core haematology Flashcards
what is haemopoiesis?
the physiological development process that gives rise to the cellular components of blood
what is the name of the cell which can divide and differentiate to form different cell lineages that will populate the blood?
multipotent haemopoietic stem cell
what is the difference between symmetric and asymmetric self-renewal of a haemopoietic stem cell?
symmetric: stem cell divides to create 2 more stem cells
asymmetric: stem cell divides to create 1 stem cell and 1 (more specialised) progenitor cell
(nb can also have ‘lack of self renewal’ when one stem cell divides to create 2 progenitor cells)
which blood cells are in the lymphoid lineage and which are in the myeloid lineage?
everything is from the myeloid lineage, EXCEPT:
- B-lymphocytes
- T-lymphocytes
what is the difference between monocytes and neutrophils?
monocytes
- become macrophages when get into tissue (circulate blood as monocytes)
- long lived
- antigen-presenting
neutrophils
- short lived
- not antigen-presenting
what is the lifespan of a RBC?
3 months/ 120 days
in the EARLY developing embryo, where does haemopoiesis occur?
(originally slightly in yolk sac)
but mainly in EMBRYONIC PLATE (between amniotic sac + yolk sac)
where does haemopoiesis occur in the developing foetus?
Aorto-gonado-mesonephros (AGM)
at day 40, the haemopoietic stem cells migrate, via the aorta, to the foetal liver (which become the subsequent site of haemopoiesis
what is the name given when there are too many RBCs?
polycythaemia
what is relative polycythaemia?
when plasma volume is REDUCED (but no. of RBCs doesn’t change)
- therefore there is a higher concentration of RBCs in the blood
what are the three main groups of leukocytes?
- lymphocytes
- monocytes
- granulocytes
what are the three types of granulocytes?
- neutrophils
- eosinophils
- basophils
what is the name given when there are more neutrophils than normal in the blood?
what might cause this? 3
neutrophilia
- bacterial infection
- inflammation
- use of steroids (flush neutrophils out of tissues into blood??)
what is the name given when there are fewer neutrophils than normal in the blood?
what might cause this?
neutropenia
side effects of certain drugs, eg:
- co-trimoxazole (an Abx)
- chemo drugs
what is it called when there are more eosinophils in the blood than normal?
what might cause this? 2
eosinophilia
- parastic infection (eg schistomiasis)
- allergies
what is it called when there are more basophils in the blood than normal?
what normally causes this?
basophilia
myeloma proliferative neoplasms
- especially: chronic myeloid leukaemia
what are the name for the macrophages in the:
- liver?
- skin?
- brain?
liver: kupffer cells
skin: langerhans cells
brain: microglia
what is it called when there are more monocytes in the blood than normal?
when might this occur?
monocytosis
tuberculosis
what is it called when there are more lymphocytes in the blood than normal?
when might this occur?
lymphocytosis
- eg in chronic lymphocytic leukaemia (CLL)
also in glandular fever (infectious mononucleosis) you get lots of ATYPICAL lymphocytes (which look like monocytes, hence the name!)
what is it called when there are fewer lymphocytes in the blood than normal?
when might this occur?
lymphopenia
- post bone marrow transplant
which lymphocyte produces cell-mediated-immunity and which produces humoral immunity?
cell mediated = t cells
humoral = b cells (via soluble antibodies they produce)
what is adaptive immunity and what is innate immunity?
adaptive = t + b lymphocytes
innate = all other white blood cells (ie myeloid lineage)
what is an increased number of plasma b cells called?
what might cause this?
plasmacytosis
benign
- eg response to infection
myeloma
what is the name of the cell which platelets are derived from?
megakaryocytes
what are the 4 main subspecialties of haematology?
- coagulation
- malignant
- non-malignant
- transfusion
what are the constituents tested for in a Full Blood Count (FBC) blood test?
Hb concentration
Red cell parameters:
- MCV (mean cell volume)
- MCH (mean cell Hb)
white cell count (WCC)
platelet count
what are the RBCs called when they have:
- too little Hb?
- too much Hb?
too little: hypochromate (pale)
too much: hyperchromate (dark)
how do coagulation screens test coagulation function?
what are the main three specific tests used? and what are they used for?
by measuring the time taken for a clot to form when plasma (from patient) is mixed with specified reagents
prothrombin time
- used for warfarin monitoring
activated partial thromboplastin time
- used for unfractioned heparin monitoring
thrombin time
- used for diagnosing specific clotting deficiencies
how are diagnostic bone marrow tests carried out?
under local anaesthetic, liquid marrow is aspirated from POSTERIOR ILLIAC CREST of pelvis and a trephine core biopsy is then taken with a hollow needle
when taking blood what things should you make sure to do? 5
- appropriate sample from patient (eg fasting or not etc)
- blood should be filled to line on tube
- mix blood well (a few inversions is fine)
- labble bottle correctly
- keep bottle with request form
what is the definition of a reference range?
the set of values for a given test that incorporates 95% of the normal population
what is the definition of sensitivity?
the proportion of abnormal results correctly classified by the test
what is the formula for calculating sensitivity?
no. true positives / (no. true positives + no. false negatives)
what is the definition of specificity?
the proportion of normal results correctly classified by the test
what is the formula for calculating specificity?
no. true negatives / (no. true negatives + no. false positives)
what might cause mild lymphocytosis? (but be completely harmless)
post-splenectomy mild lmphocytosis
what might cause lymphopenia? (but not be pathological)
3 months post-bone marrow transplant lymphopenia
what conditions cause microcytic anaemia? 5
- iron deficiency
- thalassaemia
- lead poisoning
- anaemia of chronic disease (some)
- sideroblastic anaemia (some)
what conditions cause normocytic anaemia? 6
- after acute blood loss
- renal disease
- bone marrow failure (eg post chemo, infiltration by carcinoma etc)
- mixed deficiencies
- many haemolytic anaemias
- anaemia of chronic disease (some)
what conditions cause macrocytic anaemia? 6
megaloblastic:
- vit B12 deficiency
- folate deficiency
non-megaloblastic
- alcohol
- liver disease
- myelodysplasia
- aplastic anaemia
what is the main symptom of a sickle cell crisis?
excruciating bone pain
what are megaloblastic cells (present in some forms of macrocytic anaemia)?
a type of immature progenitor RBC which didn’t divide like it should and so just kept getting bigger
(called megaloblastic erythropoiesis)
- B12 + folate deficiency
what are three main types of macrocytic anaemia?
what causes them?
megaloblastic anaemia (ie with megaloblastic erythropoiesis)
- vit B12/folic acid deficiency
- myelodysplastic syndrome
macrocytic anaemia with normoblastic erythropoiesis
- eg liver disease, alcohol, hypothyroidism, myelodysplastic syndrome
‘stress’ haemopoiesis
- eg haemolytic anaemia, recovery from blood loss (macrocytosis reflects high reticulocyte, immature RBC, count)
what are myelodysplastic syndromes (MDS)?
what are the two clinical manifestations of these conditions?
a group of cancers in which immature blood cells in the bone marrow do not mature and become healthy blood cells. Early on there are typically no symptoms. Later symptoms may include feeling tired, shortness of breath, easy bleeding, or frequent infections.
- chronic anaemia with survival for several years
- aggressive disease terminating in ACUTE MYELOID LEUKAEMIA
what is an iatrogenic cause of myelodysplastic syndrome?
- complication of treatment with chemotherapy or radiotherapy
who is most likely to be affected by myelodysplastic syndromes?
typially mid-life to older people
occasionally in younger people
why do myelodysplastic syndromes cause anaemia?
because: a mutated stem cell produces a clone of abnormal cells that replaces normal haemopoiesis
abnormal cells:
- show abnormal maturation morphologically
- often die before leaving the bone marrow
- –> peripheral blood cytopenias
so basically the right amount of cells are still made in the bone marrow but, because they’re mutated, they often die before leaving the bone marrow so there aren’t enough cells in the blood
what are the THREE typical abnormalities seen in BLOOD TESTS of patients with myelodysplastic syndrome (MDS)?
what symptoms do each of these abnormalities produce?
anaemia
- fatigue
- dyspnoea (SOB)
neutropenia
- lots of infections
thrombocytopenia
- bruising
- bleeding
what are 3 types of myelodysplastic syndrome (MDS)?
