Haematopoietic Pathology

Anaemias

= Reduction in total circulating red cell mass below normal limits Diminishes oxygen carrying capacity of the blood, leading to tissue hypoxia.

Anaemias of blood loss

Acute – Trauma

Chronic – GI or PV bleeding

Increased RBC destruction

Hereditary spherocytosis or elliptocytosis

= inherited disorders caused by intrinsic defects of RBC skeleton -> decreased membrane stability ->  splenic destruction

Glucose-6-phosphate dehydrogenase deficiency

= recessive X-linked trait, protective against Falciparum malaria. Reduced ability of RBC to protect itself against oxidative injuries, lead to haemolysis. Pyruvate kinase deficiency

Sickle cell disease

= hereditary haemoglobinopathy, common in African descentPoint mutation in beta globin -> replacement of glutamate residue with valine residue -> HbS (undergoes polymerization when deoxygenated)

Thalassemias

= inherited mutations that decrease synthesis of adult haemoglobin, classified as beta or alpha depending on chain affected(HbA = 2 x alpha and 2 x beta chains)

Paroxysmal nocturnal haemoglobinuria

Immunohaemolytic anaemia

= antibodies that bind to RBC, leading to premature destruction

• Rhesus disease
• Transfusion reactions
• Drug induced
• Autoimmune disorders

Trauma/ toxic injury to RBC

• HUS, DIC, TTP
• defective cardiac valves
• malaria
• snake venom
• lead poisoning

Hypersplenism

Decreased RBC Production

Megaloblastic

= macrocytic anaemia

• B12 deficiency
  • Inadequate diet
  • Pernicious anaemia
  • Gastrectomy
  • Ileal resection
• Folate deficiency
  • Inadequate diet
  • Alcoholism
  • Haemodialysis
  • Pregnancy/ infancy/ cancer (increased requirement)
  • Folic acid antagonists (methotrexate)

Iron deficiency

= hypochromic, microcytic anaemia

• Can result from:
  • Dietary lack (infants, impoverished, elderly)
  • Impaired absorption (sprue, steatorrhea, chronic diarrhoea)
  • Increased requirement (pregnancy)
  • Chronic blood loss (GI, GU)
• Sx:
  • Koilonychia, alopecia, atrophic changes in tongue/ mucosa, pica Plummer- Vinson Syndrome

Anaemia of chronic disease

= impaired RBC production due to chronic disease

• Categories:
  • Chronic microbial infections (osteomyelitis, infective endocarditis)
  • Immune disorders (RA)
  • Neoplasms
• Pathogenesis: Persistent systemic inflammation (IL-6) -> increased hepcidin -> reduced absorption of iron

Aplastic anaemia

= Chronic primary haematopoietic failure leading to pancytopaenia

• Causes:
  • Idiopathic (acquired stem cell defects, immune mediated)
  • Chemical (alkylating agents, benzene, chloramphenicol)
  • Whole body irradiation
  • Viruses (hepatitis, CMV, EBV, VZV)
  • Inherited (Fanconi anaemia, telomerase defects)
• Morphology: Hypocellular bone marrow, devoid of haematopoietic cells.

Marrow failure

• acute leukaemia
• myelodysplastic syndrome

EPO deficiency

• Renal failure

Bleeding disorders

Excessive bleeding can result from:

• Increased fragility of vessels
• Platelet deficiency or dysfunction
• Derangement of coagulation

Tests used to evaluate haemostasis:

• Prothrombin time (PT) = extrinsic and common pathway
  • Prolonged PT in factor V/ VII/ X/ prothrombin or fibrinogen deficiency or dysfunction
• Partial thromboplastin time (PTT) = intrinsic and common pathway
  • Prolonged PTT in factor V, VIII, IX, X XI, XII, prothrombin/ fibrinogen deficiency or dysfunction 
• Platelet count

Vessel wall abnormalities

“Non- thrombocytopaenic purpuras”

Usually cause small haemorrhages in skin/ mucous membranes.

Rarely cause significant haemorrhage.

Causes:

Infection (microbial damage to microvasculature and DIC)

• Meningococcaemia
• Infective endocarditis
• Rickettsioses

Drug reaction (hypersensitivity vasculitis)

Scurvy

Ehlers- Danlos Syndrome

Cushing’s Syndrome

Henoch Schönlein Purpura

Hereditary haemorrhagic telangiectasia

Perivascular amyloidosis

Reduced platelets

PLT <100, 000/ uL

Spontaneous bleeding often involves small vessels in skin/ genitourinary tract/ intracranial.

