Hematology

mini Davidsone notes

By Dr. Abdulrauf M. Abdullatif

DD of Microcytosis (reduced average cell size, MCV < 76 fL)

1- Iron deficiency 2- Thalassaemia 3- Sideroblastic anaemia

Diagnostic features of beta-thalassaemia

Beta-thalassaemia major (homozygotes)
1- Profound hypochromic anaemia
2- Evidence of severe red cell dysplasia
3- Erythroblastosis
4- Absence or gross reduction of the amount of haemoglobin A
5- Raised levels of haemoglobin F
6- Evidence that both parents have thalassaemia minor
Beta-thalassaemia minor (heterozygotes)
1- Mild anaemia
2- Microcytic hypochromic erythrocytes (not iron-deficient)
3- Some target cells
4- Punctate basophilia
5- Raised haemoglobin A2 fraction
6- Evidence that one parent has thalassaemia minor

DD of Target cells (central area of haemoglobinisation)

1- Liver disease 2- Thalassaemia
3- Post-splenectomy 4- haemoglobin C disease

DD of Spherocytes (dense cells, no area of central pallor)

1- Autoimmune haemolysis 2- Post-splenectomy 3- Hereditary spherocytosis
Glucose-6-phosphate dehydrogenase deficiency
Clinical features
1- Acute drug-induced haemolysis to (e.g.)
Analgesics: aspirin, phenacetin
Antimalarials: primaquine, quinine, chloroquine, pyrimethamine
Antibiotics: sulphonamides, nitrofurantoin, ciprofloxacin
Miscellaneous: quinidine, probenecid, vitamin K, dapsone
2- Chronic compensated haemolysis
3- Infection or acute illness
4- Neonatal jaundice: may be a feature of the B- enzyme
5- Favism, i.e. acute haemolysis after ingestion of the broad bean Vicia faba
Laboratory features ,The blood film will show:
1- Bite cells (red cells with a 'bite' of membrane missing)
2- Blister cells (red cells with surface blistering of the membrane)
3- Irregularly shaped small cells
4- Polychromasia reflecting the reticulocytosis
5- Denatured haemoglobin visible as Heinz bodies within the red cell cytoplasm, if stained
with a supravital stain such as methyl violet

DD of Howell-Jolly bodies (small round nuclear remnants)

1- Hyposplenism 2- Post-splenectomy 3- Dyshaematopoiesis

DD of Polychromasia (young red cells-reticulocytes present)

1- Haemolysis, acute haemorrhage 2- Increased red cell turnover

Causes of pancytopenia
Bone marrow failure
1- Hypoplastic/aplastic anaemia
Bone marrow infiltration
1- Acute leukaemia 2- Myeloma 3- Lymphoma
4- Carcinoma 5- Haemophagocytic syndrome 6- Myelodysplastic syndromes
Ineffective haematopoiesis
1- Megaloblastic anaemia 2- Acquired immunodeficiency syndrome (AIDS)
Peripheral pooling/destruction
1- Hypersplenism: portal hypertension, Felty's syndrome, malaria, myelofibrosis
2- Systemic lupus erythematosus (SLE)
Causes of acquired aplastic anaemia
1- Drugs
Cytotoxic drugs, Antibiotics-chloramphenicol, sulphonamides, Antirheumatic agents-
penicillamine, gold, phenylbutazone, indometacin, Antithyroid drugs, Anticonvulsants,
Immunosuppressives-azathioprine
2- Chemicals
Benzene toluene solvent misuse-glue-sniffing
Insecticides-chlorinated hydrocarbons (DDT), organophosphates and carbamates
3- Radiation 4- Viral hepatitis 5- Pregnancy
6- Paroxysmal nocturnal haemoglobinuria

DD of Macrocytosis (increased average cell size, MCV > 100 fL)

1- Vitamin B12 or folate deficiency 2- Liver disease, alcohol
3- Hypothyroidism 4- Drugs (e.g. zidovudine)

Clinical features of megaloblastic anaemia

Symptoms
1- Malaise (90%) 2- Breathlessness (50%) 3- Paraesthesiae (80%)
4- Sore mouth (20%) 5- Weight loss 6- Grey hair
7- Altered skin pigmentation 8- Impotence 9- Poor memory
10-Depression 11- Personality chang 12- Hallucinations
13- Visual disturbance
Signs
1- Smooth tongue 2- Angular cheilosis 3- Vitiligo
4- Skin pigmentation 5- Heart failure 6- Pyrexia

