Microcytic anaemia - vWD Flashcards
Define microcytic anaemia
Anaemia associated with a low MCV (< 80 fl).
2 main mechanisms devolving into microcytic anaemia
Defects in either haem or globin synthesis
Causes of microcytic anaemia (4)
• Defects in haem synthesis
Iron deficiency – most common
Can be caused by blood loss (e.g. GI – in Tropics, hookworm is the most common cause of GI blood loss), reduced absorption (e.g. small bowel disease), increased demands (e.g. growth/pregnancy), reduced intakes (e.g. vegans)
Anaemia of Chronic Disease – 2nd most common
Due to poor use of iron in erythropoiesis, cytokine-induced shortening of RBC survival, and reduced production of and response to erythropoietin.
Hepcidin plays a key role
Can occur in many chronic diseases e.g. chronic infection, vasculitis, rheumatoid arthritis, malignancy, renal failure
Sideroblastic Anaemia
Abnormality of haem synthesis
Can be inherited or secondary (e.g. to alcohol/drugs)
• Defects in globin synthesis
o Thalassemia
Explain anaemia of chronic disease
Due to poor use of iron in erythropoiesis, cytokine-induced shortening of RBC survival, and reduced production of and response to erythropoietin.
Hepcidin plays a key role
Can occur in many chronic diseases e.g. chronic infection, vasculitis, rheumatoid arthritis, malignancy, renal failure
S/s of microcytic anaemia (14)
• Non-Specific o Tiredness o Lethargy o Malaise o Dyspnoea o Pallor o Palpitations o Exacerbation of ischaemic conditions (e.g. angina, intermittent claudication)
• Signs of anaemia o Pallor o Brittle nails and hair o Koilonychia (if severe) • Glossitis • Angular stomatitis • Signs of thalassemia
What can lead poisoning cause and what are the s/s 9`10)
• Lead Poisoning - can cause microcytic anaemia Symptoms of lead poisoning o Anorexia o Nausea/Vomiting o Abdominal pain o Constipation
o Blue gumline o Peripheral nerve lesions (causing wrist or foot drop) o Encephalopathy o Convulsions o Reduced consciousness
Ix for microcytic anaemia (9)
Bloods
• FBC: decreased Hb, decreased MCV, Reticulocytes
• Serum iron and serum ferritin (decreases in iron deficiency)
• Total iron binding capacity (increases in iron deficiency)
Blood Film
• 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)
Hb Electrophoresis
• Checking for Hb variants and thalassemia
- Special investigations for iron deficiency anaemia if > 40 years and post-menopausal
- These are considered if no obvious cause of blood loss is identified: Upper GI endoscopy, Colonoscopy, investigations for haematuria
Mx for microcytic anaemia (think 3 main causes)
• Iron Deficiency - oral iron supplements – ferrous fumerate, IV iron can be used if oral ineffective or SEs too much • Sideroblastic Anaemia o Treat the cause o Pyridoxine used in inherited forms o Blood transfusion and iron chelation can be considered if there is no response to other treatments • Lead Poisoning o Remove the source o Dimercaprol o D-penicillinamine
Complications of microcytic anaemia
High output cardiac failure and other complications related to the cause
Define myelodysplasia
A series of haematological conditions characterised by chronic pancytopenia (anaemia, neutropenia, thrombocytopaenia) and abnormal cellular maturation.
There are FIVE subgroups:
- Refractory anaemia (RA)
- RA with ringed sideroblasts (RARS)
- RA with excess blasts (RAEB)
- Chronic myelomonocytic leukaemia (CMML)
- RAEB in transformation (RAEB-t)
What are the five subgroups of myelodysplasia
A series of haematological conditions characterised by chronic pancytopenia (anaemia, neutropenia, thrombocytopaenia) and abnormal cellular maturation.