- refractory anaemia
- refractory anaemia with excess blasts
- MDS 5Q- syndrome
what are the ACTIVE treatments for myelodysplastic syndrome? 4
who is suitable for each one?
lenalidomide
(for 5Q syndrome)
azacytidine
(for patients who aren’t well enough to have a bone marrow transplant)
chemotherapy
bone marrow transplant
what are the SUPPORTIVE treatments for myelodysplastic syndromes? 3
- RBC transfusions
- erythropoietin
- platelet transfusions
what treatment would you give to someone who had too much iron in their body? (side effect of RBC transfusions)
give iron chelation to treat iron overload
what is the process which isolates RBCs from donors blood called?
leucodepletion
how long can RBCs be stored?
how long does it usually take to transfuse 1 unit of RBCs?
up to 35 days
1.3-3 hours
what is the definition of a transfusion threshold (trigger)?
the lowest concentration of Hb that is not associated with symptoms of anaemia
(once you go below that threshold, you should transfuse the patient)
(this threshold varys hugely between patients)
what are the body’s mechanisms of adapting to anaemia? 6
what occurs after these methods have been exhausted (or if the body hasn’t had enough time to respond to the anaemia)?
- increase cardiac output
- increase cardiac artery blood flow
- increase oxygen extraction
- increase of RBC 2,3 DPG (diphosphoglycerate)
- increase production of erythropoitin (from kidneys)
- increase erythropoiesis
–> tissue hypoxia –> symptoms of anaemia
what FOUR things could cause a patient’s transfusion threshold to be lower?
basically if their body has a reduced capacity to react to anaemia due to less effective:
- cardiac output
- arterial blood flow
- O2 saturation
- Hb
eg in:
- cardiovascular disease
- respiratory disease
- haemoglobinopathies
- increased age
what are alternative treatments for anaemia? (ie not RBC transfusions) 5
correction of treatable causes of anaemia:
- iron tablets (for iron deficiency)
- B12 injections (for B12/folate deficiencies)
- erythropoietin treatment (for patients with renal disease)
correction of coagulopathy:
- discontinuation of antplatelet agents
- administration of anti-fibrinolytic agents
how much blood does a person have to loose (in an acute setting) in order for a transfusion to be necessary?
about 1.5 litres
why are patients with inherited anaemias (eg thalassaemia) given regular blood transfusions?
what is a possible adverse event of these?
to suppress endogenous erythropoiesis (which produces the abnormal RBCs)
iron overload
what is the ‘shelf life’ of platelet donations?
what is the usual transfusion for one unit of platelets?
5 days from collection
30 mins/unit
why transfuse platelets? 3
treatment of bleeding due to:
- severe thrombocytopenia (low platelets)
- platelet dysfunction
prevention of bleeding
what are the two main contraindications of platelet transfusion?
- heparin induced thrombocytopenia + thrombosis
- thrombotic thrombocytopenic purpura
how is fresh frozen plasma (FFP) stored?
frozen for up to 2 years
- thawed immediately before use
when should fresh frozen plasma be transfused? 3
when shouldn’t it be transfused? 2
- coagulopathy (problems w clotting factors) with bleeding/surgery
- massive haemorrhage
- thrombotic thrombocytopenic purpura
do not transfuse:
- for warfarin reversal
- for replacement of single factor deficiency
what is the treatment for patients who are bleeding due to too much warfarin?
prothrombin complex concentrate (PCC)
basically a lot of plasma-derived Vit K dependent factors - factors 2, 7, 9 + 10
what is a ‘group and screen’ blood test for?
- determination of patient’s ABO + Rh group
- patient’s plasma ‘screened’ for antibodies against other clinically significant blood group antigens
so that blood can be transfused safely (esp in an emergency) wwith a lower probability of adverse events
what is ‘crossmatching’?
donor red cells of the correct ABO and Rh group are selected from the blood bank
(avoid any other groups the patient has antibodies against - detected in screen)
‘crossmatching’ = patient’s plasma is mixed with aliquots of donor red cells to see if a reaction (agglutination or haemolysis) occurs
if no reaction: RBC units compatible!
if reaction: RBC units INcompatible, risk of acute haemolysis
what is the difference between an acute transfusion reaction and a delayed one?
acute reactions present: <24hr after transfusion
delayed reactions present: >24hr after transfusion
what are the possible acute transfusion reactions (to a blood transfusion)? 6
immunological:
- acute haemolytic transfusion reaction (ABO incompatibility)
- allergic/anaphylactic reaction
- TRALI (transfusion-related acute lung injury)
non-immunological:
- bacterial contamination
- TACO (transfusion associated circulatory overload)
- febrile non-haemolytic transfusion reaction
what are the possible delayed transfusion reactions (to a blood transfusion)? 4
immunological:
- transfusion-associated graft-versus-host disease (TA-GvHD)
- post transfusion purpura
non-immunological:
- transfusion transmitted infection (TTI) - viral/prion
- iron overload
what is the pathological process of an acute haemolytic reaction (ABO incompatibility)?
- haemolysis of RBCs
- > release of free Hb
- > deposition of Hb in the distal renal failure
- > stimulation of coagulation
- > microvascular thrombosis
- > stimulation of cytokine storm
- > scavenges NO resulting in generalised vasoconstriction
what are the signs and symptoms of an acute haemolytic reaction? 7
when do these symptoms occur?
- fever + chills
- back pain
- infusion pain
- chest pain
- hypotension/shock
- haemoglobinuria (may be 1st sign in anesthetised patients)
- increased bleeding (DIC)
- sense of ‘impending death’
severe reactions may occur early in the transfusion (within first 15 mins)
(milder reactions may occur later but usually before the end of the transfusion)
What is a delayed haemolytic reaction?
what are the clinical signs/symptoms of this? 3
what are the laboratory findings? 4
onset 3-14 days following RBC transfusion
- delayed haemolytic reaction is due to immune IgG antibodies against RBC antigens other than ABO
- the antibodies are formed AFTER the transfusion
clinical features:
- fatigue
- jaundice
- fever
laboratory findings:
- drob in Hb
- increased LDH (lactate dehydrogenase)
- increased indirect bilirubin
- positive antiglobulin test
what is the Coomb’s test?
what is it also known as?
rabbit antibodies to human IgG
(called: anti-human globulin (AHG))
they are used to detect IgG antibodies on RBCs
- so see if RBCs are being attacked by immune system (as in a post-transfusion haemolytic reaction)=
- get visible agglutination if there are IgG on RBCs when AHG is added
aka:
- anti-human globulin test (AHG)
- direct anti-globulin test (DAT)
what does TRALI stand for?
why does it occur?
what is the mechanism of the condition?
transfusion related acute lung injury
- DONOR has antibodies to RECIPIENT’S LEUCOCYTES
(nb almost always complicates transfusion of plasma rich components - ie platelets or fresh frozen plasma)
donor antibodies attack recipients leucocytes
- > activated leucocytes lodge in pulmonary capillaries
- > release substances that cause endothelial damage and capillary leak
when does TRALI occur?
what are the clinical signs of it?
sudden onset of ‘acute lung injury’ occuring within 6 hours of a transfusion
- hypoxia
- new bilateral chest x-ray infiltrates (consolidation)
- no evidence of volume overload (eg heart size is normal)
how do you confirm a diagnosis of TRALI?
- donor’s blood is tested for HLA and granulocyte antibodies
- recipient’s blood is tested for expression of neutrophil antigens
confirmation of diagnosis if:
- donor has antibodies against antigens that are expressed on recipient’s granulocytes
what is the treatment for TRALI?
if mild:
- supplementary oxygen therapy
if severe:
- mechanical ventilation and ICU support
nb there is no role for diuretics or corticosteroids
what does TACO stand for?
what are the:
- symptoms? 5
- signs? 2
transfusion-associated circulatory overload
symptoms:
- sudden dyspnoea (SOB)
- orthopnoea
- tachycardia
- hypertension
- hypoxaemia
signs:
- raised BP
- elevated jugular venous pulse
what are the risk factors for TACO? 5
- elderly
- small children
- patients with compromised left ventricular function
- increased volume of transfusion
- increased rate of transfusion
nb this is hugely unreported/unrecognised by clinicians (if you suspect it, hold transfusion, if just to check that it’s not bacterial infection or another more serious adverse effect)
what are the differences between the presentation and treatment of TACO + TRALI?
- type of blood component transfusion which causes it?
- affect on BP?
- affect on temp?
- do diuretics worsen or improve it?
- does fluid loading worsen or improve it?
