Haematology Flashcards
Define polycythaemia
Polycythaemia = increased haemoglobin concentration above the normal for age and sex matched individual
Polycythaemia Vera = A bone marrow neoplasm associated with excessive production of red blood cells. It is characterised by erythrocytosis, thrombocytosis, leukocytosis and splenomegaly.
What is the difference between relative and absolute polycythaemia?
Relative polycythaemia = normal red blood cell mass but decreased blood volume
Absolute polycythaemia = increased red cell mass
Summarise the aetiology of polycythaemia
Polycythaemia Rubra Vera: (Primary Polycythaemia)
Clonal proliferation of myeloid cells
Varied morphologic maturity and haematopoietic efficiency
Mutations in JAK2 tyrosine kinase
Secondary Polycythaemia:
Raised red blood cell production in response to APPROPRIATE increase in erythropoietin: Chronic hypoxia (e.g. chronic lung disease, living at high altitude) - upregulation of erythropoiesis
Raised red blood cell production in response to INAPPROPRIATE increase in erythropoeitin:
Renal (carcinoma, cysts, hydronephrosis)
Hepatocellular carcinoma
Fibroids
Cerebellar hemangioblastoma
Erythropoietin abuse by athletes
Relative Polycythaemia:
Dehydration (e.g. diuretics, burns, enteropathy)
Gaisbock’s syndrome - young male smokers with increased vasomotor tone and hypertension, which results in a decrease in plasma volume and an apparent increase in red cell count
Summarise the epidemiology of polycythaemia
Peak Age 45-60 years
UK Annual Incidence of Polycythaemia Rubra Vera: 1.5 in 100,000
Polycythaemia Vera more common in men
Very rare in children
Incidence increases with age
What are the presenting symptoms of polycythaemia?
Hyperviscosity symptoms - headaches, blurred vision
Fatigue
Plethoric/red face
Aquagenic pruritis - itching particularly after warm bath
Dizziness
Increased sweating
Dyspnoea
Tinnitus (ringing or buzzing in the ears)
Night Sweats
Tenderness & Redness of fingers, palms, heels or toes
Pain from Peptic Ulcer Disease
Angina
Gout
What are the signs on physical examination of polycythaemia?
Plethoric face
Excoriation marks from itching
Splenomegaly
Conjunctival suffusion - red conjunctiva
Retinal venous engorgement
Hypertension
What are the appropriate investigations for polycythaemia?
FBC - high Hb, high haematocrit, low MCV
Isotope Dilution Techniques:
Find plasma volume and red cell mass
Can then distinguish between relative and absolute polycythaemia
Polycythaemia Rubra Vera: High Hb High haematocrit Low MCV High WCC High platelets Low serum erythropoeitin JAK2 mutation Bone marrow trephine and biopsy - erythroid hyperplasia and raised megakaryocytes
Secondary Polycythaemia:
High serum erythropoeiti
Exclude Chronic Lung Disease/Hypoxia
Check for EPO-secreting Tumours (CT Abdo, Brain MRI
Define macrocytic anaemia
A low haemoglobin below which is normal for an sex and age-matched individual in the presence of erythrocytes with a high MV (>100fL).
There are two types: megaloblastic and non-megaloblastic
Summarise the aetiology of macrocytic anaemia
Megaloblastic:
Bone marrow produces unusually large, structurally abnormal immature RBCs
Vitamin B12 deficiency
- Decreased dietary intake (vegans)
- Defective absorption:
1. Gastric atrophy - less HCl, less pepsin, less absorption
2. Gastric bypass - food passes through too quickly to be absorbed
3. Pernicious anaemia - antibodies against intrinsic factor or parietal cells
4. Terminal ileal disease
Folate deficiency
- Decreased dietary intake (little leafy greens or citrus fruit) - alcoholics, elderly, anorexia
- Increased need (pregnancy, lactation, malignancy, chronic inflammation, haemolytic anaemia)
- Impaired absorption
- Jejunal Disease ie coeliac
- Drugs eg phenytoin
Drugs: Methotrexate, Hydroxyurea, Azathioprine, Zidovudine
NON-MEGALOBLASTIC: Alcohol Excess Liver Disease Myelodysplasia Multiple Myeloma Hypothyroidism Haemolysis Drug
Summarise the epidemiology of macrocytic anaemia
Elderly
Females
What are the presenting symptoms of macrocytic anaemia?
