Haematology Flashcards
What does normal adult Hb consist of? (HbA)
4 globin chains- 2 alpha and 2 gamma
4 haem molecules - one in each chain
In what chain is there a mutation that leads to sickle cell?
Beta chain
What is part of the clinical syndrome of sickle cell disease?
Painful crises
Systemic vasculopathy
End organ damage
Reduced life expectancy
What is the pathology behind thalassemia?
Reduced or absent production of beta or alpha chains leading to imbalance in the chains - ineffective erythropoiesis
What clinical features may be seen in thalassemia?
Effects of anaemia
Effects of iron overload in those with many transfusions
What is the genetic mutation that occurs in sickle cell disease?
Substitution of glutamate by valine in position 6 of the beta globin chain
What mode of inheritance is sickle cell disease?
Autosomal recessive
Do people who are sickle cell carriers experience symptoms?
No
What is the pathophysiology of sickle cell disease?
Polymerisation of the haemoglobin leads to deoxygenation and dehydration and sickling of the RBC leading to vaso-occlusion, infarction and haemolyisis
What are precipitating factors for a sickle cell crisis?
Hypoxia High HbS concentration (possibly via dehydration) Acidosis Infection Skin cooling Stress
What complication can arise post reperfusion after a sickle cell crisis?
Free radical damage
What are positive lab findings in sickle cell disease?
Anaemia
Haemolysis- high bilirubin, high LDH, high reticulocytes and undetectable haptoglobin
Blood film showing sickle cells
Hb electrophoresis
Hb solubility test - turns opaque if positive
What are the emergency presentations of sickle cell disease?
Acute chest syndrome Overwhelming sepsis Painful acute crisis Acute deterioration of anaemia (aplastic crisis or sequestration) Acute visual loss Priaprism Renal impairment Acute chest syndrome Fat embolism syndrome/ multi organ failure Stroke
How does a sickle cell crisis present?
Rapid onset bone pain due to bone marrow infarct
Variable severity and duration - can last hours to weeks
Fever and bone tenderness
+- swelling, hypertension, tachycardia, tachypnoea
How is a sickle cell crisis managed?
Adequate prompt analgesia (usually parental opiates)
Fluids
How is acute chest syndrome defined?
Acute illness
New infiltrate on CXR
Respiratory symptoms
When is acute chest syndrome more likely?
Surgery/anaesthesia
Pregnancy
What are complications from acute chest syndrome?
Increased risk of chronic lung disease and death
What is the pathophysiology of acute chest syndrome?
Infection, asthma and hypoventilation leading to hypoxia, inflammation and acidosis
Fat emboli and pulmonary thrombi leading to increased vaso occlusion within pulmonary microvasculature
Creates a vicious cycle
What is the immediate management of acute chest syndrome?
Adequate analgesia Incentive spirometry O2 therapy Non invasive ventilation even in the absence of severe hypoxia Fluids Antibiotics Transfusion
Why do sickle cell patients get overwhelming hypo splenic sepsis?
Splenic autoinfarction from a very young age leading to functional asplenia
What pathogens lead to overwhelming hypo splenic sepsis?
Pneumococcal
Meningococcal
H.influenzae
What age does hypo splenic sepsis typically occur?
Over 3 years
What is the mortality of splenic sepsis?
50 percent in fulminant disease
What are the symptoms of overwhelming splenic sepsis?
Febrile, coma, altered sensorium, seizures
What is the treatment for overwhelming splenic sepsis?
Urgent antibiotics
Prophylactic penicillin V
What can be done as prophylaxis in overwhelming splenic sepsis?
Prophylactic penicillin V
Vaccination
What are the signs and symptoms of sequestration?
Painful enlargement of the spleen
Drop in Hb of 2g per litre or more
High reticulocytes
What is the mortality from sequestration?
12 percent
What is the recurrence rate of sequestration?
50 percent
What percentage of sequestration cases occur in children under 2?
78 percent
What virus causes an aplastic crisis?
HPV B19 (common childhood illness)
What diseases are caused by HPV B19?
5th disease
Slapped cheek disease
What is the pathophysiology of an aplastic crisis?
Infection of red cell precursors in the marrow leading to pre red cell aplasia - giving low reticulocytes
What can be seen on blood tests with aplastic crisis?