Investigations in megaloblastic anaemia

Investigation Result
Haemoglobin Often reduced, may be very low
MCV Usually raised, commonly > 120 fL
Erythrocyte count Low for degree of anaemia
Blood film Oval macrocytosis, poikilocytosis, red cell fragmentation, neutrophil
hypersegmentation
Reticulocyte count Low for degree of anaemia
Leucocyte count Low or normal
Platelet count Low or normal
Bone marrow Increased cellularity, megaloblastic changes in erythroid series, giant
metamyelocytes, dysplastic megakaryocytes, increased iron in stores, pathological
non-ring sideroblasts
Serum ferritin Elevated
Plasma (LDH) Elevated, often markedly
Neurological findings in B12 deficiency
Peripheral nerves
1- Glove and stocking paraesthesiae
2- Loss of ankle reflexes
Spinal cord
1- Subacute combined degeneration of the cord
2- Posterior columns-diminished vibration sensation and proprioception
3- Corticospinal tracts-upper motor neuron signs
Cerebrum
1- Dementia 2- Optic atrophy
Autonomic neuropathy

Causes of folate deficiency

1- Diet: Poor intake of vegetables ,
2- Malabsorption e.g. Coeliac disease
3- Increased demand Cell proliferation, e.g. haemolysis Pregnancy
5- Drugs* Certain anticonvulsants (e.g. phenytoin), Contraceptive pill, Certain cytotoxic
drugs (e.g. methotrexate)

Investigation of folic acid deficiency

Diagnostic findings
1- Low serum folate levels (fasting blood sample)
2- Red cell folate levels low (but may be normal if folate deficiency is of very recent
onset)

DD of Neutropenia
1- Infection: viral, bacterial (e.g. Salmonella), protozoal (e.g. malaria)
2- Drugs:

Analgesics/anti-inflammatory agents Gold, penicillamine, naproxen

Antithyroid drugs Carbimazole, propylthiouracil
Anti-arrhythmics Quinidine, procainamide
Antihypertensives Captopril, enalapril, nifedipine
Antidepressants/psychotropics Amitriptyline, dosulepin, mianserin
Antimalarials Pyrimethamine, dapsone, sulfadoxine
Anticonvulsants Phenytoin, sodium valproate, carbamazepine
Antibiotics Sulphonamides, penicillins, cephalosporins
Miscellaneous Cimetidine, ranitidine, chlorpropamide
3- Autoimmune: connective tissue disease
4- Alcohol
5- Bone marrow infiltration: leukaemia, myelodysplasia
6- Congenital: Kostmann's syndrome

DD of Lymphopenia
1- Inflammation: connective tissue disease
2- Lymphoma
3- Renal failure
4- Sarcoidosis
5- Drugs: corticosteroids, cytotoxics
6- Congenital: severe combined immunodeficiency

Causes of thrombocytopenia
1- Marrow hypoplasia:
*Childhood bone marrow failure syndromes, e.g. Fanconi's anaemia, dyskeratosis congenita,
amegakaryocytic thrombocytopenia
*Idiopathic aplastic anaemia
*Drug-induced: cytotoxics, antimetabolites
*Transfusion-associated graft-versus-host disease
2- Marrow infiltration:
Leukaemia, Myeloma, Carcinoma (rare), Myelofibrosis , Osteopetrosis
Lysosomal storage disorders, e.g. Gaucher's disease
3- Haematinic deficiency: Vitamin B12 and/or folate deficiency
4- Familial (macro-)thrombocytopathies Myosin heavy chain abnormalities, e.g. Alport's
syndrome, Fechner's syndrome ,Bernard Soulier disease, Montreal platelet syndrome,
Wiskott-Aldrich syndrome (small platelets)
5- Increased consumption of platelets Immune mechanisms:
Idiopathic thrombocytopenic purpura (ITP)*, Post-transfusion purpura , Neonatal
alloimmune thrombocytopenia, Drug-associated, especially quinine
6- Coagulation activation: Disseminated intravascular coagulation (DIC)
7- Mechanical pooling : Hypersplenism
8- Thrombotic microangiopathies: Haemolytic uraemic syndrome, Liver disease ,
Thrombotic thrombocytopenic purpura
9- Others: Gestational thrombocytopenia , Type 2B von Willebrand disease
Causes of non-thrombocytopenic purpura
1- Senile purpura
2- Factitious purpura
3- Henoch-Schönlein purpura
4- Vasculitis
5- Paraproteinaemias
6- Purpura fulminans