Fatigue
Lethargy
Exertional dyspnoea
Shortness of breath
Symptoms of CAUSE:
Weight loss
Diarrhoea
Steatorrhea in coeliac disease
Regular falls and tingling of extremeties in vitamin B12 deficiency
What are the signs on physical examination of macrocytic anaemia?
Pallor
Tachycardia
Dyspnoea
Signs of pernicious anaemia: Jaundice Glossitis Angular stomatitis Weight loss
Signs of B12 deficiency: Peripheral neuropathy Subacute combined degeneration of the spinal cord Ataxia Optic atrophy Dementia
What are the appropriate investigations for macrocytic anaemia?
Bloods:
FBC: increased MCV, low Hb, pancytopenia in megaloblastic
LFTs: increased bilirubin (due to ineffective erythropoiesis or haemolysis)
Serum Vitamin B12 - low if due to B12 deficiency
Red Cell Folate - low if due to folate deficiency
Anti-parietal cell AND anti-intrinsic factor antibodies - if pernicious anaemia causing B12 deficiency
Serum protein electrophoresis – looking for dense band in Myeloma
ESR, TFT (hypothyroidism can cause non-megaloblastic)
Peripheral blood film:
Large erythrocytes
Megaloblastic: Megaloblasts, Hyper segmented Neutrophil Nuclei (>5 lobes)
Schilling Test: Method of testing for pernicious anaemia B12 will only be absorbed when given with intrinsic factor
Bone Marrow Biopsy (megaloblast, myelodysplastic changes)
What is the management of macrocytic anaemia?
Vitamin B12 deficiency:
Must be treated first!!
IM hydroxocobalamin for life
Folate Deficiency:
Oral folic acid
What are the possible complications of macrocytic anaemia?
Pernicious Anaemia: increased risk of Gastric Cancer
Pregnancy: folate deficiency increases risk of neural tube defects
Summarise the prognosis of macrocytic anaemia
Majority are treatable if there are no complications
Define microcytic anaemia
Haemoglobin lower than expected for an age and sex matched individual with a low MCV <80fL.
Summarise the aetiology of microcytic anaemia
Defects in haem synthesis:
Iron deficiency anaemia
- Chronic blood loss (heavy menstrual period, bleeding gastric ulcer, blood loss from colon cancer)
- Lack of absorption - gastrectomy, IBD, coeliac
- Increased demand - pregnancy
- Malnutrition
Lead poisoning
Sideroblastic Anaemia
Defects in globin synthesis:
Thalassemia
Summarise the epidemiology of microcytic anaemia
It is the most common form of anaemia worldwide
What are presenting symptoms of microcytic anaemia?
Tiredness Lethargy Fatigue Shortness of breath Pallor
Lead Poisoning: Anorexia Nausea/Vomiting Abdominal Pain Constipation Peripheral Nerve Lesions
What are the signs on physical examination of microcytic anaemia?
Pallor
Brittle nails and hair
Iron deficiency:
Koilonychia
Glossitis
Thalassemia: Hepatosplenomegaly Mild jaundice Peripheral nerve lesions (wrist or foot drop) Glossitis – atrophy of lung papillae Angular Stomatitis
Lead poisoning: Blue gum line Convulsions Altered consciousness Encephalopathy
What are the appropriate investigations of microcytic anaemia?
Peripheral blood smear
Iron deficiency anaemia: Microcytic, Hypochromic (central pallor <1/3 cell size), Anisocytosis (variable cell size), Poikilocytosis (variable cell shape)
Sideroblastic anaemia: Dimorphic blood film, Hypochromic microcytic cells
Lead poisoning: Basophilic stippling (coarse dots represent condensed RNA in cytoplasm)
Iron studies:
Iron deficiency - iron and ferritin low, transferrin and TIBC high
Sternoblastic - iron and ferritin high, transferrin and TIBC normal/low
Haemoglobin electrophoresis
Checking for Hb variants and thalassemia
If > 40 years and post-menopausal and no obvious cause of blood loss:
Upper GI endoscopy
Colonoscopy
Investigations for haematuria
Summarise the management of microcytic anaemia
Iron deficiency:
Oral iron supplements
Sideroblastic:
Treat the cause
If inherited: pyridoxine
If no response: blood transfusion and iron chelation
Lead poisoning:
Chelating agents
Dimercaprol
D-penicillinamine
Thalassemia:
Blood transfusions
What are the possible complications of microcytic anaemia?
High Output Cardiac Failure
Complications related to the CAUSE
What is the prognosis of microcytic anaemia?