Type of blood component transfused:
- TRALI: usually plasma
- TACO: any
BP:
- TRALI: often reduced
- TACO: often raised
temp:
- TRALI: often raised
- TACO: normal
diuretics:
- TRALI: worsens
- TACO: improves
fluid loading:
- TRALI: improves
- TACO: worsens
what are the two different types of allergic reaction to a blood transfusion?
how do they present?
urticarial rash (+/- wheeze)
- often not severe
- hypersensitivity to a ‘random’ protein (in donor’s blood)
anaphylaxis
- severe, life-threatening reaction soon after transfusion started
- wheeze/asthma
- increased pulse
- decreased BP (shock)
- laryngeal/facial oedema
what is a febrile non-haemolytic reaction (FNHTR)?
why does it occur?
how should it be managed?
during (or soon after) transfusion:
- fever, rise in temp >1degree (+/- shakes/rigors)
- +/- increased pulse
- unpleasant but not life threatening (it is self-limiting)
FNHTR are due to cytokines (or other biologically active molecules) that accumulate during storage of blood components
- discontinue transfusion until you exclude ‘wrong blood’ or bacterial infection
what are the primary and secondary aspects of haemostatic plug formation?
primary
= aggregation
—platelet aggregation -> clotting
secondary
= coagulation cascade
-> thrombin -> fibrin
both together –> haemostatic clot
how do platelets become activated?
normal platelets in flowing blood (w receptors on their surface)
- if blood contacts collagen then a protein in blood (von willebrands factor) binds to the collagen and to the platelets, creating a connection
- platelets are therefore adhered to damaged endothelium and undergo ACTIVATION
–> aggregation of platelets into a thrombus (due to fibrinogen acting as a bridge between platelets)
what activates:
- the intrinsic clotting pathway?
- the extrinsic clotting pathway?
intrinsic:
- when blood exposed to COLLAGEN (from damaged surfaces)
extrinsic:
- when blood exposed to TISSUE FACTOR (released from tissues when endothelium is damaged)
what part of the coagulation cascade do these times measure:
- activated partial thromboplastin time?
- prothrombin time?
- thrombin clotting time?
activated partial thromboplastin time:
- intrinsic pathway
prothrombin time:
- extrinsic pathway
thrombin clotting time:
- common pathway
“intrinsic pathway is activated by contact with collagen, which is a bit like PLASTIC, thromboPLASTIN”
what factors are vitamin K dependent:
- clotting? 5
- anti-clotting? 2
clotting:
- factor 2
- factor 7
- factor 9
- factor 10
- prothrombin
anticlotting:
- protein c
- protein s
what are the procoagulant (2) and anti-coagulant (4) components found in the blood?
procoagulant:
- platelets
- clotting factors
coagulant:
- protein C
- protein S
- anti-thrombin III
- fibrinolytic system
what sort of bleeding do these types of bleeding disorders tend to cause:
- platelet/vessel wall defect?
- coagulation defect?
platelet/vessel wall defect:
- mucosal + skin bleeding
coagulation defect:
- deep muscular + joint bleeds
- bleeding following trauma
what is the general role of alpha and dense granules in platelets
contain chemicals which are released of platelet activation
these chemicals stimulate the activation and aggregation of other platelets
so a positive feedback loop
what does aspirin inhibit the synthesis of?
inhibits the synthesis of thromboxane (via inhibition of COX enzyme)
thromoxane is a hormone that is released from blood platelets, which induces platelet aggregation and arterial constriction
where is tissue factor (TF) found?
TF is a transmembrane receptor expressed by cells surrounding blood vessels
what does tissue factor activate?
factor 7 -> factor 7a
extrinsic pathway
which is faster: extrinsic or intrinsic pathway?
extrinsic (fewer steps)
what does factor 12 deficiency cause?
- prolonged clotting time in vitro
- but very rarely causes clinical symptoms
what bleeding disorders are caused by:
- factor 8 deficiency?
- factor 9 deficiency?
factor 8 = haemophillia A
factor 9 = haemophillia B
“A is earlier in the alphabet than B”
what is the end product of the fibrinolytic cascade?
what does this do?
plasmin (produced from plasminogen, which is converted by t-pa)
(t-pa = tissue plasminogen activator)
plasmin breaks down fibrin clot
what are the 4 broad different types of platelet/vessel wall defects which all give rise to a prolonged bleeding time? (each with an example)
1) reduced no. of platelets (thrombocytopenia)
- many causes (eg viruses, chemo)
2) abnormal platelet function
- eg aspirin/other drugs
3) abnormal vessel wall (rarer)
- eg ehlers danlos syndrome
4) abnormal intercation between platelets + vessel wall
- eg von willebrand diseas
what is an example of an acquired condition which causes abnormal vessel walls?
scurvy
what are petechiae?
red or purple spots on the skin, caused by a minor bleed from broken capillary blood vessels
they are NON-BLANCHING
what is the classical presentation of vascular/platelet defects?
- petechiae + superficial bruises
- affects skin + mucosal membranes
- spontaneous
- bleeding immediate, prolonged + NON-recurrent
what is the classical presentation of coagulation defects?
- deep spreading haematomas
- haemarthrosis
- retroperitoneal bleeding
- bleeding preolonged and often RECUURENT
what is haemarthrosis?
bleeding into joints
what is the scientific name for nose bleeds
epistaxis
what is the most common inherited bleeding disorder?
von Willebrand disease
what are the 2 functions of von willebrand factor?
- to bind platelets to wound site (esp collagen)
- to act as a carrier of factor 8
what are the 3 types of von willebrand disease?
type 1
- vWF is normal but there’s not enough of it
- less severe
- most common (75%)
type 2
- vWF is abnormal (not as effective) but there is enough of it
- less severe
- about 20% of cases
type 3
- there is very little vWF in blood
- severe
- very rare
what other condition can vWD present similar to? why?
mild haemophillia
as vWF carries factor 8 in the blood plasma so if there is less vWF then this can lead to low levels iof factor 8
what is the inheritance pattern of von Willebrand disease?
mainly autosomal dominant
nb penetrance is very variable though, even within families
what part of haemostasis is affected in von willebrands disease?
defective primary haemostasis
ie platelets/cell walls NOT coagulation
what other things (except vWD) can affect a person’s level of vWF?
increase? 3
decrease? 1
increase:
- illness
- stress
- exercise
decrease
- being blood group O
what are women with vWD given to reduce their menorrhagia?
combined oral contraceptive pill (COCP)
when are treatments normally given for von Willebrand disease?
- when symptoms occur
- before surgery
- during pregnancy
what anti-fibrinolytic treatment is given to treat vWD?
how does it work?
tranexamic acid
bind to plasminogen or plasmin. This prevents plasmin from binding to and degrading fibrin and preserves the framework of fibrin’s matrix structure
what other treatment is occasionally given to patients with vWD? (esp type 1)
what does it do?
desmopresin (aka DDAVP)
(it is an analogue of endogenous vasopressin)
- one of its actions is to release stores of vWF in endothelial cells
- only works temporarily
- side effect is water retension
- efficacy reduces after repeated uses
what vaccinations are people with vWD given? why?
hepatitis
because they are sometimes given (donated) plasma-derived concentrates containing vWF + so at higher risk from infected blood donors
what are the two most common hereditary COAGULATION deficiencies?
Haemophilia A + B
which coagulation screening test is elongated in haemophilia? why?
activated partial thromboplastin time (APTT)
as this measures the INTRINSIC pathway - where factor 8 + 9 are
what is the function of factor 13?
what does deficiency present as?
what do coagulation screening tests show?
to crosslink fibrin, stabilises clots
Bleeding tendencies similar to hemophiliacs develop, such as hemarthroses and deep tissue bleeding.
ALL NORMAL (APTT, PT, TCT) - as these measure formation of fibrin clots whereas factor 13 is to do with stabilisation of clots
why might some female carriers of haemophilia be more symptomatic than others?
due to random X-inactivation (lyonisation)
- if more X with normal gene is inactivated then factor 8 levels will be lower than 50% so mild symptoms may occur
what is the inheritance pattern of haemophilia A + B?