There are FIVE subgroups:
- Refractory anaemia (RA)
- RA with ringed sideroblasts (RARS)
- RA with excess blasts (RAEB)
- Chronic myelomonocytic leukaemia (CMML)
- RAEB in transformation (RAEB-t)
Explain the pathophysiology of myelodysplasia
- It may be PRIMARY (intrinsic bone marrow problem)
- Or it may arise in patients who have received chemotherapy or radiotherapy for previous malignancies
- Patients may have chromosomal abnormalities
RF of myelodysplasia (5)
- Age > 70 years
- Alkylating Agents
- Topoisomerase Inhibitors
- Prior Haematopoietic Stem Cell Transplantation
- DNA Repair Deficiency Syndromes
Epidemiology of myelodysplasia
- Mean age of diagnosis: 65-75 years old
- More common in MALES
- Twice as common as AML
S/s of myelodysplasia (15)
- Anaemia (fatigue, dizziness)
- Neutropoenia (recurrent infections)
- Thrombocytopaenia (easy bruising, epistaxis)
- Anaemia (pallor, cardiac flow murmur)
- Neutropoenia (infections)
- Thrombocytopaenia (purpura or ecchymoses)
- Gum hypertrophy
- Splenomegaly, Hepatomegaly, Lymphadenopathy (RARE except in chronic myelomonocytic leukaemia CMML)
Ix for myelodysplasia (3)
Bloods
• FBC: pancytopenia
Blood Film • Normocytic or macrocytic Red Cells • Variable microcytic Red Cells in RARS • Low granulocytes • Granulocytes are not granulated • High monocytes in CMML
Bone Marrow aspiration or biopsy • Hypercellularity • Ringed siderblasts • Abnormal granulocyte precursors • 10% show marrow fibrosis
Define myelofibrosis
• Disorder of haematopoietic stem cells characterised by progressive bone marrow fibrosis associated with extramedullary haematopoiesis and splenomegaly
Explain the pathogenesis of myelofibrosis
o There is hyperplasia of megakaryocytes
o Abnormal megakaryocytes release cytokines, like platelet-derived growth factor, that stimulate fibroblast proliferation and collagen deposition in bone marrow
o This results in extramedullary haematopoiesis in the spleen and liver – causing massive hepatosplenomegaly
Epidemiology of myelofibrosis
- RARE
* Peak onset: 50-70 yrs
Associations with what other disease does myelofibrosis have
30% have previous Hx with polycythaemia rubra vera or essential thrombocytopaenia
RF of myelofibrosis (3)
- Radiation Exposure
- Industrial Solvents Exposure
- Age > 65 years
S/s of myelofibrosis (18)
o COMMON: • Weight loss • Anorexia • Fever • Night sweats • Pruritis • Abdominal discomfort o UNCOMMON: • LUQ pain • Indigestion (due to massive splenomegaly) • Bleeding • Bone pain • Gout • Infections
- SPLENOMEGALY
- Hepatomegaly (present in 50-60%)
- Pallor, petechiae, haemarthrosis, blood on PR
Ix for myelofibrosis (5)
Bloods
• FBC: Initially variable Hb, WCC and platelets.
• Later stage FBC: Anaemia, Leukopaenia, thrombocytopaenia
• LFTs - abnormal
Blood Film
• Leucoerythroblastic changes (red and white cell precursors in the peripheral blood)
• ‘Tear drop’ poikilocyte red cells
Bone Marrow Aspirate or Biopsy
• Aspiration usually unsuccessful - ‘dry tap’ (due to fibrosis)
• Trephine biopsy shows fibrotic hypercellular marrow, (dense reticulin fibres on silver staining)
Define normocytic anaemia
Anaemia with a normal MCV (80-100fl).
