Haematological aspects of systemic disease

1. Haematological aspects of systemic disease

2. Overview • Inflammation – malignancy • Renal, liver, endocrine,pregnancy • Infection, amyloid

3. Inflammation - Malignancy

4. Anaemia of chronic disease (ACD) • Normochromic or mildly hypochromic anaemia • Moderate anaemia (hb>9.0g/dl) • Reduced serum iron and tibc • Normal or raised serum ferritin with adequate bm iron stores and reduced sideroblasts

6. Pathogenesis of ACD • Pathogenesis of ACD • Hepcidin • Increased levels of cytokines • Treatment • Therapy of chronic disease • Recombinant EPO

7. Malignancy - anaemia • ACD affects almost all patients • AIHA esp. in lymphoma • MHA with disseminated • Blood loss in GI and gynaecological malignanciesmucin secreting adenocarcinoma • Leucoerythroblastic anaemia indicates marrow infiltration • Red cell aplasia is associated with thymoma, lymphoma and CLL • Other causes • Chemotherapy or radiotherapy • Folate deficiency

8. Malignancy • Polycythaemia • Tumour cells may produce EPO or EPO-like polypeptides • White cell changes • Neutrophilia (infection or bleeding) • Neutropaenia (chemotherapy) • Platelets • Thrombocytopaenia • Thrombocytosis • Coagulation changes • Haemorrhage or thrombosis (activation of both coagulation and fibrinolysis) • Chronic DIC - thrombosis and migratory thrombophlebitis • Circulating anticoagulants and specific coagulation factor inhibitors

9. Connective tissue disorders • Anaemia • ACD common. Fe def. may coexist • AIHA occurs in SLE, R.A, and mixed CTD • Red cell aplasia occurs in SLE • White cells • Inflammation – neutrophilia • Felty’s sx. (neutropaenia with splenomegaly in R.A • Antibody and immune mediated neutrophil destruction and decreased neutrophil production • Eosinophilia – SLE, R.A, polyarteritis nodosa • Platelets • Thrombocytopaenia • Thrombocytosis in CTD

10. CTD – cont. • Coagulation changes • Associated with renal disease, drug therapy, DIC and specific coagulation factor inhibitors • The Lupus anticoagulant occurs in approximately 10% of patients with SLE.

11. Renal, Liver, Endocrine - Pregnancy

12. Renal disease • Anaemia • Acute or chronic renal failure – normochromic normocytic anaemia • Reduce EPO levels • Echinocytes • Iron deficiency and haemolysis (HUS & TTP) • EPO corrects anaemia to 12g/dL • Poor response to EPO – • fe or folate def. , haemolysis, infection, occult malignancy, aluminium toxicity, hyperparathyroidism and inadequate dialysis • Hypertension and thrombosis of an AV fistula may occur • Polycythaemia • May occur with renal tumours or cysts

13. Renal disease • Haemostatic abnormalities • Coagulation factors II, XI or XIII may be reduced • Platelet function is impaired (predisposed to bleeding) • Low levels of Protein C, AT or plasminogen may lead to thrombosis

14. Endocrine disease • Anaemia • Hyper and hypothyroidism cause a mild anaemia (MCV raised in hypothyroidism and lowered in thyrotoxicosis) • Deficiencies of iron, as a result of menorrhagia or achlorhydria • B12 deficiency (increased incidence of pernicious anaemia in hypothyroidism, hypoadrenalism and hypoparathyroidism) kay complicate the anaemia • Anti-thyroid drugs (carbimazole and propylthiouracil) can cause aplastic anaemia and agranulocytosis

15. Liver disease • Anaemia • Caused by anaemia of chronic disease, haemodilution (increased plasma volume), pooling of red cells (splenomegaly) and haemorrhage (e.g. oesophageal varices) • MCV raised especially in alcoholics • Target cells, echinocytes and acanthocytes occur • Haemolysis and hypertriglyceridaemia with alcoholic liver disease is rare • Direct toxicity of copper for red cells causes haemolysis in Wilson’s disease • Viral hepatitis may lead to aplastic anaemia • Platelets may be low (hypersplenism or DIC)