X-linked recessive
nb severity levels vary BUT are consistent between family members
about 30% of haemophilia cases are new mutations
what are the definitions of the three degrees of haemophilia severity?
factor 8 or 9 levels:
- mild = 6-50%
- moderate = 1-5%
- severe = <1%
nb mild haemophiliacs will only bleed during truma and surgery, whereas severe haemophiliacs will have lots of spontaneous bleeds
the more severe the condition, the earlier in life patients will present
what types of bleed do haemophiliacs tend to get? 5
- spontaneous/post traumatic
- haemarthrosis (joint bleeding)
- muscle haemorrhage
- soft tissue bleeds
- life threatening bleeds
what is haemophilic arthropathy?
what can reduce risk?
permanent joint disease occurring in haemophilia sufferers as a long-term consequence of repeated haemarthrosis
factor injections every other day, reduce number of joint bleeds so likelihood of permanent joint damage
what is the main treatment for haemophilia?
injections (every other day) of RECOMBINANT factor 8 or 9
nb factors from donated blood products no longer used
what are the 2 main complications of haemophilia treatment?
transfusion transmitted infections
- many adults got these before use of recombinant factors was used
- eg hepatitis, HIV, parvovirus
inhibitor development
- sometimes body can produce antibodies to injected factors
- more common in haemophilia A (25% of patients)
- means normal treatment is not effective
- more commonly temporary but can be permanent
what are the 6 most common causes of acquired bleeding disorders?
- vit K deficiency
- liver disease
- massive transfusion syndrome
- disseminated intravascular coagulation (DIC)
- iatrogenic causes
- acquired inhibitors (of coagulation)
what are the most important questions to ask when assessing someone with a possible bleeding disorder?
- date of onset/previous bleeding episodes?
- responses to ‘challenges’ (ie did surgery/dental extraction cause lots of bleeding) (nb in infants use things like bleeding from umbilical stump, vaccinations, circumcision)
- have they ever needed medical/surgical intervention to stop bleeding?
- any systemic illness? (eg liver problems)
- drug history?
- family history?
if the APPT (activated partial thromboplastin time) is prolonged, how can you tell if this is due to a deficiency of a factor or an inhibitor of the factor?
repeat test but mix patient’s plasma with plasma which you know has correct factors in, if:
- correction of APPT then: deficiency in patient’s plasma
- no correction of APPT then: presence of inhibitorin patient’s plasma
In liver disease, what results will be seen in these tests:
- platelet count?
- prothrombin time?
- APPT (activated partial thromboplastin time)?
- thrombin time?
platelet count:
- low
prothrombin time:
- prolonged
APPT:
- prolonged
thrombin time:
- normal
in DIC, what results will be seen in these tests:
- platelet count?
- prothrombin time?
- APPT (activated partial thromboplastin time)?
- thrombin time?
platelet count:
- low
prothrombin time:
- prolonged
APPT:
- prolonged
thrombin time:
- grosssly prolonged
“basically everything is shit, DIC is shit!”
in Massive transfusion syndrome, what results will be seen in these tests:
- platelet count?
- prothrombin time?
- APPT (activated partial thromboplastin time)?
- thrombin time?
platelet count:
- low
prothrombin time:
- prolonged
APPT:
- prolonged
thrombin time:
- normal
in oral anticoagulants (eg warfarin), what results will be seen in these tests:
- platelet count?
- prothrombin time?
- APPT (activated partial thromboplastin time)?
- thrombin time?
what other condition can cause these results?
platelet count:
- normal
prothrombin time:
- grossly prolonged
APPT:
- prolonged
thrombin time:
- normal
vit K deficiency
why do you get low platelet count in liver disease?
because liver problems often cause portal hypertension which backs into spleen, so platelets get trapped and clogged up in spleen, so have lower levels circulating (ie due to hypersplenism)
what is the action of warfarin?
warfarin is a vitamin K reductase inhibitor
- it stops vit k being recycled
vit K is needed in the activation of some coagulation factors
what are the 4 main causes of vit K deficiency? (not including warfarin treatment)
what are the mechanisms?
obstructive jaundice
- need bile to breakdown + absorb fat, vit K is a fat soluble vitamin -> deficiency
PROLONGED nutritional deficiency
- less fat for vit K to be absorbed in
broad spectrum antibiotics
- kill off gut flora
- a lot of out vit k is synthesised by gut flora
neonates (classic 1-7 days)
- all babies are given a vit k injection at birth to prevent this (aka haemorrhagic disease of the newborn)
why might patients on ICU be at higher risk of becoming vit K deficient?
have prolonged nutritional deficiency AND often lots of antibiotics
what coagulation factors are synthesised in the liver?
all except factor 8
what is a major cause of mortality in patients with liver disease?
cirrhotic coagulopathy
- complex reduction in coagulation factors, anti-coagulation factors + platelets leads to reduction in haemostatic abilities
- less likely to get spontaneous bleeds but highly likely to bleed a lot during surgery etc
- very hard to treat effectively
what is the definition of a ‘massive transfusion’
transfusion of a volume of blood equal to:
- patient’s total blood volume in <24hrs
OR
- 50% of patient’s blood volume within 3 hours
why do you get coagulation deficits with massive transfusions? (massive transfusion syndrome)
- due to RELATIVE (/dilutional) depletion of platelets + coagulation factors (as only RBC’s are transfused)
nb give fresh frozen plasma (FFP) as well to prevent this
also, less commonly, due to:
- DIC
- underlying disease (eg liver/renal drug treatment or surgery)
what are the main causes of ACUTE DIC? 5
what is this more likely to present as?
- sepsis (most common)
- obstetric complications
- trauma/tissue necrosis
- acute intravascular haemolysis (eg ABO incompatibilty blood transfusion)
- fulminant (aka acute) liver disease
bleeding as main symptom
what are the main causes of CHRONIC DIC? 4
what is this more likely to present as?
- malignancy
- end stage liver disease
- severe localised intravascular coagulation
- obstetric: retained dead foetus
end organ damage (due to microvascular clots) is main symptom
what is the management of DIC?
treat underlying cause
- eg antibiotics, obstetric intervention, chemo for cancer
supportive treatment:
- maintain tissue perfusion
- folic acid + vit k to support recovery esp if illness is prolonged
what is the INR (international normalised ratio)?
used to monitor warfarin use
a ratio: patient’s prothrombin time/mena normal prothrombin time
what types of drugs can increase the effect of warfarin? 3
- some antibiotics
- NSAIDs
- corticosteroids
what are the treatments for overtreatment of warfarin?
depends on severity!
- if mild, just withold warfarin
- if moderate, do above + administer vit K
if severe, do above AND give four factor concentrate (PCC)
what is the antidote used in cases of over treatment with un-fractioned heparin?
protamine
nb effects of protamine on low molecular weight heparin are less predictable and more complex
what are the three commonest myeloproliferative disorders?
what % of these transform into acute leukaemia?
- polycythaemia vera
- essential thrombocytosis
- idiopathic myelofibrosis
10%
what is polycythaemia vera?
- increased RBCs (+/- neutrophils, +/- platelets)
basically bone marrow makes too many mature RBCs
(nb distinguish from secondary polycythaemias + reactive polycythaemia)
what is essential thrombocythaemia?
increased platelets (overproduction in bone marrow)
(nb distinguish from reactive thrombocytosis)
aka essential thrombocytosis
what is myelofibrosis?
proliferation of an abnormal clone of hematopoietic stem cells in the bone marrow and other sites results in fibrosis (the replacement of the marrow with scar tissue)
leading to severe anemia, weakness, fatigue and often an enlarged spleen
(varied cytopenias with a large spleen)
(nb distinguish from other causes of splenomegaly)
what is a condition that is secondary to many myeloproliferative disorders? how does this transformation present clinically?
myelofibrosis
clinically the blood cell count will be very high (due to the primary condition) but will then suddenly drop due to fibrosis in the bone marrow
what are the symptoms of polycythaemia vera? 8
- itching (aquagenic - stimulated by eg hot baths)
- plethoric face (ie red)
- headache/muzziness
- general malaise
- tinnitus
- peptic ulcer
- gout (due to uric acid released by increased cell turnover)
- gangrene of the toes
nb can present very insidiously
what are the signs of polycythaemia vera? 4
look flushed (red)
engorged (‘sausage-like’) retinal veins
splenomegaly
persistent haematocrit of over 50% (0.5)
at what age are people most likely to get polycythaemia vera?
50-70years
what are the 5 first line blood tests you would carry out on someone you suspect to have polycythaemia vera?