Causes of coagulopathy
1- Congenital
X-linked ( Haemophilia A and B)
Autosomal ( Von Willebrand disease, Factor II, V, VII, X, XI and XIII deficiencies,
Combined II, VII, IX and X deficiency, Combined V and VIII deficiency,
Hypofibrinogenaemia, Dysfibrinogenaemia
2- Acquired Underproduction: Liver failure
3- Increased consumption
Coagulation activation: Disseminated intravascular coagulation (DIC)
Immune-mediated : Acquired haemophilia and von Willebrand syndrome
Others:
Acquired factor X deficiency (in amyloid) & von Willebrand syndrome in Wilms tumour
4- Drug-induced
Inhibition of function: Heparins, Lepirudin, Fondaparinux, Rivaroxaban, Dabigatran
Inhibition of synthesis: Warfarin

Antiphospholipid syndrome (APS)

Clinical manifestations
1- Adverse pregnancy outcome
2- Recurrent first trimester abortion (≥ 3)
3- Unexplained death of morphologically normal fetus after 10 weeks' gestation
4- Severe early pre-eclampsia
5- Venous thromboembolism
6- Arterial thromboembolism
7- Livedo reticularis, catastrophic APS, transverse myelitis, skin necrosis, chorea
Conditions associated with secondary APS
1- SLE 2- Rheumatoid arthritis
3- Systemic sclerosis 4- Behçet's syndrome
5- Temporal arteritis 6- Sjögren's syndrome
Targets for antiphospholipid antibodies
β2-glycoprotein 1
Protein C
Annexin V
Prothrombin (may result in haemorrhagic presentation)

Disseminated intravascular coagulation

Underlying conditions
1- Infection/sepsis
2- Trauma
3- Obstetric, e.g. amniotic fluid embolism, placental abruption, pre-eclampsia
4- Severe liver failure
5- Malignancy, e.g. solid tumours and leukaemias
6- Tissue destruction, e.g. pancreatitis, burns
7- Vascular abnormalities, e.g. vascular aneurysms, liver haemangiomas
8- Toxic/immunological, e.g. ABO incompatibility, snake bites, recreational drugs

ISTH scoring system for diagnosis of DIC disorder

1- Platelets : > 100 = 0 < 100 = 1 < 50 = 2
2- Elevated fibrin degradation products : No increase = 0 Moderate = 2 Strong = 3
3- Prolonged prothrombin time : < 3 s = 0 > 3 s but < 6 s = 1 > 6 s = 2
4- Fibrinogen : > 1 g/L = 0 < 1 g/L = 1
Total score: ≥ 5 = Compatible with overt DIC < 5 = Repeat monitoring over 1-2 days

DD of Red cell fragments (intravascular haemolysis)

1- DIC 2- HUS 3- TTP

Indications for anticoagulation

Heparin
1- Prevention and treatment of VTE
2- Percutaneous coronary intervention
3- Post thrombolysis for myocardial infarction
4- Unstable angina pectoris
5- Non-Q wave myocardial infarction
6- Acute peripheral arterial occlusion
7- Cardiopulmonary bypass
9- Haemodialysis and haemofiltration
Coumarins (warfarin etc.)
1- Prevention and treatment of VTE
2- Arterial embolism
3- Atrial fibrillation with specific stroke risk factors
4- Mobile mural thrombus post-myocardial infarction
5- Extensive anterior myocardial infarction
6- Dilated cardiomyopathy
7- Cardioversion
8- Ischaemic stroke in antiphospholipid syndrome
9- Mitral stenosis and mitral regurgitation with atrial fibrillation

Assessing risks of anticoagulation

Contraindications
1- Recent surgery, especially to eye or central nervous system
2- Pre-existing haemorrhagic state, e.g. liver disease, haemophilia, thrombocytopenia
3- Pre-existing structural lesions, e.g. peptic ulcer
4- Recent cerebral haemorrhage
5- Uncontrolled hypertension
6- Cognitive impairment
7- Frequent falls in old age

Bleeding risk score

1- Age > 65 years (1 point) 2- Previous gastrointestinal bleed (1 point)
3- Previous stroke (1 point) 4- Medical illness (1 point)
5- Recent myocardial infarction 6- Renal failure
7- Anaemia 8- Diabetes mellitus