Depends on the cause
Define aplastic anaemia
A type of anaemia which results in panyctopenia with hypocellular bone marrow without any abnormal cells, usually due to autoimmune destruction of haematopoeitic stem cells.
Summarise the aetiology of aplastic anaemia
Most often IDIOPATHIC (> 40%):
May be due to destruction or suppression of stem cells via autoimmune mechanisms
Acquired:
Drugs (e.g. chloramphenicol, sulphonamides, methotrexate)
Chemicals (e.g. benzene, DDT, insecticides)
Radiation
Viral infection (e.g. parvovirus B19, EBV, HIV)
Paroxysmal nocturnal haemoglobinuria (PNH)
Inherited: Fanconi’s anaemia - pancytopenia, short stature, microcephaly, developmental delay, cafe-au-lait spots, predisposition to malignancy, absent or hypoplastic thumbs Dyskeratosis congenita (rare, progression bone marrow failure syndrome)
Summarise the epidemiology of aplastic anaemia
Equal between males and females (perhaps slightly more common for males)
Biphasic distribution - 10-25 years and >60 years old peak
Fanconi anaemia is one of the most common congenital causes
What are the presenting symptoms of aplastic anaemia?
Can be slow or rapid onset: Fatigue Pallor Dyspnoea Recurrent infections Mucosal bleeding Easy bruising Bleeding gums Epistaxis
What are the signs on physical examination of aplastic anaemia?
Anaemia signs: pallor
Thrombocytopenia signs: bruises, petechiae
NO HEPATOSPLENOMEGALY OR LYMPHADENOPATHY
What are the appropriate investigations of aplastic anaemia?
FBC - low Hb - normocytic anaemia, thrombocytopenia, leukopenia
Serum erythropoeitin - elevated
Reticulocyte count - decreased
Bone marrow biopsy - hypocellular (low haematopoeitic stem cells), no abnormal cells, dry tap
Fanconi’s Anaemia: Check for the presence of increased chromosomal breakage in lymphocytes cultures in the presence of DNA cross-linking agents.
Define disseminated intravascular coagulation
An acquired syndrome characterised by widespread activation of coagulation pathways, resulting in the formation of intravascular thrombi. This can lead to organ ischaemia, necrosis and failure, but also uses up clotting factors and platelets which can lead to spontaneous bleeding.
Acute overt form where there is bleeding and depletion of platelets and clotting factors
Chronic non-overt form where thromboembolism is accompanied by generalised activation of the coagulation system
Summarise the aetiology of disseminated intravascular coagulation
Sepsis
Malignancy
Obsteteric complications - Missed miscarriage, severe pre-eclampsia, amniotic emboli, Placental abruption
Trauma
Intravascular haemolysis
Immunological reactions - blood transfusion reactions, organ transplant rejection
Severe organ destruction or failure (severe pancreatitis, acute hepatic failure)
Vascular disorders (Kasabach-Merritt syndrome or giant haemangiomas, large aortic aneurysms)
Severe toxic reactions
Summarise the epidemiology of disseminated intravascular coagulation
Seen in severely ill patients
What are the presenting symptoms of disseminated intravascular coagulation?
Patients severely unwell with symptoms of underlying disease
Oligouria - suggests circulatory collapse
Dsypnoea
Cough
Confusion/delirium
Evidence of Bleeding - epistaxis, gingivial bleeding
What are the signs on physical examination of disseminated intravascular coagulation?
Signs of underlying disease
Fever
Evidence of shock - hypotension, tachycardia
Acute DIC:
Petechiae, purpura, ecchymoses
Bleeding: Epistaxis, Mucosal bleeding, Overt haemorrhage, haematuria
Signs of end organ damage – local infarction or gangrene
Oliguria due to renal failure
Respiratory distress
Delirium and coma
Chronic DIC:
Signs of deep vein and arterial thrombosis or embolism
Superficial venous thrombosis
What are the appropriate investigations for disseminated intravascular coagulation?
Serum platelets - low Serum fibrinogen - low D-dimer - high Fibrin degradation products - elevated Prolonged PT Prolonged PTT Hb - decreased
Peripheral Blood Film:
Schistocytes (red blood cell fragments)
Define myelofibrosis
A progressive myeloproliferative disorder in which the bone marrow gets replaced by fibrosis and extramedullary haematopoiesis occurs, resulting in splenomegaly. It is also associated with pancytopenia.
