Haem - general Flashcards
Anaemia in men + women
Men Hb <130 g/lWomen Hb <120 g/l
Men: 135-180 g/l (180-135=45)
Women: 115-160 g/l (160-115=45)
Alpha defect in thalassaemia on chromosome
Chr 16
Beta defect in thalassaemia on chromosome
Chr 11
Sickle cell anaemia inheritance
AR
point mutation β globin gene on Chr 11
What kind of anaemia does hypothyroidism cause?
Macrocytic anaemia which is non-megaloblastic
Causes of macrocytic anaemia
B12 deficiency deficiency
- Alcohol
- IBD + Coeliac
- Bariatric surgery
- Malnutrition (meat is the predominant source of vit B12)
- Pernicious anaemia (AI loss of parietal cells +/or IF )
Folate deficiency
- Alcohol
- IBD + Coeliac
- Anti-folate drugs
- Pregnancy
Myelodysplasia, hypothyroidism, liver disease, haemolysis, alcohol, B12 deficiency, folate deficiency
Causes of HUS
- E coli strain EO157:H7
Organisms proliferate in undercooked red meat, unpasteurized milk or milk products, water, fruits, and vegetables.
Rarely - shigella, strep. pneumoniae, genetics
Which Von Willebrand Factor cleaving protein (VWFCP) is mutated in thrombotic thrombocytic purpura?
ADAMTS-13
Deficiency of VWF cleaving enzyme (ADAMTS-13) –> unusually large VW multimers –> platelet aggregation –> thrombocytopenia + thrombi
ITP definition
Primary ITP Immune thrombocytopenic purpura
• Autoimmune haematological disorder
• Isolated thrombocytopenia (<100x10^9/L) in the absence of an identifiable cause
• Antibody-mediated destruction of peripheral platelets, antibody-mediated inhibition of platelet production
ITP in children
Happens following a viral infection or following immunisation (CMV, VZ, HCV, HIV)
What is Hodgkin’s Lymphoma?
- Uncommon haematological malignancy arsing from mature B cells
- Malignant tumour of the lymphatic system
- Characterised by the presence of Hodgkin’s cells + multinucleated giant cells (Reed-Sternberg cells)*
Happens following an infection
RF • Epstein-Barr virus infection - implicated in around 50% of cases • HIV • Immunosuppression • Smoking • FHx
*Reed strenberg cells = giant cells derived from B lymphocytes containing >2 oval nuclei with eosinophilic nuclei resembling “owl eyes”
Hodgkin’s lymphoma epidemiology
- Young adults
* Peak in 20-34, second peak in >70
Non-Hodgkin’s lymphoma epidemiology
- > 50
- M>F
- More common than Hodgkin’s lymphoma
- The 2 most common types of NHL are diffuse large B cell lymphoma and follicular lymphomas
Which species causes the most severe malaria?
How is it transmitted?
When do patients present?
Plasmodium falciparum
o Transmitted to humans through a bite by an infected female Anopheles mosquito
o Patients present within the 1st month or within the first 6 months of infection
What is the myelodysplastic sydrome?
- Dysplastic changes in one or more cell lineages
- Ineffective + dysplastic haematopoiesis resulting in 1 or more cytopenias
- Blasts <20%
- Variable predilection to development of acute myeloid leukaemia (AML if blasts >20% (incl 20%))
• The bone marrow
Becomes hypercellular
With disordered growth
Maturation of a clonal proliferation of abnormal cells
Extrinsic pathway of the clotting cascade
How is it measured
Normal value
Affected by
PT
14s
Warfarin, Liver disease
Intrinsic pathway of the clotting cascade
How is it measured
Normal value
Affected by
APTT
34s
Heparin, Haemophilias, von Willebrand disease
Platelet deficiency causes
petechial haemorrhages
Ecchymoses
Clotting factor deficiency produces
haematomas + hemarthroses
Which clotting factor is deficient in haemophilia A?
F VIII
Which clotting factor is deficient in haemophilia B?
F IX
How is haemophilia inherited?
X-linked recessive disorder
therefore it affects MALES born to carrier mothers
Which is the most common haemophilia?Which is the most severe haemophilia?