Hb nadir 15 days post infection
What is the management of an aplastic crisis?
Urgent blood transfusion
Which chromosomes are effected in beta thalassemia?
11 and 16
What is the pathophysiology of beta thalassemia?
Lack of production of beta chains so increased alpha chain inclusion which is toxic to red cell progenitors
Leads to ineffective erythropoiesis
What is the clinical syndrome of beta thalassemia?
Severe anaemia - leads to growth failure and plasma volume expansion (probably leading to worsening anaemia)
Bone marrow expansion - gives thalassemia facies and hairy skull on X-ray, also causes bone disease, poor dentition and extramedullary erythropoiesis
What is the prognosis of beta thalassemia?
Death in first to second decade without transfusion
How is beta thalassemia managed?
Regular transfusions to maintain Hb over 10/dl
Be aware of iron overload (haemosiderosis)
What is the clinical sequelae of iron overload?
Cardiac failure Arrhythmia Cardiomyopathy Pituitary - impaired growth and infertility Hypoparathyroidism Hepatic cirrhosis Hypogonadism DM
How can iron status be assessed?
Serum ferritin - although is an acute phase reactant so non specific
TIBC
Liver biopsy - invasive
Cardiac and liver MRI (gold standard)
What is the gold standard way of assessing iron status?
Cardiac and liver MRI
How does liver MRI grade iron status?
Liver (mg/g dry weight)
Normal15
How does a cardiac MRI grade iron status?
Cardiac (msec)
Normal >20
Moderate 10-20
Severe
Name some iron chelation agents?
Desferoxamine (continuous infusion)
Deferiprone (oral)
Deferassirox (oral)
Which features in the history may point to iron overload?
Short stature Splenectomy Osteoporosis Amenorrhoea Hair loss
How many alpha globin chains does a normal person have?
4, 2 from each parent
What is the pathophysiology in alpha thalassemia?
Reduced production of alpha chains so increased beta chains but these are less toxic that increased alpha chains
What different genotypes are relevant to alpha thalassemia?
Normal - 2 alpha on each chromosome
Silent carrier - single alpha deletion on one chromosome
Alpha plus thalassemia trait - single alpha deletion on each chromosome
Alpha 0 thal trait - double alpha deletion on one chromosome
What is HbH?
Beta tetramers- non functional
What is HbBarts?
Y tetramers
Which ethnic groups are high risk for Alpha 0 thalassemia?
China
South East Asia
East Mediterranean
Middle East
What is the clinical syndrome of alpha thalassemia trait?
Asymptomatic
Low or very low MCV/MCH with no evidence or iron deficiency
Definitive diagnosis with genetic testing
What mode of inheritance is alpha thalassemia?
Mendelian codominant
What happens in the event of homozygous alpha 0 thalassemia?
Incompatible with life
Hydrops fetalis
What is the genotype for HbH disease?
A single alpha deletion on one chromosome with a double alpha deletion on the other
What are the clinical features of HbH disease?
Microcytic/hypochromic anaemia of variable severity
HbH inclusion bodies
Tendency for iron overload
What is the clinical picture for thalassemia intermedia?
Significant anaemia but not transfusion dependent
Increased iron absorption so risk of iron overload disproportionate to transfusion history
What are common examples of thalassemia intermedia?
- Beta thal major with alpha thal trait so less beta and alpha imbalance
- Beta thal trait with triplicate alpha chains so more alpha and beta imbalance
What is the purpose of heel prick antenatal screening test?
To identify significant haemoglobinopathy including sickle cell and offer penicillin prophylaxis, immunisation and parent education
How much haemoglobin is made daily and lost daily?
1ml made, 1ml lost
What can cause a normocytic anaemia?
Haemolytic Bone marrow disorder Hypersplenism Acute blood loss Anaemia of chronic disease
What can cause a macrocytic anaemia?
B12 and folate deficiency
Liver disease
Hypothyroidism
Reticulocytosis
What can lead to normocytic anaemia with a high Hct?
Thalassemia
What can lead to a microcytic anaemia with a low Hct?
Iron deficiency
Lead poisoning
Anaemia of chronic inflammation
Sideroblastic
What acute compensatory mechanisms are there for anaemia?