Summarise the aetiology of myelofibrosis
Primary myelofibrosis: due to mutation in haematopoietic stem cells - often JAK2 mutation
Primary stem cell defect is UNKNOWN - results in increased numbers of abnormal megakaryocytes which release growth factors resulting in fibrosis
Seconary myelofibrosis: caused by essential thrombocthaemia or polycythaemia vera - 30% of patients have a history of one of these
Summarise the epidemiology of myelofibrosis
Occurs in adults More common in White patients More common in males Median age at diagnosis is 65 years old RARE Peak onset = 50-70
What are the presenting symptoms of myelofibrosis?
Can be asymptomatic and diagnosed after routine blood count
Bone pain History of frequent infections Fatigue Easy bruising Fever Itching Weight loss Anorexia Night sweats
UNCOMMON: LUQ pain Indigestion (due to massive splenomegaly) Bleeding Gout
Symptoms of pulmonary hypertension due to extramedullary haematopoeisis in lungs:
Shortness of breath
Fatigue
Presyncope
What are the signs on physical examination of myelofibrosis?
Hepatosplenomegaly
Petechiae
What are the appropriate investigations of myelofibrosis?
FBC - anaemia, thrombocytopenia, leukocytopenia
LFTs - abnormal
Peripheral blood film - tear drop RBCs, increased number of abnormal megakaryocytes, pancytopenia, immature nucleated RBCs, red and white cell precursors in film
Bone marrow aspiration - dry tap
Bone marrow biopsy - trephine biopsy shows fibrotic hypercellular marrow
Define myelodysplasia
Characterised by ineffected and dysplastic haematopoeisis, leading to abnormal cell maturation and cytopenias, with <20% bone marrow being made up of blasts.
Summarise the aetiology of myelodysplasia and the risk factors
Primary myelodysplasia is most common and is idiopathic
Secondary myelodysplasia can be due to chemotherapy or radiotherapy, DNA alkylating agent use
May have chromosomal abnormalities
Risk factors: Age > 70 years Alkylating Agents Topoisomerase Inhibitors Prior Haematopoietic Stem Cell Transplantation DNA Repair Deficiency Syndrome
Summarise the epidemiology of myelodysplasia
Median age 65-70 years old
Secondary can occur in younger patients
More common in males
What are the presenting symptoms of myelodysplasia?
Can be asymptomatic and diagnosed on routine bloods
Symptoms of pancytopenia: Anaemia: Fatigue Dizziness Decreased exercise tolerance
Leukopenia:
Increased recurrent infections
Thrombocytopenia:
Easy bruising
Epistaxis
Occupational exposure to toxic chemicals
Prior chemotherapy or radiotherapy
What are the signs on physical examination of myelodysplasia?
Anaemia: Pallor, cardiac flow murmur
Thrombocytopenia: Petechiae, purpura, ecchymosis
Leukopenia: infections
Gum hypertrophy
What are the appropriate investigations of myelodysplasia?
FBC - anaemia, thrombocytopenia, leukopenia
Bone marrow aspirate - increased blast cells in bone marrow (<20%), dysplastic cells
Bone marrow biopsy - hypercellularity
Peripheral blood smear: ringed sideroblasts, large oval shaped RBCs, abnormal WBCs and platelets
Define von Willebrand disease
A bleeding disorder caused by a quantitative deficiency or functional defiency of von Willebrand factor, resulting in mucocutaneous bleeding, increased bleeding after trauma, easy bruising and menorrhagia.
Type I - decreased quantity of vWF
Type II - decreased function of vWF, but normal levels
Type III - severe quantitative deficiency/NO vWF
Summarise the aetiology of von Willebrand disease
Mutation in vWF gene
Type I - decreased amounts of vWF, AUTOSOMAL DOMINANT, most common
Type II - normal quantities but abnormal function, AUTOSOMAL DOMINANT
Type III - no vWF - AUTOSOMAL RECESSIVE
Rarely can get acquired von Willebrand’s disease:
Lymphoproliferative disorders - multiple myeloma
Aortic stenosis
Myeloproliferative disorders
Hypothyroidism
vWF is an adhesive bridge between platelets and the exposed subendothelial collagen
vWF also binds to factor VIII stabilising it and thus preventing its degradation
What are the risk factors of von Willebrand disease?