Four major categories:

• Decreased production (drug induced, ETOH, measles, HIV, B12/ folate deficiency, aplastic anaemia, leukaemia, cancer, myelodysplasia)
• Decreased survival (autoimmune, SLE, B cell lymphoid neoplasm, post transfusion, drug associated such as heparin/quinidine, DIC, thrombotic microangiopathies)
• Sequestration  (hypersplenism)
• Dilution (transfusions)

Defective platelet function

Inherited: Defects of

• Adhesion (Bernard Soulier Syndrome = deficiency of glycoprotein complex Ib-IX)
• Aggregation (Glanzmann thrombasthenia = deficiency of glycoprotein IIb-IIIa)
• Secretion (defective release of mediators)

Acquired:

• Aspirin/ NSAID
• Uraemia

Clotting abnormalities

Inherited: Deficiency of single clotting factors

• Haemophilia A (factor VIII)
• Haemophilia B (factor IX)
• Von Willebrand Disease (vWF) -> lead to abnormal PLT adhesion/clot formation

Acquired: Can affect multiple coagulation factors, due to decreased protein synthesis or shortened t ½

• Vitamin K deficiency (impaired production of protein C/S and factors II, VII, IX and X)
• Chronic liver disease
• DIC

Disseminated intravascular coagulation

= Acute, subacute or chronic thrombo-haemorrhagic disease characterised by excessive activation of coagulation -> thrombi formation in microvasculature and consumption of PLT/ clotting factors

Pathogenesis:

• Not a primary disease
• Results from pathologic activation of haemostatic pathways and impaired clot inhibiting mechanisms
• Two major triggers:
  • Release of tissue factor (TF)
  • Widespread endothelial injury
• Associated with sepsis, obstetric complications, burns, trauma and neoplasms
• Consequences:
  • Widespread fibrin deposition -> ischaemia, microangiopathic haemolytic anaemia (fragmentation of RBC as they squeeze through narrowed vessels)
  • Consumption of PLT and clotting factors + activation of plasmin -> haemorrhage

Morphology:

• Thrombi in brain, heart, kidney, liver, spleen
• Hyaline membranes by fibrin deposition in alveolar capillaries
• Adrenal haemorrhage (Waterhouse- Friderichsen Syndrome)
• Sheehan post partum pituitary necrosis

Clinical features:

• Fulminant such as in endotoxic shock, amniotic fluid embolism
• Insidious onset such as in carcinoma, obstetric complications
• Definitive treatment is to remove the inciting cause

Blood groups

• Multiple blood groups known including ABO, Rhesus, Kidd, Kelly, Duffy
• Important ones are ABO and Rhesus blood group
• Transfusion with ABO incompatible blood can result in fatal reactions
• Rhesus D antigen is highly immunogenic and can cause haemolysis in certain settings
• In the ABO group, there are four different groups depending on which antigen the RBC carries
• In normal individuals, RBC antibodies are made against A or B antigens that are not expressed on self RBC

Disorders of white cells

Leukopaenia

Decreased number of WBC

Two types:

Neutropenia = reduced neutrophils (more common)

Lymphopenia = reduced lymphocytes (less common – due to congenital immunodeficiency, HIV, glucocorticoid therapy, cytotoxic drugs or autoimmune)

Neutropenia/ Agranulocytosis

• Increased susceptibility to infection, especially when count <500 per mm3
• Caused by:

Inadequate granulopoiesis:

1. Suppression of stem cells due to aplastic anaemia, tumours, granulomatous disease. Accompanised by anaemia and thrombocytopaenia.
2. Suppression of granulocytic precursors due to drug toxicity (most common) – chloramphenicol, sulfonamides, chlorpromazine, thiouracil
3. Ineffective haematopoiesis such as megaloblastic anaemia and myelodysplastic syndrome
4. Congenital disorders

Accelerated removal of neutrophils from blood:

1. Immune mediated injury such as SLE
2. Splenomegaly
3. Increased peripheral utilisation in bacterial/ fungal/ rickettsial infections.

Leukocytosis

Increased number of WBC

Mechanisms:

• Increased production in marrow (chronic infection/ inflammation, paraneoplastic, myeloproliferative disorders)
• Increased release from marrow (endotoxaemia, infection, hypoxia)
• Decreased margination (exercise, catecholamines)
• Decreased extravasation (glucocorticoids)

Causes:

• Neutrophilia = acute bacterial infections
• Eosinophilia = allergic disorders, parasitic infections, malignancy
• Basophilia = rare, myelodysplasia
• Monocytosis = chronic infections, SLE, IBD
• Lymphocytosis = accompanies monocytosis in many disorders with chronic inflammation

Last Updated on August 25, 2021 by Andrew Crofton