- FBC
- ferritin
- epo level
- U+Es
- LFTs
what conditions can cause secondary polycythaemia?
central hypoxic process:
- chronic lung disease
- right-to-left shunts heart disease
- carbon monoxide poisoning
- smoker
- high altitude
drug associated
- treatment with androgen preparations
- post-renal transplant erythrocytosis
congenital
- high oxygen affinity Hb
- erythropoetin receptor-mediated
- renal disease
- EPO production tumours (type of kidney tumour)
what 2nd line tests for polycythaemia vera would you use if:
- epo was elevated? 3
- epo was normal or low? 3
elevated epo
- chest x-ray
- arterial blood gas
- abdominal ultrasound
normal or low epo
- test for JAK2 mutation
- test for EXON12 mutation
- bone marrow examination
what does a high haematocrit indicate?
what may cause a relatively high haematocrit?
polycythaemia (primary or secondary)
dehydration (as reduced level of plasma means haematocrit rises but no RBCs hasn’t actually risen)
what is thrombopoietin?
aka tpo
similar to erythropoietin (but for platelets instead of RBCs)
stimulate production of megakaryocytes/platelets
what is the genetic mutation that occurs in most myeloproliferative disorders?
why does it encourage the overproduction of blood cells?
JAK2 mutation
means that the epo (or tpo) receptors in the cell membranes of the bone marrow cells are permanently switched on so bone marrow cells think there is a higher amount of epo/tpo than there actually is –> more blood cells!
what is the treatment for polycythaemia vera?
- venesections (taking blood out, ie opposite of traansfusion)
- aspirin daily (prevent platelet clots)
what are the two conditions which polycythaemia vera most commonly develops into?
acute myeloid leukaemia
myelofibrosis
what things can cause reactive thrombocytosis? 9
- surgery
- drug induced
- infection
- inflammation
- iron deficiency
- hyposlenism
- haemolysis
- malignancy
- rebound post chemo
what 2 types of drugs can result in drug-induced reactive thrombocytosis?
- steroids
- adrenaline
if, after doing first line tests to rule out reactive thrombocytosis, there is no known primary cause, what tests would you do?
- look for JAK2 mutation
- look for CALR mutation (similar effect to JAK2)
if those negative then do bone marrow biopsy
what is the treatment for essential thrombocytosis?
- daily aspirin
- assess thrombotic risk factors, if at high risk of clot then do CYTOREDUCTION
what types of cytoreduction are used for patients with essential thrombocytosis who are at high risk of clots? 4
hydroxycarbamide
- suppresses the bone marrow (but affect all bone marrow cells, so will cause anaemia)
interferon
- unknown mechanism but works, however bad side effects
anagrelide
- just targets megakaryocytes but increased risk of myelofibrosis
- P32
how does myelofibrosis present? 3
- pancytopenia (ie all blood cells are low)
- B symptoms
- massive splenomegaly
what are B symptoms? 3
- weight loss
- fever
- night sweats (so drenched you have to change clothes)
“B symptoms are associated with Blood malignancies”
what tests would you do to diagnose myelofibrosis? 4
what would these show?
blood film
- tear drop shaped RBCs
- ertyhroblasts outside bone marrow
bone marrow biopsy
- lots of fibrous bands
JAK2 mutation
- in 50% f cases
CALR2 mutation
- in 30% of cases
what are the common causes of splenomegaly?
what is the acronym to remember these?
CHICAGO
C - cancer
H - haematological (myelofibrosis, CML)
I - Infection (schistomiasis, malaria)
C - Congestion (liver disease/portal hypertension)
A - autoimmune (haemolysis)
G - glycogen storage disorders
O - Other (amyloid etc)
what is the treatment for myelofibrosis? 3
- JAK2 inhibitors
- bone marrow transplant
- supportive care (transfusions, symptom management etc)
what is the prognosis for:
- polycythaemia vera?
- esssential thrombocytosis?
- myelofibrosis?
polycythaemia vera
= good, 15 years
essential thrombocytosis
= good, 20 years
myelofibrosis
= poor, 5 years
what is the median age of diagnosis of chronic myeloid leukaemia?
55-60 years
what are the signs/histological results of chronic myeloid leukaemia (CML)? 4
- leucocytosis
- leucoerythroblastic blood picture (should be in bone marrow)
- anaemia
- splenomegaly
what are the symptoms of CML? 5
why do these occur?
abdominal discomfort
- splenomegaly
abdominal pain
- splenic infarction
fatigue
- anaemia
- catabolic state
venous occlusion (eg retinal vein, DVT, priapism)
gout
- hyperuricaemia
nb about half are asymptomatic and present following an incidental blood test finding
what is priapism?
priapism is an involuntary, prolonged erection unrelated to sexual stimulation and unrelieved by ejaculation
what is the genetic mutation seen in CML?
translocation from C22 (philadelphia chromosome) to C9
- puts together BCR and ABL gene to make BCR-ABL oncogene which makes tyrosine kinase
what is the most effective treatment for CML?
how does it work?
what was the standard treatment before this?
gleevec (imatinib)
a tyrosine kinase inhibitor
-this stops the cell cycle in cancerous cells but, very specific, does not affect healthy cells
interferon was standard treatment before imatinib
what is the main problem with imatinib?
malignant cells can develop resistance to it
in polycythaemia vera, would epo levels be low or high?
low!!
if high, then polycythaemia is secondary to something else
if you have acute gout, what will show up in the blood tests? why?
low uric acid
- as all uric acid has condensed into gout so lower levels in blood
where is gout classically found?
on first metatarsal joint (bottom of big toe)
what is more common: b cell lyphomas or t cell lymphomas?
b cell lymphomas
what do scientists use to work out the differentiation level of different b-cell malignancies?
- presence or absence of certain antigens on the b cell clones indicate what level of maturity/differentiation the clonal cells are at!
which pathway is almost always mutated in lymphoma?
NF-kB pathway (plasma cell differentiation pathway)
what are the 2 different types of light chains on immunoglobulins (aka antibodies)?
kappa
lamda
“sound like names of american sororities - the people in these sororities are often very skinny = light”
what are the 5 different types of heavy chains on immunoglobulins (aka antibodies)?
IgA
- 2 antibodies
- found in mucous, saliva, tears + breast milk
- protects against pathogens
- “Archiologists, always need to work in pairs as work is so boring, do a lot of outdoor work”
IgD
- 1 antibody
- part of the B-cell receptor
- activates basophils + mast cells
- “Dentistry, no one really knows what they do all day, few of them”
IgE
- 1 antibody
- protects against parasites
- responisble for allergic reactions
- very few norm in body
- “economics, likely to rile against really parasites (eg donald trump) but fake ones too (eg poor people), rarely see them”
IgG - 1 antibody - secreted by plasma cells in blood - only Ig able to cross placenta - most numerous "Geography, they are everywhere, able to use a map to get to the placenta"
IgM
- 5 antibodies
- responsible for early stages of immunity
- may be attached to surface of B cell or secreted in blood
- “Medics, always the first to the scene, so keen! hang around in groups”
what is a paraprotein?
what are they indicative of?
a monoclonal immunoglobulin or light chain present in the blood or urine; it is produced by a clonal population of mature B cells, most commonly plasma cells
ie identical Igs (fully formed or not) which are produced by malignant b cell clones
multiple myeloma
how are paraproteins picked up in the blood?
protein electrophoresis (ie looking at the protein content of the blood)
should have lots of albumin (+ other non-Ig proteins) and then a variety of different Igs, but if malignancy then lots of one specific Ig (and fewer other Igs)
multiple myeloma:
- median age at presentation?
- ethnic variation?
- preceeded by?
median age: 70 years
higher incidence in afro-caribbean groups (lower in caucasians)
asymptomatic MGUS
what does multiple myeloma progress to?
plasma cell leukaemia (PCL)
basically myeloma but spread more into blood (not just bone marrow)
what is the diagnostic criteria for myeloma?
- clonal bone marrow plasma cells >10% (of plasma cells in bone marrow)
- OR plasmacytoma present
AND one or more of:
- CRAB features
- MDEs (myeloma defining events)
what is a plasmacytoma?
what are the 2 different types?
A plasmacytoma is a discrete, solitary mass of neoplastic monoclonal plasma cells in either bone or soft tissue
types:
- Soft-tissue = extramedullary plasmacytoma (EMP)
- bone = Solitary bone plasmacytoma (SBP)
what are the ‘CRAB’ features of myeloma?
C - hyperCalcaemia
R - Renal insufficiency
A - Anaemia
B - Bone lesions (seen on imaging)
what are ‘myeloma defining events’ (MDEs)? 3
> 60% clonal plasma cells on bone marrow biopsy
SFLC ratio is over certain threshold (and no. light chains is high)
more than 1 focal lesion on MRI measuring >5mm
what is SFLC ratio?
serum free light chain ratio
measures ratio between kappa and lamda light chains in blood
- should be equal as about same amount produced by healthy cells but if lots of one type being produced by clonal cancer cells then this will skew ratio
also no. of light chains will increase in myeloma as cancer cells don’t bother making whole antibodies
what % of patients with myeloma will have renal insufficiency at some point during the disease course?