5 general causes of normocytic anaemia
- Acute blood loss
- Failure of RBC production
- Haemolysis (can be macrocytic)3
- Uncompensated increase in plasma volume
- Pooling of red cells in the spleen
Causes of decreased RBC production leading to normocytic anaemia (7)
Bone marrow failure or suppression e.g. aplastic anaemia, chemotherapy
Bone marrow infiltration e.g. malignancy
Renal failure – abnormal erythropoietic drive
Early stages of iron deficiency or anaemia of chronic disease
Hypothyroidism (can be macrocytic)
Vitamin B2 deficiency
Vitamin B6 deficiency
S/s of normocytic anaemia (8)
Typical signs and symptoms of anaemia (depends on severity)
- Breathlessness
- Fatigue
- Dizziness
- Conjunctival Pallor and pallor
- Heart Palpitations
- Tachycardia
- Heart Murmur
- Signs of heart failure i.e. oedema and pleural effusion
Ix for normocytic anaemia (7)
Bloods
• FBC: Normal MCV, decreased Hb, decreased Haematocrit
• TFTs: decreased T3/T4 (if hypothyroidism is a cause of anaemia)
Peripheral Blood Smear:
• Target Cells
• Spherocytes
• Elliptocytes
Others include screening for:
• Renal Insufficiency (U&Es)
• Subclinical Infections
• Autoimmune diseases and neoplasias
Define polycythaemia and the difference between relative and absolute (true) polycythaemia
An increase in haemoglobin concentration above the upper limit of normal for a person’s age/sex.
- Relative Polycythaemia = normal red cell mass but low plasma volume
- Absolute (True) Polycythaemia = increased red cell mass
What is primary polycythaemia vera known as
• Polycythaemia Rubra Vera
Define the characteristics of polycythaemia rubra vera and the mutation involved
o Characterised by clonal proliferation of myeloid cells
o They have varied morphologic maturity and haematopoietic efficiency
o Mutations in JAK2 tyrosine kinase are involved
What is secondary polycythaemia
increase in EPO
What can cause appropriate secondary polycythaemia vera (2)
- Due to chronic hypoxia (e.g. chronic lung disease, living at high altitude)
- This leads to upregulation of erythropoiesis
What can cause inappropriate secondary polycythaemia vera (7)
- Renal (carcinoma, cysts, hydronephrosis)
- Hepatocellular carcinoma
- Fibroids
- Cerebellar haemangioblastoma
- Secondary polycythaemia may be due to erythropoietin abuse by athletes
Causes of relative polycythaemia (4 acute, 5 chronic)
o May be acute – due to dehydration (e.g. diuretics, burns, enteropathy, alcohol)
o Chronic form associated with obesity, hypertension, high alcohol and tobacco intake
o Gaisbock’s syndrome
• Occurs in young male smokers with hypertension, which results in a decrease in plasma volume and an apparent increase in red cell count
Epidemiology of polycythaemia vera (age)
- Annual UK incidence: 1.5/100,000
* Peak age: 45-60 yrs
S/s of polycythaemia vera (16)
- CNS: Headaches, blurred vision
- 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
- Plethoric Complexion: facial redness
- Scratch marks as a result of itching
- Conjunctival suffusion (redness of the conjunctiva)
- Retinal venous engorgement
- Hypertension
- Splenomegaly
- Signs of Underlying causes in 2o Polycythaemia
RF of polycythaemia vera
- Age > 40 years
- Bud-Chiari Syndrome
- Family history
Ix for polycythaemia vera (specific to polycythaemia rubra vera and secondary)
FBC: Required for Diagnosis
• High Hb
• High haematocrit
• Low MCV
Isotope Dilution Techniques
• Allows confirmation of plasma volume and red cell mass
• Distinguishes between relative and absolute polycythaemia
Polycythaemia Rubra Vera • High WCC • High platelets • Low serum EPO • JAK2 mutation • Bone marrow trephine and biopsy shows erythroid hyperplasia and raised megakaryocytes
Secondary Polycythaemia
• High serum EPO
• Exclude Chronic Lung Disease/Hypoxia
• Check for EPO-secreting Tumours (CT Abdo, Brain MRI)
Define sickle cell disease
• A chronic autosomal recessive condition with sickling of red blood cells caused by inheritance of haemoglobin S (HbS)