DD of Neutrophilia
1- Infection: bacterial, fungal
2- Trauma: surgery, burns
3- Infarction: myocardial infarct, pulmonary embolus, sickle-cell crisis
4- Inflammation: gout, rheumatoid arthritis, ulcerative colitis, Crohn's disease
5- Malignancy: solid tumours, Hodgkin lymphoma
6- Myeloproliferative disease: polycythaemia, chronic myeloid leukaemia
7- Physiological: exercise, pregnancy
DD of Eosinophilia
1- Allergy: hay fever, asthma, eczema
2- Infection: parasitic
3- Drug hypersensitivity: e.g. gold, sulphonamides
4- Skin disease
5- Connective tissue disease: polyarteritis nodosa
6- Malignancy: solid tumours, lymphomas
7- Primary bone marrow disorders: myeloproliferative disorders, hypereosinophilia
syndrome (HES), acute myeloid leukaemia

DD of Basophilia
1- Myeloproliferative disease: polycythaemia, chronic myeloid leukaemia
2- Inflammation: acute hypersensitivity, ulcerative colitis, Crohn's disease
3- Iron deficiency

DD of Monocytosis
1- Infection: bacterial (e.g. tuberculosis)
2- Inflammation: connective tissue disease, ulcerative colitis, Crohn's disease
3- Malignancy: solid tumours

DD of Lymphocytosis
1- Infection: viral, bacterial (e.g. Bordetella pertussis)
2- Lymphoproliferative disease: chronic lymphocytic leukaemia, lymphoma
3- Post-splenectomy

Risk factors for leukaemia

1- Ionising radiation
After atomic bombing of Japanese cities (myeloid leukaemia)
Radiotherapy for ankylosing spondylitis
Diagnostic X-rays of the fetus in pregnancy
2- Cytotoxic drugs
Especially alkylating agents (myeloid leukaemia, usually after a latent period of several
years) Industrial
exposure to benzene
3- Retroviruses
One rare form of T-cell leukaemia/lymphoma appears to be associated with a retrovirus
similar to the viruses causing leukaemia in cats and cattle
4- Genetic
Identical twin of patients with leukaemia
Down's syndrome and certain other genetic disorders
Immunological Immune deficiency states (e.g. hypogammaglobulinaemia)

Staging of chronic lymphocytic leukaemia

Clinical stage A (60% patients)
No anaemia or thrombocytopenia and fewer than three areas of lymphoid enlargement
Clinical stage B (30% patients)
No anaemia or thrombocytopenia, with three or more involved areas of lymphoid
enlargement
Clinical stage C (10% patients)
Anaemia and/or thrombocytopenia, regardless of the number of areas of lymphoid
enlargement

Imatinib and chronic myeloid leukaemia

'As first-line therapy in CML, imatinib is better tolerated and induces a cytogenetic
response in ∼87% of cases at 18 months, compared with ∼35% response to interferon +
cytarabine.'

Causes of lymphadenopathy
1- Infective
Bacterial: streptococcal, tuberculosis, brucellosis
Viral: Epstein-Barr virus (EBV), human immunode ficiency virus (HIV)
Protozoal: toxoplasmosis
Fungal: histoplasmosis, coccidioidomycosis
2- Neoplastic
Primary: lymphomas, leukaemias
Secondary: lung, breast, thyroid, stomach
3- Connective tissue disorders : Rheumatoid arthritis, (SLE)
4- Sarcoidosis
5- Amyloidosis
6- Drugs: Phenytoin

Causes of splenomegaly
1- Intrahepatic portal hypertension : Cirrhosis, Hepatic vein occlusion
2- Extrahepatic portal hypertension : Thrombosis, Stenosis or malformation of the
portal or splenic vein
3- Cardiac : Chronic congestive cardiac failure, Constrictive pericarditis
4- Infective:
Bacterial : Endocarditis, Septicaemia, Tuberculosis , Brucellosis, Salmonella
Viral : Hepatitis, Epstein-Barr, Cytomegalovirus
Protozoal : Malaria*, Leishmaniasis (kala-azar)* , Trypanosomiasis
Fungal : Histoplasmosis
5- Inflammatory: Felty's syndrome in rheumatoid arthritis, Systemic lupus
erythematosus, Sarcoidosis
6- Haematological Red cell disorders: Megaloblastic anaemia, Haemoglobinopathies,
Autoimmune haemolytic anaemias, Myeloproliferative disorders, Chronic myeloid
leukaemia*, Myelofibrosis*, Polycythaemia rubra vera, Essential thrombocythaemia
7- Neoplastic: Leukaemias, Lymphomas , Metastatic cancer-rare
8- Lysosomal storage diseases: Gaucher's disease, Niemann-Pick disease
9- Miscellaneous Cysts, amyloid, thyrotoxicosis