50%
what are the 9 main reasons why myeloma is likely to cause renal insufficiency?
- renal vein thrombosis (myeloma is prothrombotic)
- hyperviscosity of blood
- cryoglobulinaemia (Igs in blood clump + become insoluble)
- hypercalcaemia
- bisphosphonates (used to treat hypercalcaemia)
- dehydration (occurs w myeloma)
- CT contrast
- NSAIDs
- ACEi
nb also:
- increased age of patients
- often have comorbidities which require treatment w nephrotoxic drugs
what are the common clinical symptoms of myeloma? 3
- fatigue + malaise
- bone pain (particularly back + rib pain)
- infective episodes (particularly pneumococcal chest infections secondary to failure of production of normal Igs)
what are the symptoms of hypercalcaemia? 4
- anorexia
- confusion
- constipation
- polyuria
what are the symptoms of renal impariment? 2
- confusion
- oligouria/anuria
what is MGUS?
what are the diagnostic criteria?
monoclonal gammopath of uncertain significance
basically ‘pre-myeloma’
- is asymptomatic
- serum paraproteins lower than certain point
- <10% clonal plasma cells in the bone marrow
- absence of end-organ damage (CRAB) or myeloma-related events (MREs)
what is the risk of progression from MGUS to myeloma?
approx 1% a year progress
nb majority progress to myeloma but can also progress to other lymphocyte disorders
what 3 things makes a patient with MGUS more likely to progress to myeloma?
higher paraprotein levels
if have IgA/IgM paraproteins (IgG less likely to progress)
abnormal SFLC ratio
what is AL amyloidosis?
what organs can it affect?
what is the prognosis?
Amyloid Light chain amyloidosis
light chains are abnormally produced, they fold and aggregate in organs -> organ damage
- kidney (nephrotic syndrome)
- liver (hepatomegaly)
- neuropathy (nerves)
- heart (heart failure)
very poor prognosis (but rare
what is the difference between nephrotic syndrome and nephritic syndrome?
nephrotic syndrome
- proteinuria
- hypoalbuminaemia (as albumin is peed out)
- oedema (due to low albumin)
- hyperlipidaemia (liver compensates low albumin by increaasing production, side effect is more lipid production)
“there’s an O in nephrOtic and in prOtein”
nephritic:
- haematuria
- proteinuria (small amount)
- oligouria
nb nephritic is more serious condition as blood cells are bigger than protein so if that’s coming through then kidneys are more damaged
what is the treatment for AL amyloidosis?
same as for myeloma:
- aim to ‘switch off’ production of light chains by the plasma cells
- very difficult to remove the proteins which have already deposited -> significant morbidity + mortality
what are the two different groups of non-hodgkin B lymphomas? give some examples of each
high-grade
- burkitt lymphoma
- diffuse large b-cell lymphoma
low-grade
- follicular lymphoma
- marginal zone lymphoma
- hairy cell leukaemia
- mantle cell lymphoma
what are the differences between high-grade and low-grade lymphomas? 5
onset
- high-grade = sub-acute onset (weeks/couple of months)
- low-grade = months/years
lymph nodes (LN):
- high-grade = lots of LN involved at presentation
- low-grade = only a few LN sites involved at presentation
symptoms:
- high-grade = systemic symptoms (weight loss, night sweats, fatigue)
- low-grade = clinically well
bloods
- high-grade = often abnormal
- low-grade = often normal
prognosis:
- high-grade = curative (very chemoresponsive as high cell turnover), but poor prognosis if relapse
- low-grade = non-curative but relapsing/remitting course over years
what are the possible causes of a neck mass:
- malignant? 3
- non-malignant? 5
malignant:
- lymphoma
- chronic lymphocytic leukaemia (CLL)
- metastatic cancer of lung/breast/cervix
non-malignant:
- infective (bacterial, viral, mycobacterial)
- inflammatory (sarcoidosis)
- lipoma
- fibroma
- haemangioma
what do you see on lymph node biopsies if lots of B cells are proliferating (norm clonally)?
lots of follicles
what is follicular lymphoma?
what genetic mutation is seen?
- a type of low-grade non-hodgkin lymphoma
- neoplastic disorder of lymphoid tissue
- translocation from C14 to C18
- “from the ages of 14-18 people tend to be very cliquey and live in their own little bubbles = follicles”
what is hodgkin lymphoma?
what age does it occur?
- neoplastic lymphocytes characterised by Hodgkin Reed-Sternberg (HRS) cells SURROUNDED BY a lot of non-malignant inflammatory cells (eg eosinophils)
nb HRS cells are large + look like popcorn
nb often present with B symptoms!
can occur at any age!!
what are LDH tests used for?
lactate dehydrogenase tests
- present in all cells of body, if high in blood means there is lots of cellular damage and/or high cell turnover
used to measure progression of:
- some cancers
- kidney problems
- liver disease
(nb used to be used for heart attacks but not anymore)
what is the treatment for hodgkin lympohoma?
- chemotherapy (ABVD)
- —- “like ABCD but get rid of the C for cancer”
- radiotherapy
what is the prognosis for hodgkin lymphoma?
very good
however there are long term effects due to treatments and chance of relapse
what is a pet ct scan?
using pet AND ct scan to find areas of high cell turnover
what does a typical lymph node biopsy of a patient with hodgkin’s lymphoma look like?
big popcorn (hodgkins cells) with lots of inflammatory cells
what is chronic lymphocytic leukaemia (CLL)?
whao is it predominately seen in?
- malignant disorder of MATURE B-cells
- low-grade non-hodgkins lymphoma
- most common type of leukaemia
- seen in older people
what does presenation of CLL vary between?
incidental finding of lymphocytosis
to..
widespread lymphadenopathy, splenomegaly, bone marrow failure + systemic symptoms
what is the system used to stage CLL?
what 3 factors does it use?
binet system
- Hb level (low is bad)
- platelet level (low is bad)
- no. of areas of lympadenopathy (more is bad)
what is a rare, but serious , complication of CLL?
transformation to a high-grade lymphoma
- acute onset of severe symptoms
- rapidly enlarging lyph nodes
- poor prognosis (less than a year, even with chemo)
what is the treatment for any weakness of the bone (also used for hypercalcaemia)?
biphosphates
what are 6 cancers which commonly metastasise to bone? (and so often cause pathological fractures)
- myeloma
- breast cancer
- lung cancer
- prostate cancer
- renal cancer
- thyroid cancer
what is a bence jones protein?
where is it found?
if found, what does it indicate?
monoclonal immunoglobulin light chain
found in the urine
multiple myeloma
what is myeloma?
Myeloma is a malignant disorder of plasma cells whereby neoplastic plasma cells
proliferate in the bone marrow and secrete monoclonal immunoglobulin.
what are the 6 most common clinical presentations of myeloma (aka multiple myeloma)?
- anaemia
- fatigue
- weight loss
- BONE PAIN
- hypercalcaemia
- renal impairment
nb these are a result of:
- bone marrow infiltration
- infiltration into organs
- kidney damage secondary to serum free light chain deposition
name 10 causes of macrocytic anaemia
- B12 deficiency
- folate deficiency
- alcohol excess
- liver disease
- smoking
- hypothyroidism
- pregnancy
- haemolysis (causing a reticulocytosis)
- myeloproliferative neioplasm
- myelodysplastic syndrome
what is the IPSS-R scoring sytem used for?
to work out prognosis of patients with myelodysplatic syndrome (and likelihood of progression to AML)
based on:
- blood count parameters
- blast count
- cytogenetic abnormalities
what are the main sites of haematopoiesis at:
- 1 month gestation
- 5 months gestation
- birth
- adult
1 month = yolk sac
5 months = liver (+ spleen)
birth = bone marrow (in femur + tibia)
adult = - vertebrae - pelvis - sternum (- ribs) (- lymph nodes)
what is the % of foetal Hb at birth?
55-65%
what are the main differences between new born blood and adult blood?
- foetal Hb is larger than adult Hb
- therefore RBCs are also larger
- therefore haematocrit is also higher
what chains make up:
- foetal Hb
- adult Hb
- adult 2 Hb
foetal Hb = a2y2
adult Hb = a2B2
adult 2 Hb = a2d2
(d = delta, y = gamma)
which antibodies can be transfered from mother to baby via:
- the placenta?