Haemophilia A
Pathophysiology of haemochromatosis
Deficiency of hepcidin
HFE gene mutations on the short arm of Chr 6
Known mutations of the HFE gene are C282Y and H63D (must be homozygous)
Increased intestnal absorption of iron causes accumulation in tissues , esp liver
This can lead to organ damage
normally hepcidin prevents enterocytes from allowing iron into the hepatic portal system, thereby reducing dietary iron absorption
RF for ALL
- Insulation from common infections in early life may predispose children to abnormal immune responses when they encounter them later, placing them at higher risk of developing ALL
RF for AML
Radiation
Benzene
Chemo
Constitutional karyotype abnormalities (T21, XXY, T13 (Patau’s syndrome)T8:21, inverted 16)
RF for CLL
What conditions is it assosicated with?
What can it transform to?
FHx
- Can be associated with AI thrombocytopenia + anaemia
- Can transform to aggressive NHL – Richter’s syndrome
RF for CML
T9:22 transolcation –> shortened Chr22 –> Philadelphia chromosome (encodes for a protein with tyrosine kinase activity)
Transolaction places an oncogene (abl) from the long arm of Chr 9 to the long arm of Chr 22 in the BCR region
BCR-ABL - causes an abnormal expansion of the myeloid cells in the BM + peripheral blood
Most common leukaemia in children
ALL
Acute lymphoblastic leukaemia
Multiple myeloma definition
Plasma cell disorder
Infiltration of the bone marrow by plasma cells
Presence of a monoclonal immunoglobulin in the serum +/or urine
Classified by the type of ab they produce
IgG myeloma is the most common type
Malignant proliferation of plasma cells that secrete monoclonal antibodies + light immunoglobulin chains
What causes renal impairement in multiple myeloma?
Light chains (Bence Jones’ proteins) precipitate out as casts in the distal tubule, causing tubular obstruction + tubulo-interstitial inflammation + AKI
Other causes of renal impairement in patients with myeloma
- Amyloid deposition
- Dehydration
- Hypercalcaemia
- Hyperviscosity
- Nephrotoxic drugs
Sickle cell disease pathophysiology
• AR
Amino acid glutamic acid (hydrophilic) is replaced by valine (hydrophobic) at position 6 in the beta globin chain
This causes the RBC to sickle in acidosis, hypoxia, dehydration
Sickling causes vasoocclusion + haemolysis (intravascular + extravascular)
On which chromosome are the genes that are mutated in Thalassaemia A?
Chr 16
Two copies of α genes on each chromosome 16
On which chromosome are the genes that are mutated in Thalassaemia B?
Chr 11
One copy of β gene on each chromosome 11
How is thalassaemia inherited and what is the pathophysiology?
AR inheritance
Deceased/absent synthesis of one of the two polypeptide chains (α or β) that form HbA
Function of VWF
o Assists in platelet plug formation by attracting circulating platelets to the site of damage (exposed vascular subendothelium)
o Binds to coagulation factor VIII preventing its clearance from the plasma
Difference bn VWD + haemophilia
- VWD F>M (as opposed to haemophilias were Males are always affected)
- In VWD patients might present later in life, in haemophilia the defect is usually apparent in infancy
- VWD usually presents with mucocutaneous bleeding as opposed to haemophilias which present with musculoskeletal bleeding
Which are the different types of VWD
o Type 1 - quantitative defect AD, reduced VWF
60-80% of all cases
Normal lifespan
Occasionally easy bruising +/or menorrhagia
Bleeding after dental work, major surgery
o Type 2 - qualitative defect (multimers abnormal or subgroups absent) AD, defective VWF
20-30% of all cases
Bleeding tendency varies
o Type 3 - quantitative defect AR, complete absence of VWF, low FVIII
1-5% of cases
no vWF antigen, low F VIII
Severe mucosal bleeding
May have hemarthrosis (as in haemophilia)
I heterozygous (AD) for gene defect, reduced levels of vWF II normal vWF levels but structurally abnormal IIA abnormality in synthesis of vWF or with proteolysis IIB increased function of vWF, leading to spontaneous platelet binding III homozygous (AR) for gene defect resulting in severe bleeding tendencies
Classifications of polycythaemia
Primary Polycythaemia vera
Secondary
Appropriate (hypoxia in e.g. COPD, smoking)
Inappropriate (EPO secreting tumour e.g. kidney, hepatocellular carcinomas)
Fluid loss (dehydration, severe burns - decrease in plasma volume causes apparent increase in RBC mass)
Polycythaemia vera might evolve into
Myelofibrosis (spent phase of PV) (30%) Secondary AML (5%)
Which are the 2 phases of PV
Blast phase
BM produces lots of RBC because of JAK2 V617F mutation that stimulates they haematopoietic cell to produce RBC
Spent phase RBC start to die out + form scar tissue within the BM BM can no longer produce RBC Anaemia - decreased RBC levels Thrombocytopenia - decreased plt levels Leukopenia - decreased WBC levels This is MYELOFIBROSIS
PV complications
Prone to blood clots • Stroke • Heart attack • DVT • Budd-Chiari syndrome – when it occurs, it raises suspicion of PV
Which muatted gene produces antiphospholipid ab?
