Anemia of Chronic Disease (ACD)

• Study notes on Hematological Aspects of Systemic Diseases

Anemia of Chronic Disease (ACD)

• Characterized by normochromic or mildly hypochromic anemia
• Results in moderate anemia, with hemoglobin levels >9.0g/dl
• Iron levels are reduced
• TIBC (total iron-binding capacity) is reduced
• Ferritin levels are normal or raised
• BM (bone marrow) iron stores are adequate
• Sideroblasts are reduced in number

Conditions Associated with ACD

• Chronic infections include osteomyelitis, bacterial endocarditis, tuberculosis, chronic abscesses, bronchiectasis, chronic urinary tract infections, HIV, AIDS, and malaria.
• Other chronic inflammatory disorders include rheumatoid arthritis, polymyalgia rheumatic, systemic lupus erythematosus, scleroderma, inflammatory bowel disease, and thrombophlebitis.
• Malignant diseases include carcinoma, especially metastatic or associated with infection, and lymphoma.
• Other conditions are congestive heart failure and ischaemic heart disease.

Pathogenesis and Treatment of ACD

• Involves hepcidin and increased levels of cytokines
• Therapy involves treating the underlying chronic disease, with recombinant EPO as a secondary treatment.

Malignancy-Related Hematological Changes

• ACD affects almost all patients with malignancy
• Autoimmune Hemolytic Anemia (AIHA) is especially seen in lymphoma
• Micro-Angiopathic Hemolytic Anemia (MAHA) can occur with disseminated intravascular coagulation
• Anemia may arise from blood loss in GI and gynaecological malignancies, such as mucin-secreting adenocarcinoma
• Leucoerythroblastic anaemia indicates bone marrow infiltration
• Red cell aplasia is associated with thymoma, lymphoma, and CLL
• Chemotherapy or radiotherapy and folate deficiency can also cause anemia
• Polycythemia can occur if tumor cells produce EPO or EPO-like polypeptides
• WBC changes include neutrophilia (infection or bleeding) and neutropaenia (chemotherapy)
• Platelet count changes include thrombocytopaenia and thrombocytosis.

Coagulation issues in Malignancy

• Hemorrhage/thrombosis is caused by activation of both coagulation and fibrinolysis
• Chronic DIC (Disseminated Intravascular Coagulation) manifests as thrombosis and migratory thrombophlebitis.
• Coagulation Inhibition occurs due to circulating anticoagulants and specific coagulation factor inhibitors

Connective Tissue Disorders and Anemia

• ACD is common, but iron deficiency may coexist
• AIHA also can occur in SLE, RA, and mixed CTD
• Red cell aplasia can also occur in SLE
• Inflammation can cause neutrophilia

Felty's Syndrome

• Neutropenia with splenomegaly is present
• Associated with Rheumatoid Arthritis (RA)
• The pathology involves antibody and immune-mediated neutrophil destruction with decreased neutrophil production
• Eosinophilia can occur in SLE, RA, and polyarteritis nodosa
• Thrombocytopaenia/thrombocytosis can be associated with Connective Tissue Disorders Coagulation abnormalities are associated with renal disease, drug therapy, DIC, and specific coagulation factor inhibitors
• Lupus anticoagulant is present in approximately 10% of patients with SLE

Anemia in Renal Disease

• Acute or chronic renal failure results in normochromic normocytic anaemia
• Reduced EPO levels contributes to anemia
• Echinocytes (burr cells) may be present
• Iron deficiency and haemolysis (HUS & TTP) are clinical features
• Treatment goal is to correct anaemia to 12g/dL through Erythropoietin (EPO) therapy
• Poor response to EPO occurs for iron or folate deficiency, hemolysis, infection, occult malignancy, aluminium toxicity, hyperparathyroidism, or inadequate dialysis.
• Complications include hypertension and thrombosis of an AV fistula

Polycythaemia in Renal Disease

• May occur with renal tumors or cysts

Hemostatic Abnormalities in Renal Disease

• Coagulation factors II, XI, or XIII may be reduced
• Platelet function may be impaired (predisposing to bleeding)
• Low levels of Protein C, AT, or plasminogen may lead to thrombosis.