Family history of Von Willebrand Disease Consanguineous relationships Lymphoproliferative disorders Aortic Stenosis Myeloproliferative disorders Hypothyroidism
Summarise the epidemiology of von Willebrand disease
It is the most common inherited bleeding disorder
Males and females affected equally
Most common form is type 1 - 75% of cases
Women more often diagnosed due to more severe symptoms - menorrhagia
Type 2 and type 3 have more severe symptoms
What are the presenting symptoms of von Willebrand disease?
Mucocutaneous bleeding - gingival bleeding
Menorrhagia
Easy bleeding from trauma
Easy and excessive bruising
Epistaxis - prolonged or requires medical intervention
Excessive/prolonged bleeding from minor wounds or gums after dental procedures
GI Bleeding
CNS bleeding
Haematuria
What are the signs on physical examination of von Willebrand disease?
Petechiae
Ecchymoses
Hemarthrosis
What are the appropriate investigations for von Willebrand disease?
Platelets - normal
PT - normal
PTT - increased due to decreased factor VIII activity
Bleeding time - increased
vWF function assay ristocetin assay - usually would cause platelet aggregation
Factor VIII activity decreased
vWF antigen – DIAGNOSTIC if <0.3 international units/mL
Define haemophilia
A bleeding disorder characterised by a lack of or lack of effectiveness of clotting factors which is usually inherited via an X-linked recessive pattern, but can be aqcuired.
Haemophilia A is most common - deficiency of factor VIII
Haemophilia B - deficiency of factor IX
Haemophilia C - deficiency of factor XI
Summarise the aetiology of haemophilia
Due to deficiency in one or more clotting factors
Inherited haemophilia due to X-linked recessive inheritance
Haemophilia A is mutation in F8 gene on X chromosome - causes factor VIII deficiency
Haemophilia B is mutation in F9 gene on X chromosome - causes factor IX deficiency
Acquired haemophilia: Renal failure DIC Autoimmune attack of clotting factor Vitamin K deficiency
Risk factors of acquired haemophilia: Age > 60 IBD Diabetes Hepatitis Pregnancy Postpartum Malignancy
Summarise the epidemiology of haemophilia
Mostly seen in males
Men have disease, women are carriers
Haemophilia A is more common
What are the presenting symptoms of haemophilia?
Prolonged bleeding following injury Easy bruising Severe nosebleeds Oozing following dental procedures Haematuria Blood in stool HAEMARTHROSIS - Painful swelling of joints without trauma/occuring spontaneously Painful bleeding into muscles Bleeding usually deep eg into muscles and joints
Female carriers usually asymptomatic - may have excessive bleeding after trauma
What are the signs on physical examination of haemophilia?
Haemarthrosis: Painful joint Swelling Decreased range of movement Warmth
Muscle haematomas/painful bleeding into muscles:
Pain, swelling, decreased range of motion, erythema, increased local warmth
Ecchymosis
Excessive bruising
Extensive Cutaneous Purpura
Nerve palsies (due to nerve compression by haematomas)
Signs of Iron Deficiency anaemia: Pallor Fatigue Weakness SOB
What are the appropriate investigations for haemophilia?
FBC- normal platelets, may be anaemic due to bleeding
Bleeding time - normal
PT - normal
PTT - prolonged
Genetic testing
Mixing study - aPTT normal
Coagulation factor assays - decreased factor 8, 9 or 11
Define immune thrombocytopenic purpura
Immune destruction of platelets due to IgG autoantibodies resulting in bruising and bleeding tendency.
Primary ITP - isolated thrombocytopenia with no underlying cause
Secondary ITP - due to underlying systemic cause, often virus eg HIV, HCV, CMV or SLE
Summarise the aetiology of immune thrombocytopenic purpura
Mostly idiopathic
Autoantibodies against platelet GlpIIb/IIIa receptor causing autoimmune destruction of platelets
Secondary has underlying cause:
Viruses - HCV, HIV, CMV, malaria - often causes ACUTE ITP following viral infection in children
Autoimmune conditions - SLE, thyroid disease
Malignancy
Drugs (e.g. quinine)
Summarise the epidemiology of immune thrombocytopenic purpura
Acute ITP - children post-infection
Childhood ITP equal between sexes and has spontaenous resolution within 2 months
Chronic - females of child bearing age
What are the presenting symptoms of immune thrombocytopenic purpura?
Asymptomatic Easy bruising Purpura Petechiae on lower limbs Submucosal bleeding Epistaxis Menorrhagia
What are the signs on physical examination of immune thrombocytopenic purpura?