Right shift of 2,3 DPG curve
Increased cardiac output through SV and HR
Redistribution of blood flow
What are the chronic compensatory mechanisms for heart failure and how do they lead to worsening heart failure?
Chronic severe anaemia ➡️ peripheral vasodilation ➡️ decreased BP ➡️ raised neurohormones like catecholamines, RAA, natriuretic peptide, AVP ➡️ decreased blood flow and GFR ➡️ increased salt and water retention ➡️ raised plasma volume and extracellular volume ➡️ increased workload of the heard leading to LV remodelling and dysfunction and increased LV mass ➡️ worsening heart failure
How does alcoholic liver disease lead to a macrocytic anaemia?
Excess cholesterol
What type of anaemia does myelodysplasic syndrome lead to?
Macrocytic
What are the complications of DVT?
Increased risk of recurrence
Post thrombotic syndrome
Pulmonary hypertension
What are mechanical methods for VTE thromboprophylaxis?
Graduated compression stockings
Intermittent pneumatic compression
What are pharmacological methods of thromboprophylaxis?
Unfractionated heparin 5000 u bd or qds
Or fondaparinux
What are complications due to heparin?
Heparin induced thrombocytopenia
Renal excretion - patients may have renal impairment
Lack of reversibility
Bleeding
Which clotting factor does dabigatron inhibit?
Thrombin (IIa)
What factor does rivaroxaban inhibit?
Xa
Which clotting factor does apixaban inhibit?
Xa
The new type anticoagulants should not be given when?
Pregnancy
What are the contraindications to graduated compression stockings?
Known peripheral vascular disease
Leg and buttock pain on exercise
Previous or planned revascularisation surgery
Leg oedema where stockings cannot be fitted
Skins abnormalities including dermatitis, gangrene and recent skin grafts
How should VTE be treated?
Anticoagulant therapy to treat and to prevent prophylaxis
- Immediate therapy with LMWH
- Overlap with warfarin until INR in the therapeutic range which is a minimum of 5 days
- Stop heparin and continue warfarin for 3m
What should the target INR be with warfarin?
2-3
What the two enantiomers of warfarin?
R (less active) and S (more active)
What is the half life of warfarin?
36 hours
Which organ metabolises warfarin?
The liver
What is the mechanism of warfarin?
Vitamin K antagonist that stops factor II, VII, and X and protein C and S production from hepatocytes
Which should warfarin not be given in pregnancy?
Teratogenic and increased bleeding risk
Which enzyme metabolises R warfarin?
CYP2C19
CYP1A2
CYP3A4
Which enzyme metabolises S warfarin?
CYP2C9
How many times more potent is S warfarin than R warfarin?
3-5x
Which enzyme does warfarin inhibit?
VKORC1 that normally converts vitamin K hydroquinone to vitamin K epoxide
Which enzyme normally converts vitamin K epoxide back to vitamin K hydroquinone?
Gamma glutyl carboxylase
What percentage of dabigatran is renally cleared?
80 percent
What is malaria?
Systemic tropical parasitic infection of the red blood cells caused by plasmodium spp and transmitted by the female anopheles mosquito
Which species of plasmodium is most common?
Falciparum
Which species of plasmodium lead to uncomplicated relapsing pneumonia?
Viral
Ovals
Which species of plasmodium leads to uncomplicated non relapsing malaria?
Malariae
Which species of plasmodium causes monkey malaria?
Knowlesi- restricted to certain parts of South East Asia
Which is the female anopheles mosquito active?
Dusk to dawn
How else other than mosquito bite can malaria be spread?
Congenital
Blood transfusion
What is the incubation period for malaria?
7-30 days (shorter for P.falciparum and longer for P.malariae)
What is “airport malaria”?
Mosquitos stored in aircrafts and luggage that affect people that have not travelled
How many cases are there world wide of malaria?
200 million
Which area of the world brings in the most malaria cases in travellers returning to the UK?
Sub Saharan Africa (1 in 5 cases)
Describe the malaria life cycle
Mosquito- mosquito ingests a bloody meal containing gameocytes. Gameocytes undergo sexual reproduction in the mosquito’s mid gut and produce thousands of sporozoites. Sporozoites migrate to the mosquito salivary gland and initiate another cycle when transmitted to the human host.