- breast milk?
placenta
- IgG ONLY
breast milk
- ALL (IgA, IgD, IgE, IgG, IgM)
at what age to babies start to produce their own antibodies?
at what age can they make a satisfactory immune response?
antibodies = 2-3 months old
satisfactory immune response = 6 months
how to white cell counts differ between newborns and adults?
- similar numbers
but babies have higher lymphocyte counts
how are infant’s and adult’s platelets different?
functionally different, infant’s are:
- hyporesponsive to certain agonists
- hyperresponsive to vWF
so babies are hyperresponsive to blood vessel tears (as vWF lives in endothelial cells)
balances out (ie babies have about the same functionality of platelets as adults)
coagulation factors:
- which cross the placenta?
- which are present (at normal levels) at birth?
- at what age does the infant have adult levels?
NONE cross the placenta
- to prevent clot forming in umbilical cord in the womb
at birth:
- factors 5, 8 and 13
- “5+8 = 13”
normal levels at 6 months
what is the difference between haemorrhagic disease of the newborn and haemolytic disease of the newborn?
haemorrhagic
= haemorrhages in baby due to vit K deficiency
(nb all babies are slightly vit K deficient)
haemolytic
= anti-rhesus antibodies from Rh- mother attack Rh+ baby’s RBCs
how is haemorrhagic disease of the newborn prevented?
all babies are given a vit K injection at birth
what drugs, taken by the mother, will increase the risk of haemorrhagic disease of the newborn in the baby?
- warfarin
- anti-convulsants (aka anti-epileptic drugs)
what are congenital causes of anaemia in childhood? 5
haemoglobin synthesis problem (ie haemoglobinopathy)
- eg sickle cell, thalassaemia
bone marrow failure syndromes
bone marrow infiltration (ie cancer)
peripheral destruction (you are making something but it’s being destroyed)
blood loss
what are the causes of peripheral destruction (leading to congenital anaemia)? 4
ie causes of haemolytic anaemia
Rh/ABO or other incompatibility
membrane defect
- eg hereditary spherocytosis
enzyme defect:
- G6PD deficiency
- Pyruvate Kinase (PK) deficiency
infection
what is hereditary spherocytosis?
why does it result in haemolytic anaemia?
how do the cells look on a blood screen?
spherical RBCs, not flexible, will break at the slightest insult
(so much shorter lifespan than normal RBCs)
(nb normal RBCs bend to fit through capillaries, spherical RBCs can’t do this so break)
RBCs don’t have the normal central palor on blood screen
what is G6PD deficiency?
deficiency of enzyme Glucose 6 Phosphate Dehydrogenase
causes haemolytic anaemia in presence of:
- fava beans (and other foods)
- infection
- some drugs
what are two causes of congenital blood loss?
- twin to twin transfusion (nb twin with extra blood is also not healthy as blood is too thick, hard to get through capillaries)
- fetomaternal haemorrhage
What is a common cause of acquired anaemia in children?
- iron deficiency
nb B12 + folate deficiencies in children are rare - unless mum is vegan
what are three congenital causes of bleeding/bruising?
- platelet problem
- clotting factor problem
- connective tissue disorder
what is the function of the globin part of the haemoglobin molecule? 3
- protects haem from oxidation
- renders the molecule soluble
- permits variation in oxygen affinity (resulting in sigmoid dissociation curve)
what are the % of HbA, HbA2 + HbF in normal adult blood?
HbA = >95%
HbA2 = <3.5%
HbF = <1%
what are thalassaemias (alpha or beta)?
change in globin gene expression (none or reduced rate) leads to reduced rate of synthesis of NORMAL globin chains. Pathology is due to imbalance of alpha and beta chain production (free globin chains damage red cell membrane)
(nb sickle cell disease produces correct amount of globin proteins, they are just abnormal!)
what physiological changes occur in the blood during pregnancy? 8
- plasma volume expands by 50% (therefore lower haematocrit) - called HAEMODILUTION
- RBC mass expands by 25%
- increased requirement for iron (often become iron deficient)
- leucocytosis (mainly a neutrophilia)
- left shift (outflow of some blasts into blood)
- thrombocytopenia (normal but rule out other causes too!)
- increase in coagulation factors + thrombin generation
- reduction in anti-coagulant factors + fibrinolysis
nb pregnancy (+ 2 months following birth) is a pro-thrombotic state -> ^risk of clots
what do RBCs look like in thalassaemias?
small, pale and red
ie microcytic anaemia
(resembles iron deficient anaemia)
sickle cell anaemia:
- what is the NORMAL genetic cause?
- why does it cause RBCs to ‘sickle’?
valine substituted for glutamine at position 6 of the B globin gene
Sickle Hb polymerises at low oxygen saturations to form long fibrils (tactoids) which distort RBC membrane –> sickel shape
what is the average lifespan of:
- sickle cell?
- normal RBC?
sickle = 10-20 days
normal RBC = 120 days
what can reduce the levels of polymerisation of sickle Hb?
if other Hb is present, eg foetal Hb
apart from the direct effects of sickling caused by sickle cell disease, what secondary effects does this cause?
inflammatory response due to haemolysis of sickle cells, confusing, don’t need to know detail
what are the acute complications of sickle cell disease?
- vaso-occlusive crisis (aka sickle cell crisis, accounts for 80% of hosp admissions)
- septicaemia
- aplastic crisis (temporary cessation of RBC production)
- sequestration crisis (spleen, liver)
what are reticulocytes?
Reticulocytes are immature red blood cells, typically composing about 1% of the red blood cells in the human body. In the process of erythropoiesis, reticulocytes develop and mature in the bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells
so if you have a high reticulocyte count then likely to have a haemolytic anaemia so your boduy is producing more RBCs
where in the body do sickle cell crises normally occur?
- hands and feet (dactylitis)
- chest syndrome
- mesenteries (abdo pain)
- bones (long bones, ribs, spine)
- brain
- penis (priapism)
what is a sequestration crisis?
Splenic sequestration crises are acute, painful enlargements of the spleen, caused by intrasplenic trapping of red cells and resulting in a precipitous fall in haemoglobin levels with the potential for hypovolemic shock.
which acute complication is the highest cause of mortality in sickle cell patients?
chest syndrome
nb opiate painkillers given for painful crisis decrease resp drive + so may be a contributing factor to chest syndrome
what are four chronic complications of sickle cell disease? 9
hyposplenism
- due to infarction + atrophy of spleen
renal disease
avascular necrosis (AVN) of femoral/humeral heads - due to poor collateral circulation, if clot, no blood can get there
leg ulcers
osteomyelitis
gall stones
retinopathy
cardiac problems
resp problems
what is osteomyelitis?
infection in the bone
what treatment do sickle cell disease sufferers recieve from age 6 months?
penicilin
as prophylaxis
what treatment is given in a vaso-occlusive (sickle cell) crisis?
- analgesia (norm opiates)
- hydration
- treatment of precipants
(nb no evidence that transfusions help in crises!)
what treatment is given to sickle cell patients who have a lot of vaso-occlusive crises?
how does it work?
hydroxycarbamide
- increases Foetal Hb
(thus reducing polymerisation)
(also acts as an anti-inflammatory, reduces inflammatory response to crisis, recover quicker!)
when would you give a blood transfusion (or exchange) to a sickle cell patient? 5
- splenic sequestration
- aplastic crisis
- acute chest crisis
- acute stroke
- pre-operative
what treatment is given to sickle cell patients to reduce burden of chronic complications? 5
transcranial doppler
- monitors blood flow in brain, likelihood of stroke
MRI
- for monitoring of avascular necrosis of bone ends
- may need joint replacement
cholecystectomy
- for symptomatic bilary disease
monitoring of renal function via blood tests
opthalmic review (annually)
nb can be cured by bone marrow transplant!
what is it called if you are:
- heterozygous carrier of a thalassaemia?
- homozygous for a thalassaemia?
heterozygous = thalassaemia minor (clinically normal)
homozygous = thalassaemia major
nb thalassaemia is a very heterogeneous condition! many mutations cause it and all have slightly different phenotypes, also have thalassaemia intermedia!
what complications can occur due to thalassaemias?
- pulmonary hypertension
- extramedullary haemaopoiesis (start making blood in liver + spleen)
- bone changes + osteoprosis
- endocrine + fertility problems
- leg ulcers
nb lots of problems are caused by iron overload as body brings in more iron from guts as wants more Hb but RBCs are also breaking down releasing more Hb/iron and body has no way of excreting iron!
what is the pathophysiology of B-thalassaemia major?
alpha chain excess
- > ineffective erythropoiesis (RBCs die in marrow)
- > shortened RBC lifespan (haemolysis)
- —> anaemia
increased marrow activity
- > skeletal deformity, stunted growth
- > increased iron absorption from gut + organ damage (exacerbated by blood transfusion)
- > protein malnutrition
enlarged + overactive spleen (+liver)
- > pooling of RBCs (increased anaemia)
- > increased transfusion requirement
- > extramedullary haemopoiesis
what head bone abnormalities can occur in thalassaemias? why?