Visible petechiae
Bruises
Haemorrhagic bullae
No hepatosplenomegaly
No lymphadenopathy
No systemic symptoms
What are the appropriate investigations of immune thrombocytopenic purpura?
DIAGNOSIS OF EXCLUSION
FBC - isolated thrombocytopenia
PT, PTT, fibrinogen - NORMAL
Autoantibodies - antiplatelet antibodies present
Peripheral blood smear - isolated thrombocytopenia
HIV and Hepatitis serology - look for secondary cause
Bone Marrow Biopsy/aspiration – to exclude other pathology: normal or increased megakaryocytes
Define thrombotic thrombocytopenic purpura
A disorder causing extensive microscopic clots to form in the small blood vessels throughout the body.
A condition characterised by a pentad of symptoms:
Microangiopathic haemolytic anaemia
Thrombocytopenic purpura
Neurological deficits
Fever
Renal failure
Summarise the aetiology of thrombotic thrombocytopenia purpura
Deficiency in ADAMTS13 likely due to autoimmune antibody destruction
ADAMRS13 usually cleaves vWF
Abnormally large vWF multimers form which causes large clots to develop
Risk factors: Female SLE African Sepsis Pregnancy Liver disease Pancreatitis
Summarise the epidemiology of thrombotic thrombocytopena prupura?
RARE
More common in women
More common in black patients
Average age 39 years old
What are the presenting symptoms of thrombotic thrombocytopenia purpura?
Neurological - headache, seizure, coma, confusion
Microangiopathic haemolytic anaemia - dark urine, fatigue, weakness
Fever
Easy bruising
Mucocutaneous bleeding - menorrhagia, epistaxis
GI symptoms - diarrhoea, nausea, vomiting, abdo pain
Renal failure - oligouria/anuria, haematuria
What are the signs on physical examination of thrombotic thrombocytopenia purpura?
Pallor (due to anaemia) Jaundice (due to haemolysis) Bruising (severe thrombocytopenia) Generalised oedema Hypertension Retinopathy
Gastrointestinal: Abdominal tenderness
CNS: Weakness, reduced vision, fits, reduced consciousness
What are the appropriate investigations for thrombotic thrombocytopenia prupura?
FBC - thrombocytopenia, normocytic anaemia, increased reticulocytes
Creatinine and urea - elevated due to renal failure
Increased potassium, decreased sodium
LDH increased
Unconjugated bilirubin - elevated
Peripheral blood smear - schistocytes, thrombocytopenia, increased reticulocytes, spherocytes
Urinalysis - haematuria, proteinuria
ADAMTS13 activity assay - decreased
Define antiphospholipid syndrome
An autoimmune disease caused by the presence of antiphospholipid autoantibodies, resulting in thrombocytopenia, arterial and venous thrombosis and pregnancy-related morbidity.
Summarise the aetiology of antiphospholipid syndrome
Aetiology unknown
Antiphospholipid antibodies such as anti-beta2-glycoprotein-1, anticardiolipin and lupus anticoagulant cause the formation of thromboses
Risk factors:
History of SLE or autoimmune rheumatological disorders
Other autoimmune diseases
Autoimmune haematological disorders
Summarise the epidemiology of antiphospholipid syndrome
Can be primary or secondary
Secondary often associated with SLE
More common in young women
What are the presenting symptoms of antiphospholipid syndrome?
Symptoms of DVT - painful, swollen leg Headache, seizures Symptoms of MI, stroke, limb ischaemia History of miscarriages History of pregnancy loss or pregnancy related morbidity History of vascular thrombosis
What are the signs on physical examination of antiphospholipid syndrome?
New onset murmur - development of Libman-Sacks endocarditis
Livedo reticularis - mottled blue/purple rash
Features of thrombocytopenia - petechial rash, mucosal bleeding
Arthralgia/arthritis
Signs of SLE: Malar Flush, Discoid Lesions, Photosensitivity
Oedema
What are the appropriate investigations for antiphospholipid syndrome?
FBC - decreased platelets
Clotting Screen - increased APTT
U&Es - increased creatine and urea due to antiphospholipid nephropathy
ELISA Testing for:
Anticardiolipin and Anti-β2-glycoprotein 1 antibodies
Lupus Anti-coagulant Assays:
Clotting assays showing effects of APL on the phospholipid dependent factors in coagulation cascade
Define sick cell disease
A chronic condition caused by inheritance of HbS, leading to sickling of haemoglobin which results in anaemia, painful crises and red blood cell haemolysis.