o Sickle Cell Anaemia = Homozygous HbSS
o Sickle Cell Trait = Carrier of one copy of HbS
Causes no disability (except in hypoxia e.g. anaesthesia – may cause vaso-occlusive event) and protects from falciparum malaria
o Sickle Cell Disease = includes compound heterozygosity for HbS and:
• HbC (abnormal haemoglobin in which glutamic acid is replaced by lysine at the 6th position in the beta-globin chain) - HbSC
• Beta-thalassemia – HbS/Bthal
What is the mutation in sickle cell anaemia
- Autosomal Recessive Trait
- Point mutation in the beta-globin gene (glutamic acid valine) abnormal HbS
- Deoxygenation of HbS alters the conformation resulting in sickling of red cells
What is the issue with sickle red blood cells
o Sequestration and destruction (reduced red cell survival ~ 20 days)
o Occlusion of small blood vessels causing hypoxia, which leads to further sickling and occlusion
Factors that precipitate sickling (4)
I HAD o Infection o Dehydration o Hypoxia o Acidosis
Why does sickle cell rarely present before 4-6 months
• Rarely presents before 4-6 months (because HbF can compensate for the defect in adult haemoglobin)
Epidemiology of sickle cell anaemia
• Common in Africa, Caribbean, Middle-East and other areas with a high prevalence of malaria
S/s of sickle cell anaemia due to vaso-occlusion or infarction (13)
- Auto splenectomy (splenic atrophy or infarction): Leads to increased risk of infections with encapsulated organisms (e.g. pneumococcus, meningococcus) Bones
- Painful crises affect small bones of hand & feet – causing dactylitis in CHILDREN
- Painful crises MAINLY affect the ribs, spine, pelvis & long bones in ADULTS
- Abdominal Pain
- Myalgia and Arthralgia
- CNS - Fits and strokes (hemiplegia)
- Retina - Visual loss (proliferative retinopathy)
o Bone - joint or muscle tenderness or swelling (due to avascular necrosis)
o Short digits - due to infarction in small bones of the hands
• Retina - cotton wool spots due to retinal ischaemia
S/s of sickle cell anaemia due to sequestration crisis (9)
o NOTE: sequestration crises occur due to pooling of red cells in various organs (mainly the spleen). Mainly affects children as spleen has not yet undergone atrophy. o Liver --> exacerbation of anaemia o Lungs --> acute chest syndrome • Breathlessness • Cough • Pain • Fever o Corpora cavernosa • Persistent painful erection (priapism) • Impotence • Symptoms of APLASTIC ANAEMIA: due to parvovirus B19 with sudden reduction in marrow production, especially RBCs Anaemia and infection
• Signs secondary to SEQUESTRATION CRISES
o Organomegaly
• The spleen is ENLARGED in early disease
• Later on, the spleen will reduce in size due to splenic atrophy
o Priapism
• Signs of anaemia
Ix for sickle cell disease
• Bloods o FBC • Low Hb • Reticulocytes: HIGH - in haemolytic crises LOW - in aplastic crises o U&Es • Blood Film o Sickle cells
o Anisocytosis (variation in size of red cells)
o Features of Hyposplenism:
• Target cells
• Howell-Jolly bodies
• Sickle Solubility Test
o Dithionate is added to the blood
o In sickle cell disease you get increased turbidity
• Haemoglobin Electrophoresis
o Shows HbS
o Absence of HbA (if homozygous HbS)
o High HbF
• Hip X-Ray
o Femoral head is a common site of avascular necrosis
• MRI or CT Head
o If there are neurological complications
When are reticulocytes high and when are they low in sickle cell anaemia
HIGH - in haemolytic crises
LOW - in aplastic crises
How can an aplastic crisis occur in sickle cell anaemia
• Aplastic crises
o Infection with Parvovirus B19 can lead to a temporary cessation of erythropoiesis (which can cause red cell count to plummet in sickle cell patients because their red cells have a shortened life span and can’t tolerate a cessation of erythropoiesis)
Sickle cell anaemia differentials
Gout
Septic arthritis
Connective tissue disease