Liver- sporozoites enter hepatocytes via blood and develop into schizonts that contain several daughter cells known as merozoites (with P.vivax and P.ovale some sporozoites enter a dormancy period called hypnozoites and may remain as such for years). Schizonts rupture leading to release of merozoites into blood.
What are global vector control methods for malaria?
Insecticide treated nets
Indoor residual spray
Genetically modified mosquitos
What personal protective measures can be done against malaria?
DEET based insect repellent
Insecticide treated bed nets
Clothing
Why must a combination of prophylaxis be taken for malaria?
No regime is 100 percent effective
Based on countries malaria species and resistance patterns
How can non-falciparum malaria be treated?
Chloroquine
Eradication therapy for liver stages of vivax and ovale with primaquine (avoid in severe G6PD deficiency and pregnancy)
What antibiotic should be replaced in pregnancy and children in malaria treatment and why?
Replace doxycycline with clindamycin as greater chance of complications
If you doubt the species of plasmodium, how should you treat it?
As P.falciparum
What is the pathogenesis of malaria?
Infected red blood cells adherence to host endothelium causes:
Microvascular occulsion
Metabolic derangement and metabolic acidosis
Intravascular haemolysis due to schizont rupture evoking vigorous cytokine response
How should falciparum malaria be treated?
- Parasitaemia less than 2% and no signs of severity:
Oral quinine sulphate +- doxycycline
Oral artemether and lumefantlin (riamet and co-artem)
Oral atovaquone and proguanil (Malarone) - Parasitaemia greater than 2% +- signs of severity
Involve ITU or HDU
iv quinine dihydrochloride (needs ECG and glucose monitoring)
iv artesunate (unlicensed use in EU)
What is the clinical presentation of malaria?
Fever Headache and muscle aches Diarrhoea Vomiting Foreign travel (last 12m for falciparum and longer for other types) Malaria prophylaxis? Pregnancy- high risk for complications
Which type of blood film is more sensitive in diagnosing malaria generally?
Thick
Which type of blood film is better for finding the exact species in malaria?
Thin
Which type of blood film is better for determining the level of parasitaemia in malaria?
Thin
What is seen with P.falciparum on LM?
Numerous fine ring forms
Double chromatin dots
Red cells not enlarged
What is seen with P.vivax on LM?
Enlarged red cells
Developing and thick signet ring forms
What is seen with P.ovale on LM?
Oval shape trophozoite
Comet like red cell
Enlarged red cell
What is seen with P.malariae on LM?
Broad band form in red blood cell
Red cells not enlarged
What is seen with P.knowlesi on LM?
Ring stages resemble falciparum
Mature stages indistinguishable from malariae
Molecular methods needed to confirm diagnosis
What are the rapid tests for plasmodium antigens?
- Histidine rich protein 2 (HRP2)
2. Plasmodium lactate dehydrogenase (pLDH)
What the non infectious complications of blood transfusions?
ABO incompatible DHTR (other red cell antibodies e.g. Rh and kell) FNHTR urticarial rash IgA deficiency (anaphylaxis) PTP TRALI Immunomodulation TA GVHD
What are the non immune complications of a blood transfusion?
Iron overload Fluid overload (TACO)
What percentage of people are each blood group?
A - 42%
B - 9 %
AB - 3%
O - 46%
What is the most common blood group?
O
How does ABO mismatch lead to complement activation?
Haemolysis leads to C5b-9, thromboplastic substances and release of histamine and other vasoactive amines. These cause cytokines to be released resulting in decreased blood pressure (causing shock and renal failure). The processes also increase coagulation (leading to DIC), inflammation and increased vascular permeability.
Why does an acute haemolytic reaction occur?
Wrong blood group leading to immediate complement mediated lysis
What is the clinical picture of an acute haemolytic reaction?
Can be fatal soon after starting transfusion
Shock , high fever, kidney failure, death
How should an acute haemolytic reaction be managed?
Stop transfusion Iv fluids to maintain blood pressure FBC, coagulation screen and chemistry Repeat blood group Return blood unit to blood bank Blood cultures Treat DIC and admit to ITU
How long after a transfusion does an acute haemolytic reaction occur?
