Haematological aspects of systemic disease

OverviewInflammation – malignancy

Renal, liver, endocrine,pregnancy

Infection, amyloid

Inflammation - Malignancy

Anaemia of chronic disease (ACD)

Normochromic or mildly hypochromic anaemiaModerate anaemia (hb>9.0g/dl)Reduced serum iron and tibcNormal or raised serum ferritin with adequate bm iron stores and reduced sideroblasts

Conditions associated with anaemia of chronic disorders

Chronic infectionsEspecially osteomyelitis, bacterial endocarditis, tuberculosis, chronic abscesses, bromchiectasis, chronic urinary tract infections, HIV, AIDS, malaria.

Other chronic inflammatory disordersRheumatoid arthritis, polymyalgia rheumatica, systemic lupus erythmatosus, schleroderma, inflammatory bowel disease, thrombophlebitis.

Malignant diseasesCarcinoma, especially metastatic or associated with infection, lymphoma

OthersCongestive heart failure, ischaemic heart disease

Pathogenesis of ACDPathogenesis of ACD

HepcidinIncreased levels of cytokines

TreatmentTherapy of chronic diseaseRecombinant EPO

Malignancy - anaemiaACD affects almost all patientsAIHA esp. in lymphomaMHA with disseminated Blood loss in GI and gynaecological malignanciesmucin secreting adenocarcinomaLeucoerythroblastic anaemia indicates marrow infiltrationRed cell aplasia is associated with thymoma, lymphoma and CLL

Other causesChemotherapy or radiotherapyFolate deficiency

Malignancy Polycythaemia

Tumour cells may produce EPO or EPO-like polypeptidesWhite cell changes

Neutrophilia (infection or bleeding)Neutropaenia (chemotherapy)

PlateletsThrombocytopaeniaThrombocytosis

Coagulation changesHaemorrhage or thrombosis (activation of both coagulation and fibrinolysis)Chronic DIC - thrombosis and migratory thrombophlebitisCirculating anticoagulants and specific coagulation factor inhibitors

Connective tissue disorders

AnaemiaACD common. Fe def. may coexistAIHA occurs in SLE, R.A, and mixed CTDRed cell aplasia occurs in SLE

White cellsInflammation – neutrophiliaFelty’s sx. (neutropaenia with splenomegaly in R.AAntibody and immune mediated neutrophil destruction and decreased neutrophil productionEosinophilia – SLE, R.A, polyarteritis nodosa

PlateletsThrombocytopaeniaThrombocytosis in CTD

CTD – cont.Coagulation changes

Associated with renal disease, drug therapy, DIC and specific coagulation factor inhibitorsThe Lupus anticoagulant occurs in approximately 10% of patients with SLE.

Renal, Liver, Endocrine - Pregnancy

Renal diseaseAnaemia

Acute or chronic renal failure – normochromic normocytic anaemiaReduce EPO levelsEchinocytes Iron deficiency and haemolysis (HUS & TTP)EPO corrects anaemia to 12g/dLPoor response to EPO –

fe or folate def. , haemolysis, infection, occult malignancy, aluminium toxicity, hyperparathyroidism and inadequate dialysisHypertension and thrombosis of an AV fistula may occur

PolycythaemiaMay occur with renal tumours or cysts

Renal diseaseHaemostatic 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 diseaseAnaemia

Hyper and hypothyroidism cause a mild anaemia (MCV raised in hypothyroidism and lowered in thyrotoxicosis)Deficiencies of iron, as a result of menorrhagia or achlorhydriaB12 deficiency (increased incidence of pernicious anaemia in hypothyroidism, hypoadrenalism and hypoparathyroidism) kay complicate the anaemiaAnti-thyroid drugs (carbimazole and propylthiouracil) can cause aplastic anaemia and agranulocytosis

Liver diseaseAnaemia

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 alcoholicsTarget cells, echinocytes and acanthocytes occurHaemolysis and hypertriglyceridaemia with alcoholic liver disease is rareDirect toxicity of copper for red cells causes haemolysis in Wilson’s diseaseViral hepatitis may lead to aplastic anaemiaPlatelets may be low (hypersplenism or DIC)

Liver disease cont.Platelets and haemostasis

Defects of platelets, coagulation and fibrinolysisReduced 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 impairedReduced levels of proteins C,S,AT, antiplasmin – DICDysfibrinoginaemia may lead to haemorrhage, or thrombosis

Coagulation changesIncreased PT,APTT, N or increased TT, decreased platelets and dysfibrinogenaemia

PregnancyAnaemia

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 normalAIHA, HELLP syndrome, DIC

White cellsMild neutrophil leucocytosis with left shift

PlateletsGestational ThrombocytopeniaMaternal ITPPre-eclampsia

Coagulation changes Increased risk of thrombosis and DIC

Infection, Amyloid

Infection - virusesAnaemia

AIHAErythema variegata (fifth disease) - B19 ParvovirusVirus associated bone marrow aplasia (Hep, HIV, CMV)MAHA with TTP

White cellsNeutropaenia with lymphopaenia or lymphocytosis

PlateletsThrombocytopenia – 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

AnaemiaACD 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 cellsNeutrophilia is most common.

PlateletsThrombocytosis is frequently reactive. Thrombocytopenia may also occur, caused by immune destruction, circulating immune complexes, decreased platelet production and DIC

HaemostasisDIC

Infection – bacterial, fungal and protozoal cont.

MalariaAnaemia 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.

LeishmaniasisProtozoal infection Hepatosplenomegaly, hypergammaglobulinaemia, normochromic anaemia and a raised ESR occur.

AmyloidTissue 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 occurAmyloid P protein is deposited in both AL and AA typesAmyloid 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.