Haematological aspects of systemic disease

Overview Inflammation – malignancy Renal, liver, endocrine,pregnancy Infection, amyloid

Inflammation - Malignancy

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

Conditions associated with anaemia of chronic disorders Chronic infections Especially osteomyelitis, bacterial endocarditis, tuberculosis, chronic abscesses, bromchiectasis, chronic urinary tract infections, HIV, AIDS, malaria. Other chronic inflammatory disorders Rheumatoid arthritis, polymyalgia rheumatica, systemic lupus erythmatosus, schleroderma, inflammatory bowel disease, thrombophlebitis. Malignant diseases Carcinoma, especially metastatic or associated with infection, lymphoma Others Congestive heart failure, ischaemic heart disease

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

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

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

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

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.

Renal, Liver, Endocrine - Pregnancy

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

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

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

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)

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

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

Infection, Amyloid

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

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

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.

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.