Epidemiology and aetiology of Hodgkin lymphoma

1- Incidence : Approximately 4 new cases/100 000 population/year
2- Sex ratio: Slight male excess (1.5:1)
3- Age Median age 31 years; first peak at 20-35 years and second at 50-70 years
4- Aetiology Unknown
More common in patients from well-educated backgrounds and small familie
Three times more likely with a past history of infectious mononucleosis but no causal link
to Epstein-Barr virus infection proven

Epidemiology and aetiology of non-Hodgkin lymphoma

1- Incidence: 12 new cases/100 000 people/year
2- Sex ratio: Slight male excess
3- Age : Median age 65-70 years
4- Aetiology: No single causative abnormality described
Lymphoma is a late manifestation of HIV infection
Specific lymphoma types are associated with EBV, human herpes virus 8 (HHV8) and human
T-cell lymphotropic virus (HTLV) infection
Gastric lymphoma can be associated with Helicobacter pylori infection
Some lymphomas are associated with specific chromosome lesions; the t(14:18)
translocation in follicular lymphoma results in the dysregulated expression of the BCL-2
gene product, which inhibits apoptotic cell death
Lymphoma occurs in congenital immunodeficiency states and in immunosuppressed patients
after organ transplantation
WHO pathological classification of Hodgkin lymphoma (HL)
Type Histology classification Proportion of HL
Nodular lymphocyte-predominant HL ------------------- 5%
Classical HL Nodular sclerosing 70%
Mixed cellularity 20%
Lymphocyte-rich 5%
Lymphocyte-depleted Rare

Clinical stages of Hodgkin lymphoma (Ann Arbor classification)

Stage Definition
I Involvement of a single lymph node region (I)
II Involvement of two or more lymph node regions (II) on the same side of (above or
below) the diaphragm
III Involvement of lymph node regions on both sides of the diaphragm
IV Diffuse involvement of one or more extralymphatic tissues, e.g. liver or bone marrow
Each stage is subclassified:
A No systemic symptoms
B Weight loss, drenching sweats

The Hasenclever prognostic index for advanced Hodgkin lymphoma

Score 1 for each of the following risk factors present at diagnosis:
1- Age > 45 years 2- Male gender
3- Serum albumin < 40 g/L 5- Hb < 105 g/L
6- Stage IV disease 7- WBC > 15 × 109/L
8- Lymphopenia < 0.6 × 109/L

Score 5-year rate of overall survival (%)

0-1 90
≥2 74
≥3 70
≥4 59

Causes of a raised platelet count

Reactive thrombocytosis
1- Chronic inflammatory disorders 2- Malignant disease
3- Tissue damage 4- Haemolytic anaemias
5- post-splenectomy 6- Post-haemorrhage
Clonal thrombocytosis
1- Primary thrombocythaemia
2- Polycythaemia rubra vera (PRV)
3- Myelofibrosis
4- Chronic myeloid leukaemia
5- Myelodysplastic syndromes

Complications of allogeneic bone marrow transplantation

1- Mucositis 2- Infection 3- Bleeding
4- Cataract formation 5- Pneumonitis 6- Infertility
7- Chronic graft-versus-host disease 8- Acute graft-versus-host disease
9- Secondary malignant disease

Score: annual rate of major haemorrhage 0 = 3% 1-2 = 12% 3-4 = 30-48%

Haematological malignancy in old age

Median age: approximately 70 years for most haematological malignancies.
Poor-risk biological features: adverse cytogenetics or the presence of a multidrug
resistance phenotype are more frequent.
Prognosis: increasing age is an independent adverse variable in acute leukaemia and
aggressive lymphoma
Chemotherapy: may be less well tolerated. Older people are more likely to have
antecedent cardiac, pulmonary or metabolic problems, tolerate systemic infection less well
and metabolise cytotoxic drugs differently.
Cure rates: similar to those in younger patients, in those who do tolerate treatment.
Decision to treat: should be based on the individual's biological status, the level of social
support available, and the patient's wishes and those of the immediate family, but not on
chronological age.