HLA DR7
Antiphospholipid syndrome epidemiology
- Young females
- Venous Thrombosis most common in females – DVT, PE
- Arterial thrombosis most common in males – MI, stroke, limb ischaemia, libman sacks endocarditis (vegetations (mixture of immune cells + blood clots) form on the mitral valve)
- Typical history – young adults (<50) with ischaemic stroke, women with recurrent miscarriages, young patient presenting with arterial thrombosis in any vessel
Which factor initiates the clotting process
F VII initiates the clotting process due to tissue damage
How to reverse
a) warfarin
b) heparine
warfarin - vitamin K
Heparin - protamine sulphate
Aplastic crisis cause
Parvovirus B19 infection
Sickle cell anaemia
Hereditary spherocytosis
Which are the 3 microangiopathic haemolytic anaemias
DIC
TTP
HUS
What is promyelocytic leukaemia
- Subtype of AML
- Very aggressive
- T(15;17)
- Associated with DIC
Difference bn CLL and CML
CLL
• Accumulation of mature incompetent lymphocytes (unable to undergo apoptosis)
CML
• Uncontrolled proliferation of granulocyte precursors in BM but in slower progression than AML
Describe the 3 phases of CML
o Chronic (<5% blasts) - responsive to treatment
o Accelerated – increased BM/peripheral blasts, increased BM/peripheral basophils + eosinophils, resistance to therapy, increased constitutional symptoms, progressive splenomegaly, leucocytosis, thrombocytosis/thrombocytopenia (10-19% blasts)
o Blast crisis/blastic phase – severe constitutional symptoms due to tumour burden (weight loss, fever, night sweats, bone pain) (>20% blasts) [disease progresses into an acute leukaemia usually AML]
What is Burkitt’s lymphoma
Burkitt’s lymphoma • Subtype of NHL (B cell) • EBV • African child • Large lesion in the jaw (fast growing) • Under microscopy – starry sky appearance
What is monoclonal gammopathy of unknown significance
Monoclonal gammopathy of unknown significance
• Pre-malignant condition – accumulation of some monoclonal plasma cells
• 1% acquire additional mutations – MM
• Absent CRAB features
What can precipitate DIC?
Sepsis (esp children with meningococcal septicaemia)
Trauma
Obstetric complications
Malignancy
Incompatible blood transfusion, transplant rejection
Severe liver disease, pancreatitis
• Anaemia with increased reticulocyte count
vs
• Anaemia with decreased reticulocyte count
• Anaemia with increased reticulocyte count
haemolytic crises
(ddx: haemorrhage) [response to breaking down RBC or losing them]
• Anaemia with decreased reticulocyte count
parovirus B19 infection
aplastic crisis in patients with sickle cell anaemia
blood transfusion
B12 deficiency
Dx for normocytic anaemia + reticlocytosis + spherocytosis + jaundice
Haemolytic anaemia due to
a) Hereditary spehrocytosis
b) Autoimmune haemolytic anaemia
(increased reticulocytes suggest haemolysis, spherocytes present in hereditary spherocytosis + autoimmune haemolytic anaemia)
carry out Coomb’s test to differentiate bn the 2 (Coomb’s test positive in autoimmune haemolytic anaemia, negative in spherocytosis)
What is aplastic anaemia?