Summarise the aetiology of sickle cell disease
It is an autosomal recessive disorder
Mutation of the 6th amino acid from glutamic acid to valine on the beta globin chain
Causes sickling of RBCs when deoxygenated
Sickled cells are prone to premature destruction and occlusion of small blood vessels, causing painful crises and end organ damage
Sickling precipitated by: Acidosis Dehydration Hypoxia Infection
Summarise the epidemiology of sickle cell disease
Common in Africa and south Asia where plasmodium falciparum malaria is common
Symptoms present a few months after birth when HbA overtakes HbF as the predominant haemoglobin
What are the presenting symptoms of sickle cell disease?
Symptoms due to anaemia:
Fatigue
SOB
Symptoms due to vaso-occlusion:
Hands and feet - dactylitis - swollen painful fingers and toes
Painful crises MAINLY affect the ribs, spine, pelvis & long bones in ADULTS
Pulmonary vessels - acute chest syndrome - chest pain, SOB, cough
Penis - priapism - painful prolonged erection
Renal papillae - haematuria
Auto splenectomy: increased risk of infections with encapsulated organisms (e.g. pneumococcus, meningococcus)
Abdominal Pain (may get bilirubin gallstones)
Myalgia and Arthralgia
CNS - Fits and strokes (hemiplegia)
Retina - Visual loss (proliferative retinopathy)
What are the sings on physical examination?
Signs of haemolytic anaemia:
Pallor
Scleral icterus
Jaundice
Enlarged cheeks
Hepatomegaly due to extramedullary haematopoeisis
Bone: joint or muscle tenderness or swelling (due to avascular necrosis)
Retina: Cotton wool spots (retinal ischaemia)
Signs secondary to sequestration crisis:
Tachycardia
Splenomegaly (later reduces in size due to splenic atrophy)
Priapism
What are the appropriate investigations for sickle cell disease?
FBC - anaemia, increased reticulocytes
LFTs - increased LDH and unconjugated bilirubin
Decreased haptoglobin
Protein electrophoresis - HbS dark band as opposed to normal HbA
Peripheral blood smear - Howell-Jolly bodies and target cells (suggest hyposplenism), sickled cells, reticulocytes, anisocytosis (variation in size)
Sickle Solubility Tests: Dithionate added to blood causes increased turbidity in sickle cell disease
Hip X-Ray: Femoral head is a common site of avascular necrosis
MRI or CT Head: If there are neurological complications
Summarise the management of sickle cell disease?
Advice: Avoid triggers - excessive exercise, excessive hot or cold, high altitude, dehydration Good hygiene and nutrition Genetic counselling Prenatal screening
Painful occlusive crisis:
Oxygen and IV fluids - remove triggers
IV opioids analgesia
Antibiotics
Prophylaxis due to autosplenectomy:
Penicillin V, regular vaccinations (against capsulated bacteria)
Folic Acid: If severe haemolysis or in pregnancy
HYDROXYUREA: Increases HbF, reduces the frequency and duration of sickle cell crisis
Red Cell Transfusion - For SEVERE anaemia and repeated crises
Need to give with iron chelation to prevent iron overload
Surgical:
Bone marrow transplantation
Joint replacement in cases with avascular necrosis
What are the possible complications of sickle cell disease?
Increased susceptibility to infection with encapsulated-bacteria Acute chest syndrome Priapism Painful occlusive crises Anaemia Bilirubin gallstones Splenic sequestration Pulmonary hypertension Aplastic crises: infection with Parvovirus B19 - temporary cessation of erythropoiesis Haemolytic crises Cholecystitis Renal papillary necrosis Leg ulcers Cardiomyopathy
Summarise the prognosis of sickle cell disease
Most patients who manage it well will survive until around the age of 50 years
Mortality is usually the result of pulmonary or neurological complications in ADULTS and infection in CHILDREN
Most common cause of death is upper respiratory tract infection
Define haemolytic anaemia
Anaemia due to the premature destruction of erythrocytes, leading to decreased RBC lifespan less than 120 days.