16. Liver disease cont. • Platelets and haemostasis • Defects of platelets, coagulation and fibrinolysis • Reduced synthesis of Vit. K. dependent factors (II,VII,IX,X,pC,pS) • Impaired synthesis of other coagulation proteins (I,V) • Thrombocytopaenia (hypersplenism) and abnormal platelet function (cirrhosis) • Fibrinolysis impaired • Reduced levels of proteins C,S,AT, antiplasmin – DIC • Dysfibrinoginaemia may lead to haemorrhage, or thrombosis • Coagulation changes • Increased PT,APTT, N or increased TT, decreased platelets and dysfibrinogenaemia

17. Pregnancy • Anaemia • Plasma volume increases up to 50%, RCM increases 20-30% - haemodilution, MCV rises • Fe. def. frequent (RCM, fe. to foetus, blood loss) • Increased folate requirements (catabolism) ,B12 falls below normal • AIHA, HELLP syndrome, DIC • White cells • Mild neutrophil leucocytosis with left shift • Platelets • Gestational Thrombocytopenia • Maternal ITP • Pre-eclampsia • Coagulation changes • Increased risk of thrombosis and DIC

18. Infection, Amyloid

19. Infection - viruses • Anaemia • AIHA • Erythema variegata (fifth disease) - B19 Parvovirus • Virus associated bone marrow aplasia (Hep, HIV, CMV) • MAHA with TTP • White cells • Neutropaenia with lymphopaenia or lymphocytosis • Platelets • Thrombocytopenia – either immune (infectious mononucleosis, HIV) , caused by bone marrow aplasia, or increased consumption (e.g. DIC, TTP,HUS, Haemophagocytosis) • Reactive thrombocytosis

20. Infection – bacterial, fungal and protozoal • Anaemia • ACD is frequent. • Haemolytic anaemia may be immune or non-immune. • DIC and MAHA may occur. HUS may follow infection by E.coli, Shigella and Campylobacter. • Blood loss can occur with H.pylori and ankylostoma infections. • White cells • Neutrophilia is most common. • Platelets • Thrombocytosis is frequently reactive. Thrombocytopenia may also occur, caused by immune destruction, circulating immune complexes, decreased platelet production and DIC • Haemostasis • DIC

21. Infection – bacterial, fungal and protozoal cont. • Malaria • Anaemia is caused by haemolysis, splenic sequestration, haemodilution and ineffective erythropoeisis. • Malaria antigens attached to red cells may cause immune haemolysis. Acute intravascular haemolysis with haemoglobinuria and renal failure (blackwater fever) occurs rarely in Plasmodium falciparum. ACD may also occur. • Eosinophilia is variable. • Thrombocytopenia may be caused by immune destruction, splenic sequestration and DIC. • Leishmaniasis • Protozoal infection • Hepatosplenomegaly, hypergammaglobulinaemia, normochromic anaemia and a raised ESR occur.

22. Amyloid • Tissue deposition of a homogenous eosinophilic protein material which is birefringent and stains with Congo red. • 2 types • Amyloid derived from clonal lymphocyte or plasma cell proliferation (AL) (e.g. myeloma, primary amyloidosis) • Reactive amyloidosis (AA) which occurs when serum amyloid A protein is deposited in chronic inflammatory disease (e.g. rheumatoid arthritis, inflammatory bowel disease) or chronic infection (e.g. tb, leprosy, osteomyelitis and bronchiectasis) • Localized amyloid may occur • Amyloid P protein is deposited in both AL and AA types • Amyloid deposition leads organ enlargement and dysfunction. Tissues involved include: kidneys, heart, skin, tongue, endocrine organs, liver, spleen, GI tract, respiratory tract and the autonomic nervous system.