7 to 10 days post transfusion
Why does a delayed haemolytic reaction occur?
Due to red cell antibodies such as Rh system, Kell, Fya, Jkb etc
How is a delayed haemolytic transfusion reaction diagnosed?
Positive direct antiglobulin test
What is the clinical picture of a delayed haemolytic transfusion reaction?
Starts 7 to 10 days post transfusion
Jaundice
Failure of Hb to rise
When does a febrile non haemolytic transfusion reaction occur?
During or after transfusion
What is seen clinically with FNHTR?
Rise in temperature more than 1C (fever) +- rigors
Is FNHTR life threatening?
No but must exclude wrong blood group and infection
What process has lowered the incidence of FNHTR?
Leucodepletion of blood and platelets
What is seen in an allergic reaction to transfusion products?
Either urticarial rash (+- wheeze) or anaphylaxis
Why does an urticarial rash occur?
Hypersensitivity to one of the plasma proteins
What is the clinical picture of anaphylaxis?
Life threatening soon after wheeze has started Increased wheeze/asthma Shock (tachycardia with low BP) Laryngeal or facial oedema May be related to IgA deficiency
Which antibody deficiency is linked to anaphylaxis?
IgA
What pulmonary complications are linked to transfusion?
Transfusion associated circulatory overload (TACO)
Transfusion related acute lung injury (TRALI)
Who is at risk of TACO?
Elderly
Pre existing heart disease
Very small patients with high volume transfusion
Why does TRALI occur?
Transfused anti leukocyte antibodies in donor plasma reacts with the patients white blood cells
What is seen on X-ray with TRALI?
Bilateral pulmonary infiltrate
How is TRALI managed?
Supportively with ventilation
Does diuretics improve TACO or TRALI?
TACO as it is fluid overload
What is the pulmonary arterial pressure in TACO vs TRALI?
Over 18mmHg in TACO and less than or equal to 18mmHg in TRALI
What are some of the other rare immune complications that can occur in transfusion?
Post transfusion purpura (PTP)
Transfusion associated graft vs host disease
TA-GVHD
When does PTP occurs?
7-10 days after transfusion of blood or platelets
What causes PTP?
HPA1 negative patients form antibodies after transfusion or pregnancy
After further transfusion there is destruction of one’s own platelets
Is transfusion associated graft vs host disease always fatal?
Yes, but rare
Why does transfusion associated graft vs host disease occur?
Mediated by viable lymphocytes in donor blood or platelets (prevented by irradiation)
How is TA-GVHD avoided?
Avoid by HLA matching or use blood from first degree relative
Who is prone to TA-GVHD?
Very immunosupressed such as bone marrow transplant, on fluidarabine, Hodgkin’s disease, foetus needing intrauterine infusion, congenital immunodeficiency
How are observations done during a transfusion?
Baseline
Every 15 mins
Hourly after transfusion had ended
Which framework has been put in place to ensure better use of blood products?
HSC 2007/01
Which viruses are commonly spread through transfusion?
Hepatitis: HPV, HBV, HCV, HDV (HDV needs HBV to survive)
Other than transfusion, what are other ways HBV, HIV and HCV be transmitted?
HBV - intravenous drugs, sexually (homosexuals more prone), vertically
HIV - sexually (homosexuals more prone) >intravenous drugs, vertically
HCV - intravenous drugs»sexually, vertically
Why is HBV more likely in blood transfusion related infections?
The initial period of 3-4months post infection the HBsAg is negative so must exclude high risk donors
What is prion disease?
Mad cow disease
Transmission through blood and sheep in humans
Cannot diagnose with blood test only biopsy
What steps have been taken to reduce the incidence of blood transfusion related prion disease?
Leucodepletion
U.K. Plasma not used for fractionating
Imported FFP for all patients born after 1996
Any recipient of blood after 1980 barred from donation
What are the complications of bacterial contamination into blood products?
Can be fatal
Bacterial sepsis - especially if endotoxin produced e.g. Gram negative rods (E.coli)
Shock, kidney failure and death
How can bacterial contamination of blood products be reduced?
Stringent cleansing of donor skin
