular venesection • 500g of whole blood removed weekly until iron stores are removed (can take up to 18 months) • Then every 3 months forever • Chelation therapy with desferrioxamine for pts not tolerating venesection • Avoid alcohol • Surveillance for hepatoma • Risk is x200 • Test AFP and liver US • Treat diabetes, HF, hypogonadism, pituitary failure etc.

30. Important bits! • Caused by excessive iron deposition • Causes multi-organ dysfunction/failure • Liver • Pancreas • Spleen • Skin • Hepatoma risk x200 • Management – regular venesection and treat other factors.

31. Sickle Cell Anaemia Hereditary condition characterised by chronic haemolysis and vessel blockage leading to various complications. Common in people of African descent.

32. Sickle cell anaemia • Autosomal recessive • Causes abnormal beta globulin chain formation (HbS rather than HbA) – deformed RBCs • These are fragile and tend to haemolyse and block small vessels • Common in people of African origin • Can be symptomatic even if heterozygous • Homozygous – sickle cell anaemia • Heterozygous – sickle cell trait (no disability) • Symptoms are variable – chronic haemolitic anaemia • Investigations – HB 6-9; Film – sickle and target cells; Hb electrophoresis • Management – hydroxycarbamide (↑HbF), antibiotics for prophylaxis (ceftriaxone), febrile child admit to hospital, bone marrow transplant (controversial)

34. Sickle cell crisis • Due to micro-vascular occlusion • Severe pain • Precipitated by cold, dehydration, infection, hypoxia • Hands and feet affected in children <3yrs; mesenteric ischaemia – acute abdomen! • Cerebral infarction in children -stroke, seizures, cognitive defects • Management – analgesia, cross match blood, O2, rehydrate, ABx if >38°, give transfusion if Hb or reticulocytes fall sharply

35. Other complications • Aplastic crisis • Due to Parvovirus B19 • Sudden reduction in marrow production • Self-limitting • Sequestration crises • Children only (spleen still there!) • Pooling of blood in spleen and liver with organomegaly, severe shock and anaemia • Urgent transfusion • Splenic infarction (2 yrs) • Growth impairment • Bone necrosis • CRF • Gallstones • Leg ulcers • Retinal disease and visual impairment • Iron-overload – from multiple transfusions • Long-term lung damage – hypoxia, fibrosis and pulmonary hypertension

36. Important bits! • Caused by formation of abnormal beta globulin chains causing deformed RBCs • Heterozygous don’t usually become symptomatic • Common in Africans • Chronic haemolytic anaemia picture • Management – hydroxycarbamide, ABx, ?bone marrow transplant • Sickle cell crisis • SEVERE pain • Analgesia, O2, fluids, cross-match for ?transfusion (Hb/reticulocytes↓)

37. Thallassaemia Genetic disease of unbalanced Hb synthesis as there is underproduction of one globulin chain. It is a cause of hameolytic anaemia

38. Thalssaemia • Due to underporuction of one globulin chain • Unmatched globins precipitate, damaging RBC membranes • This causes haemolysis while still in bone the marrow • Common from Mediterranean to Far East • There are various combinations of mutations possible causing different severities of disease…

40. Beta ThalassaemiaMinor (trait) and Intermedia Intermedia Carrier state Usually asymptomatic Mild well tolerated anaemia Hb > 9 Worse in pregnancy Often confused with iron deficiency anaemia Moderate anaemia Does not need transfusions May have splenomegaly Minor

41. Beta ThalassaemiaMajor (Cooley’s anaemia) • Presents within 1styear • Severe anaemia • Failure to thrive • Production of RBCs outside bone marrow (extramedullary haematopoiesis) in response to anaemia • Frontal bossing • Hepatosplenomegaly (also due to haemolysis) • Imaging - hair on end x-ray • Blood film - hypochromic microcytic cells (target cells and nucleated RBCs • Management - life long blood transfusions • Eventually iron overload, endocrine failure, liver disease and cardiac toxicity

43. Major Treatment • Transfusions: • Hb >9g/dL • Supresses extramedullaryhaematopoesis • Allows normal growth • Iron-chelators (deferoxamine)– prevent iron deposition • Ascorbic acid - encourage urinary excretion of iron# • Splenectomy – best avoided until >5yrs due to infection risk. • Hormonal replacement for endocrine problems • Histocompatable bone marrow transplant

44. Bleeding measurements

45. Questions 34 YO female presents due to the development of a purpuric rash on the back of her legs. Only regular meds are Micorgynon 30. Also reports frequent nose bleeds and menorrhagia. FBC requesterd Hb 11.7, platelets 62, WCC 5.3 What is the most likely diagnosis? • Drug induced thrombocytopenia • Henoh-Schonleinpurpura • TTP • ITP • Antiphospholipidsymdrome

46. Answer : D. ITP

47. A 73 YO woman presents with lethargy for the past 2 weeks. Clinical examination unremarkable. PMHx PMR and IHD. Screening bloods – FBC as follows Hb 12.9, platelets 158, WBC 19, Neuts 42, Lymphs 14.1 What is the most likely diagnosis? • Lymphoma • Nicorandil-related lymphocytosis • Transient viral illness • CLL • Secondary to steroid use

48. Answer: D. CLL

49. A 72 year old man is referred to haematology with a raised Hb. A diagnosis of polycythemiavera is suspected. Which other abnormality of the blood would be most consistent with the diagnosis? • Raised alkphos • Hupokalaemia • Throbocytopaenia • Raised ferritin level • Neutrophilia

50. E. Neutrophilia