Mx for sickle cell disease acutely (6)
• ACUTE (PAINFUL CRISES) o Oxygen o IV Fluids o Strong analgesia (IV opiates) o Antibiotics o Cross match blood o Give transfusion if Hb or reticulocytes fall sharply
Mx for sickle cell anaemia infection prophylaxis
• Infection Prophylaxis – as splenic infarction leads to hyposplenism
o Penicillin V
o Regular vaccinations (particularly against capsulated bacteria e.g. pneumococcus
Mx for sickle cell anaemia frequent crises
• Hydroxyurea/Hydroxycarbamide – if frequent crises
o Increases HbF levels
o Reduces the frequency and duration of sickle cell crisis
Mx for sickle cell anaemia surgical
• Surgical
o Bone marrow transplantation – may be curative
o Joint replacement in cases with avascular necrosis
When is a red cell transfusion, hydroxyurea, or folic acid indicated in sickle cell anaemia
• Folic Acid
o If severe haemolysis or in pregnancy
• Hydroxyurea/Hydroxycarbamide – if frequent crises
o Increases HbF levels
o Reduces the frequency and duration of sickle cell crisis
• Red Cell Transfusion
o For SEVERE anaemia
o Repeated transfusions (with iron chelators) may be required in patients suffering from repeated crises
Complications of sickle cell anaemia (13)
• Aplastic crises o Infection with Parvovirus B19 can lead to a temporary cessation of erythropoiesis (which can cause red cell count to plummet in sickle cell patients because their red cells have a shortened life span and can't tolerate a cessation of erythropoiesis) • Infection • Poor growth in children • Chronic renal failure • Haemolytic crises • Pigment gallstones • Retinal disease • Cholecystitis • Renal papillary necrosis • Leg ulcers • Cardiomyopathy • Iron overload from repeated transfusion • Lung damage
Prognosis of sickle cell anaemia and usual reason for mortality
• Most patients with sickle cell disease who manage their disease well will survive until around the age of 50 yrs
• Mortality is usually the result of:
o Pulmonary or neurological complications in ADULTS
o Infection in CHILDREN
Define thalassemia and what the problem is in it and mode of inheritance
- A group of genetic disorders characterised by reduced globin chain synthesis
- There is under or no production of one globin chain
- Unmatched globins precipitate, damaging RBC membranes causing their haemolysis whilst still in the marrow
- Autosomal recessive
What does thalassemia result in
Result in an imbalance of globin chain production and deposition in erythroblasts and erythrocytes
4 main things thalassemia leads to
o Ineffective erythropoiesis
o Haemolysis
o Anaemia
o Extramedullary haematopoiesis
What are the 2 types of thalassemia and the 4 and 3 sub-types of each and what they result in
o ALPHA THALASSEMIA - reduction in alpha-globin chain synthesis. There are FOUR alpha-globin genes on the chromosome.
• 4 gene deletion = Haemoglobin Barts Hydrops Fetalis (intrauterine death)
• 3 gene deletion = Haemoglobin H microcytic hypochromic anaemia and splenomegaly
• 2 gene deletion = Alpha 0 thalassemia microcytic hypochromic red cells, NO ANAEMIA
• 1 gene deletion = Alpha+ thalassemia microcytic hypochromic red cells, NO ANAEMIA
o BETA THALASSEMIA
• Beta Thalassemia Major (homozygous beta thalassemia) little or no beta-chain synthesis
• Beta Thalassemia Intermedia - mild defect in beta-chain synthesis due to a variety of causes, e.g. co-inheritance of beta thalassemia trait with another haemoglobinopathy like HbC, leads to:
Microcytic anaemia
Reduced alpha-chain synthesis
Increased gamma-chain synthesis
• Beta Thalassemia Trait (heterozygous carrier state)
ASYMPTOMATIC
Mild microcytic anaemia
Increased red cell count
Epidemiology of thalassemia
- WORLDWIDE
* Most common in the MEDITERRANEAN and areas of the Middle-East
S/s of thalassemia (10)
• Beta Thalassemia Major o Severe anaemia o Presenting at 3-6 months • This is when the change from HbF to HbA takes place • Failure to thrive • Prone to infection • Alpha or Beta Thalassemia Trait o May be ASYMPTOMATIC o Detected during routine blood tests or due to family history