Anemia in Endocrine Disorders

• Related to hypothyroidism or hyperthyroidism
• In hypothyroidism, anemia is mild and MCV is raised

Clinical Picture of Anemia in Endocrine Disorders

• Iron deficiencies can result from menorrhagia or achlorhydria
• B12 deficiency may complicate anemia, with increased incidence of pernicious anemia in hypothyroidism, hypoadrenalism, and hypoparathyroidism
• Aplastic anemia and agranulocytosis can be caused by anti-thyroid drug use (carbimazole & propylthiouracil)

Anemia in Liver Disease

• Anemia of chronic disease
• Hemodilution (increased plasma volume)
• Pooling of red cells (splenomegaly)
• Hemorrhage (e.g., oesophageal varices)

Examination Findings of Anemia in Liver Disease

• MCV is raised, especially in alcoholics
• Target cells, echinocytes, and acanthocytes are common
• Haemolysis and hypertriglyceridaemia with alcoholic liver disease is rare
• Direct toxicity of copper for red cells causes haemolysis in Wilson’s disease (Wilson's disease)

Complications in Liver Disease

• Aplastic anemia can arise from viral hepatitis
• Platelets may be low (hypersplenism or DIC)

Platelets and Haemostasis in Liver Disease

• 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 is impaired
• Reduced levels of proteins C, S, AT, antiplasmin → DIC
• Dysfibrinoginaemia may lead to hemorrhage or thrombosis

Coagulation Changes in Liver Disease

• Increased PT and APTT
• Normal or increased TT
• Decreased platelets
• Dysfibrinogenaemia

Anemia During Pregnancy

• Plasma volume increases up to 50%
• RCM (Red Cell Mass) increases 20-30% → Hemodilution
• MCV rises
• Iron deficiency is frequent (RCM, iron to foetus, blood loss)
• Folate requirements are increased (catabolism)
• B12 levels fall below normal
• Complications include AIHA, HELLP syndrome, and DIC

White Cells During Pregnancy

• Mild neutrophil leucocytosis with left shift

Platelets During Pregnancy

• Gestational thrombocytopenia
• Maternal ITP
• Pre-eclampsia

Coagulation Changes During Pregnancy

• Increased risk of thrombosis and DIC

Anemia in Viral Infections

• AIHA can be a mechanism
• Erythema variegata (fifth disease) can lead to B19 Parvovirus infection
• Virus associated bone marrow aplasia (Hep, HIV, CMV)
• MAHA can be present with TTP

White Cells in Viral Infections

• Neutropenia
• Lymphopaenia or lymphocytosis

Platelets in Viral Infections

• Thrombocytopenia can be caused by immune mechanisms (infectious mononucleosis, HIV)
• Bone marrow aplasia
• Increased consumption (e.g. DIC, TTP, HUS, Haemophagocytosis)
• Reactive thrombocytosis can also occur

Infections: Bacterial, Fungus and Protozoa

• ACD is frequent
• Hemolytic anemia 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

Infections: White Cells

• Neutrophilia is most common

Infections: Platelets

• Thrombocytopenia is caused by immune destruction
• Circulating immune complexes
• Decreased platelet production
• DIC
• Thrombocytosis is Frequently reactive

Infections: Haemostasis

• HAEMOSTASIS results in DIC

Malaria-Related Anemia

• Causes include hemolysis, splenic sequestration, hemodilution, and ineffective erythropoiesis
• Mechanism involves malaria antigens attaching to RBCs causing immune haemolysis
• Acute intravascular haemolysis with haemoglobinuria and renal failure (blackwater fever) is rare in Plasmodium falciparum
• ACD may also occur

WBCs in Malaria

• Eosinophilia is variable

Platelets in Malaria

• Thrombocytopenia may be caused by immune destruction, splenic sequestration, or DIC

Leishmaniasis

• Nature is protozoal infection

Leishmaniasis: Clinical Picture

• Hepatosplenomegaly
• Hypergammaglobulinaemia
• Normochromic anemia
• Raised ESR occurs