Summarise the aetiology of haemolytic anaemia
Hereditary:
Membrane Defects: Hereditary Spherocytosis, Elliptocytosis
Metabolic Defects: G6PD deficiency, Pyruvate kinase deficiency
Haemoglobinopathies: Sickle cell disease, Thalassemia
Acquired:
Autoimmune: Antibodies attach to erythrocytes - intravascular/extravascular haemolysis
Iso-immune: transfusion reaction, haemolytic disease of the Newborn
Drugs: Penicillin, Quinine (formation of a drug-antibody-erythrocyte complex)
Trauma: Microangiopathic haemolytic anaemia (caused by RBC fragmentation in abnormal microcirculation) - haemolytic Uraemic syndrome, DIC, malignant hypertension
Infection: Malaria, Sepsis
Paroxysmal Nocturnal Haemoglobinuria
Risk factors: Autoimmune disorders Lymphoproliferative Disorders Prosthetic Heart Valve Family history of haemoglobinopathy or RBC Membrane Defects Paroxysmal Nocturnal Haemoglobinuria
Summarise the epidemiology of haemolytic anaemia
COMMON
Genetic causes are prevalent in African, Mediterranean & Middle Eastern populations
Hereditary spherocytosis: most common inherited haemolytic anaemia in Northern Europe
What are the presenting symptoms of haemolytic anaemia?
Fatigue Pallor Shortness of breath Dizziness Jaundice Haematuria Dark urine
What are the signs on physical examination of haemolytic anaemia?
Jaundice
Pallor
Hepatosplenomegaly
What are the appropriate investigations for haemolytic anaemia?
FBC:
Decreased Hb
Increased reticulocytes, increased MCV, increased unconjugated BR
Decreased haptoglobin (a protein that binds to free Hb released by RBCs)
U&Es: Increased creatinine and urea in Thrombotic Thrombocytopenic Purpura or Haemolytic Uraemic Syndrome
Peripheral Blood Films: Leucoerythroblastic, macrocytosis, nucleated erythrocytes or reticulocytes, polychromasia, specific abnormal cells such as: Spherocytes, Elliptocytes, Sickle Cell, Schistocytes, Malaria Parasites
Urine:
Increased urobilinogen
Haemoglobinuria, Hemosiderinuria
Direct Coombs’ Tests: Tests for autoimmune haemolytic anaemia, identifies erythrocytes coated with antibodies
Osmotic fragility test or Spectrin mutation analysis: Identifies membrane abnormalities
Ham’s Test: Lysis of erythrocytes in acidified serum in Paroxysmal Nocturnal Haemoglobinuria
Hb Electrophoresis or Enzyme Assays: To exclude other causes
Bone Marrow Biopsy (rarely performed): Erythroid Hyperplasia
Define haemolytic uraemic syndrome
A triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney failure. Most commonly diarrhoea-associated and caused by enterohaemorrhagic e.coli, causing a prodrome of bloody diarrhoea and abdominal pain.
Associated with TPP which also has fever and neurological symptoms more than the abdominal and kidney features.
Summarise the aetiology of haemolytic uraemic syndrome
Diarrhoea associated: Enterohaemorrhagic E. coli Shigella Camplyobacter Salmonella
Atypical haemolytic uraemic syndrome:
Genetic mutations
Medication - COCP, Ciclosporin, Mitomycin, 5-Flurouracil
Autoimmune
Other causes: malignant hypertension, malignancy, pregnancy, SLE, scleroderma
Summarise the epidemiology of haemolytic uraemic syndrome
Uncommon
Diarrhoea-positive HUS caused by shiga-toxin producing e. coli most common in CHILDREN
TTP mainly affects adult females
What are the presenting symptoms of haemolytic uraemic syndrome?
Symptoms of e. coli infection:
Bloody diarrhoea
Abdominal pain
Symptoms of MAHA: Pallor Fatigue Jaundice Weakness Lethargy
Symptoms of thrombocytopenia:
Easy bruising
Purpura
Symptoms of acute kidney failure:
Oligo/anuria
Haematuria
TTP:
Fever
CNS changes - visual disturbance, altered mental status
What are the signs on physical examination of haemolytic uraemic syndrome?
Fever Hepatosplenomegaly Pallor Jaundice Purpura Abdominal tenderness Periorbital oedema Peripheral oedema
CNS (especially in TTP): Weakness, reduced vision, fits, reduced consciousness
What are the appropriate investigations for haemolytic uraemic syndrome?
FBC - thrombocytopenia, normocytic anaemia, increased neutrophils
LDH - raised
ESR/CRP - raised
Unconjugated bilirubin - elevated
U+Es - increased urea, creatinine and K+, decrease Na+
PT and PTT - normal
Peripheral blood smear - schistocytes, helmet cells
Urinalysis - haematuria, proteinuria, increased urea and creatinine
Stool culture