• Beta Thalassemia Major
o Pallor
o Malaise
o Dyspnoea
o Mild jaundice
o Extramedullary haematopoiesis occurs in response to anaemia causing frontal bossing and hepatosplenomegaly
o Thalassaemia facies (facial features caused by marrow hyperplasia)
o Hepatosplenomegaly (due to erythrocyte pooling and extramedullary haematopoiesis) o Patients with beta-thalassemia intermedia may also have these signs
Ix for thalassemia
Bloods
• FBC: Low Hb, low MCV (microcytic anaemia), low MCH
Blood Film • Hypochromic microcytic anaemia • Target cells • Nucleated red cells • High reticulocyte count
Hb Electrophoresis
• Absent or reduced HbA
• High HbF
Bone Marrow
• Hypercellular
• Erythroid hyperplasia
Genetic Testing (rarely used)
Skull X-Ray
• ‘Hair on end’ appearance in beta thalassemia major
• This is caused by expansion of marrow into the cortex
What is the mechanism and location of B12 absorption
- B12 is found in meat and animal protein foods
- Absorption occurs in the terminal ileum
- Absorption requires intrinsic factor (produced by gastric parietal cells)
What does IF do
Bind to vitamin B12 to allow it to be absorbed
Causes of B12 deficiency (10)
Pernicious anaemia
- Gastric: gastrectomy, atrophic gastritis
- Inadequate intake (e.g. vegan)
- Intestinal: malabsorption, ileal resection, Crohn’s affecting terminal ileum, tropical sprue
- Drugs - colchicine, metformin
Drugs that can cause B12 deficiency (2)
Metformin, colchicine
What does pernicious anaemia involve (basic)
Pernicious anaemia is an AI condition involving:
- Gastritis
- Atrophy of all layers of the body and fundus of the stomach
- Loss of normal gastric glands, parietal and chief cells
- Lack of intrinsic factor
RF of B12 deficiency (9)
- Age > 65 years
- Gastric Surgery
- Chronic GI Disease
- Vegan Diet
- Metformin Use
- PPI/H2 antagonist use or H. pylori infection
- Anticonvulsant use
- Diabetes mellitus
- Pregnancy
S/s of B12 deficiency
Typical anaemia symptoms: Fatigue, Lethargy, SOB, Faintness, Palpitations, Headache
Neurological Symptoms
- Paraesthesia (may be an early & subtle symptom of neurological damage)
- Numbness
- Cognitive changes
- Visual disturbances
- Pallor (late sign)
- Heart failure (can occur with severe anaemia)
- Glossitis (late sign)
- Angular stomatitis
- Petechiae (late sign)
- Positive Romberg’s Test
- Decreased Vibration Sense
- Ataxia
- Neuropsychiatric: irritability, dementia, depression
Define VWD and the types
• Von Willebrand’s disease is a bleeding disorder which may present with mucocutaneous bleeding (mouth, epistaxis, menorrhagia), increased bleeding after trauma and easy bruising
o Type 1 - the von Willebrand factor works well but there isn’t enough of it
60-80%, mild symptoms, autosomal dominant
o Type 2 - there are normal levels of von Willebrand factor but it is abnormal and doesn’t function correctly
20-30%, bleeding tendency varies amongst the 4 subtypes, usually autosomal dominant
o Type 3 - there is NO von Willebrand factor
1-5%, severe symptoms, autosomal recessive
What are vWF’s 3 roles
To bring platelets into contact with exposed subendothelium
To make platelets bind to each other
To bind to factor 8, protecting it from destruction in the circulation
What inheritance pattern does vWD follow
Autosomal dominant
S/s of vWD (7)
- Easy bruising
- Epistaxis - hard to stop
- Prolonged bleeding from gums after dental procedures
- Heavy or prolonged menstrual bleeding – menorrhagia
- Blood in stools – haematochezia
- Blood in urine – haematuria
- Heavy bleeding from a cut or other accident
Ix for vWD (6)
• Bleeding time - HIGH
• APTT - HIGH
Usually normal PT
• Factor VIII - LOW
• vWF Ag - LOW in type 1 and 3, normal in type 2
• INR and platelets – normal
• Ristocetin cofactor – normal in type 2, abnormal in type 1 and 3