pancytopenia (anaemia + leukocytopenia + thrombocytopenia)
Autoimmune destruction of the hematopoietic stem cells
HLA-DR2
(do not confuse with aplastic crisis that happens in sickle cell disease + hereditary spherocytosis as a result of parvovirus B19 infection – in this case aplastic crisis means BM failure to produce erythrocytes alone)
RF for aplastic anaemia
o Genetic disorders – Fanconi’s anaemia (pancytopenia, predisposition to malignancy, short stature, microcephaly, developmental delay, café au lait skin lesions, absent/hypoplastic thumbs)
o Environmental agents -Drugs chemotherapeutic agents NSAIDs (indomethacin) anti-seizure medications antithyroid medications (propylthiouracil, methimazole) antibiotics (chloramphenicol, sulphonamides)) -Hepatitis -Infectious agents (EBV, HIV) -Toxins (insecticides) -Industrial agents that contain benzene -Radiation
Causes of macrocytic megaloblastic anaemia
o Vitamin B12 deficiency
o Folate
Causes of macrocytic non megaloblastic anaemia
(Alcoholics May Have Liver Failure) o Alcohol o Liver disease o Hypothyroid o Myelodysplasia o Acute leukaemia
Tear drop shaped cells
Myelofibrosis Pernicious anaemia Thalassaemia Polycythemia vera ACD
Bleeding after an infection
Think ITP
Hallmark of ITP - isolated thrombocytopenia
- FBC - isolated thrombocytopenia
- Blood film
Difference between ITP + TTP
ITP - normal morphology of RBC
TTP - fragmented RBC - schistocytes
A 35-yo man presents with multiple bruises on his arms. He is deeply jaundiced and has recently been found to have gallstones + a dilated biliary tree on US examination
Abnormalities of the following clotting factors are likely to be responsible for his bruising except
F II F VII F IX F X F V
F V
Vitamin K - fat soluble vitamin, requires bile salts for absorption
Necessary for the activity of PT, F 2, 7, 9, 10
Deficiency - impaired coagulation activity
Von Willebrand factor gene found on Chr
12
Relative polycythaemia
vs
Absolute polycythaemia
Relative polycythaemia – normal cell mass but reduced plasma volume
Absolute polycythaemia – increased red cell mass
Causes of Microcytic anaemia
Microcytic anaemia – TAILS Thalassaemia ACD Iron deficiency anaemia Lead poisoning Sideroblastic anaemia Sideroblastic anaemia – inability of haem synthesis resulting in the inability to incorporate iron in Hb
Causes of Macrocytic anaemia
Macrocytic anaemia Myelodysplasia Hypothyroidism Liver disease Haemolysis Alcohol B12 deficiency Folate deficiency
Causes of normocytic anaemia
Normocytic anaemia MR I CAALMM Marrow failure Renal failure Iron deficiency (early) ACD (early) Aplastic anaemia Acute blood loss Leukaemia Myelofibrosis MM Sickle cell
What type of anaemia do they cause
Myelodysplasia
Myelofibrosis
MM
Myelodysplasia - macrocytic
Myelofibrosis - normocytic
MM - normocytic
Schistocytes present in
Microangiopathy haemolytic anaemias (MAHA) - HUS, DIC, TTP
Macroangiopathic haemolytic anaemias - aortic stenosis, prosthetic heart valves, infections
What is the most appropriate investigation to determine iron store levels?
Serum ferritin as it originates from the storage pools in the BM, spleen, liver
Only accurate when CRP levels are normal since ferritin is an acute phase protein
Transfusion complications buzzwords
Tissue related lung injury
Immediate haemolytic transfusion reaction
Delayed haemolytic transfusion reaction
IgA deficiency
Febrile non-haemolytic transfusion reaction
Tissue related lung injury
2-6h after tranfusion
fever, hypotension, cyanosis, pulmonary oedema
Immediate haemolytic transfusion reaction
Hypotension, tachycardia, abdominal pain, loin pain, nausea, SOB, pain, fever
<24h (occurs within minutes of transfusion)
Delayed haemolytic transfusion reaction
similar as above
>24h
IgA deficiency
Anaphylactic type reaction
bronchospasm, laryngeal oedema, hypotension
Febrile non-haemolytic transfusion reaction
history of previous blood transfusions, pregnancy
How to differentiate between AML + ALL
Sudan black B preferentially stains myeloblasts against lymphoblasts - useful in differentiating between AML + ALL
Sudan black will stain cells in AML but not in ALL
Myeloperoxidase staining
ALL Lack staining for myeloperoxidase
ALL Will not have granules in the cytoplasm (compared to AML)
ALL stains with periodic acid achiff stain
Sudan black B + flow cytometry are the most appropriate ix
Leukocyte ALP raised in, low in
Raised in
PCV, myelofibrosis, essential thrombocytopenia
Low in
CML, paroxysmal nocturnal haemoglobinuria
EPO + RBC mass in
A. renal failure
B. BM failure
C. RCC
D. Polycythaemia vera
A Low erythropoietin and low red cell mass
B Raised erythropoietin and low red cell mass
C Raised erythropoietin and raised red cell mass
D Low erythropoietin and raised red cell mass
Difference bn Aplastic crisis and sequestration crisis
• Aplastic crisis has reduced reticulocytes, whereas sequestration crisis has increased reticulocytes