- frontal bossing
- maxillary hypertrophy
- -> abnormal dentition
all due to expanded bone marrow
what is the treatment for B-thalassaemia major?
monthly transfusions
- suppress marrow RBC production
- prevents skeletal deformity
- prevents liver/spleen enlargement
iron chelation therapy
- to prevent iron overload
(bone marrow transplant)
- nb only successfukl if early in life + before iron overload occurs
what different types of iron chelation therapy are there?
how is iron level monitored?
- long subcutaneous injection (via overnight syringe pump) of DESFERRIOXAMINE (older treatment)
- new oral iron chelators (inlcude DEFERIPRONE + DEFERASIROX)
“the longer drug name takes the longer time to give”
measuring ferritin levels in the blood
(nb ferritin is a carrier of iron in the blood)
what comlications can be seen in B-thalassaemia major?
increased rate of infections
- eg line infections (as loose peripheral access)
- eg transfusion transmitted infection
endocrine complications
- eg can get diabetes
- eg hypothyroidism + hypoparathyroidism
liver disease
- cancer can develop secondary to cirrhosis + iron overload
bone problems
- give bisphosphates, don’t over-chelate
fertility
- issues due to hypogonadism
- norm need IVF to stimulate ovaries
- need low iron + perfect health before get pregnant
what organs are affected by iron overload? what happens?
gonads/hypothalamus
- failure of puberty, growth failure
pancreas
- diabetes
heart
- dilated cardiomyopathy + heart failure
liver
- cirrhosis
what are the three corners of virchovs triangle?
- blood flow
- blood composition
- vascular endothelium
factors which affect risk of arterial or venous clots
which parts of virchovs triangle are normally abnormal in formation of:
- arterial clots?
- venous clots?
arterial clots:
- vascular endothelium (atheromatous plaques)
venous clots:
- blood flow (stasis)
- blood composition (hypercoaguable state)
what are the main components of:
- arterial clots?
- venous clots?
arterial:
- mainly platelets
venous
- mainly fibrin
what % of DVTs are clinically silent?
80%
what are the risk factors for venous thromboembolism (VTE)? 16
- oestrogen containing contraceptive
- pregnancy + post-natal period
- hormone replacement therapy
- active cancer (or cancer treatment)
- critical care admission
- surgery
- major trauma
- immobility
- one or more significant medical comorbidities
- varicose veins with phlebitis
- known thrombophilias
- personal history of VTE
- first degree relative with VTE
- age over 60
- obesity
- dehydration
what are 3 bits of general advice of how patient risk of VTE can be easily reduced?
- don’t allow patients to become dehydrated (unless clinically indicated)
- encourage patients to mobilise as much as possible
- do not regard aspirin (or other antiplatelets as adequate prophylaxis for VTE)
what are the two type of prophylaxis for VTE?
- TED stockings
- low-dose anticoagulant (normally low-dose lmwh)
who can’t use TED stockings?
patients who have:
- peripheral neuropathy
- peripheral blood problems
- skin problems
what’s the difference between unfractionated heparin and lmwh?
both enhance the effect of antithrombin!
unfractionated:
- acts on thrombin AND factor 10a
- also acts on other molecules
- less reliable effect
lmwh:
- only acts on factor 10a
- more reliable effect
if a patient has a suspected VTE, what tests should you do?
calculate likelihood of risk using WELLS SCORE
if wells
what is the gold standard test for:
- DVT?
- PE?
DVT = ultrasound
PE = multislice CT with contrast
if a patient with a suspected PE cannot have a multislice CT with contrast, what scan can they have instead?
how does this work?
who would this be used for?
VQ scan
- inhaled radioisotope is administered to look for ventilation
- injected radioisotope is administered to look for perfusion
- then compare images to see if any mismatches
useful for:
- pregnancy (no x-rays)
- renal insufficiency (contrast is nephrotoxic)
what is the normal treatment for confirmed VTE?
- high dose lmwh
- – then start and gradually shift over to warfarin (heparin is faster acting)
what is the newer alternative treatment for VTE?
NOACs
eg rivaroxaban + apixaban
- they work as DIRECT factor 10a inhibitors (heparin + warfarin work via anti-thrombin)
- they can be used as one drug (ie not like lmwh then warfarin)
- can be taken orally
- predictable effect, less dose monitoring
- however there is no antidote!
“apiXAban = inhibits Xa, ie 10a”
name 6 heritable thrombophilias
- antithrombin deficiency
- protein C deficiency
- protein S deficiency
- Factor V leiden (aka activated protein C resistance)
- dysfibrinogenaemia
- prothrombin 20210A
name an acquired thrombophilia
antiphospholipid syndrome
an autoimmune condition
- get autoantibodies against negatively charged phospholipids
- confusing but main effect is that it increases risk of arterial and venous thrombosis
nb can occur secondary to lupus (SLE)
what is factor V leiden
aka activated protein C resistance
basically, normally protein C cleeves activated factor 5 to break up clots
- however, in factor V leiden, the protein C can’t bind to the factor 5a (as it’s mutated) and so cannot deactivate it!
leading to a prothrombotic effect
nb most common european familial thrombophilia (can be heterozygous or homozygous)
nb interacts with other VTE risk factors, unlikely to cause a clot on its own but has an additive effect
what is prothrombin 20210A?
- point mutation in enhancer region of prothrombin gene
leads to INCREASED prothrombin levels
–> increased likelihood of clots
a weak risk factor for VTE on its own, interacts with other risk factors to have an additive effect
in haematology, what is MCV?
mean cell volume
used to differentiate between macrocytic, normocytic + microcytic anaemia
what are 7 causes of macrocytic anaemia?
- B12 deficiency
- folate deficiency
- alcohol
- liver damage
- drugs (cytotoxics/folate antagonists/N2O)
- haematological malignancy (or other bone marrow problems)
- haemolysis (due to increased production of reticulocyte, which are bigger than mature RBCs)
what are 2 causes of normocytic anaemia?
- anaemia of chronic disease
- blood loss
what are 3 causes of microcytic anaemia?
- iron deficiency
- haemoglobin disorders (sickle cell, thalassaemia)
( - sometimes anaemia of chronic disease)
in the body, what molecules is iron:
- transported by?
- stored in?
where in GI tract is iron absorbed?
can iron be excreted?
transported by transferrin
stored in ferritin
absorbed in duodenum (+ bit in jejunum)
no!
what lab test is most commonly used to diagnose iron-deficient anaemia?
ferritin
there is no other known cause of low ferritin apart from iron deficiency
what type of RBCs are present in iron-deficient anaemia?
microcytic (low MCV)
AND
hypochromic (low MCH)
MCH = mean cell Hb
what are the main causes of iron deficient anaemia? 3
blood loss from anywhere (sub-acute/chronic)
increased demand
- pregnancy/growth
reduced intake
- diet/malabsorption (eg coeliac)
what are the most likely causes of iron-deficient anaemia in:
- children? 3
- young women? 3
- old people?
children:
- diet
- growth
- malabsorption
young women:
- menstrual loss/problems
- pregnancy (even long after)
- diet
old people:
- bleeding
- GI problems (malignancy, ulcer, gastritis, diverticulitis, GI surgery etc)
nb in elderly rule out bleeding + canceer first as these most severe
what is the treatment for iron deficient anaemia?
- iron tablets (but can be poorly tolerated due to GI side effects)
- IV iron, better tolerated
how does B12/folate deficiency cause anaemia?
- DNA consists of purine/pyramidine bases
- folates are required for their synthesis
- B12 is essential for cell folate generation
- so low folate OR B12 starves DNA of bases
so they are clinically indistinguishable
problems with what things cause B12 deficiency?
- gastric parietal cells (produces intrinsic factor)
- intrinsic factor (binds to B12 to allow absorption)
- receptors in terminal illeum (where intrinsic factor/B12 complex absorbed)
nb low dietary B12 causing B12 deficiency is very rare! as only need a small amount and is stored for long periods of time (years)
nb also get a lower level in pregnancy but this is normal doesn’t need treatment
what are 2 diseases affecting the stomach can cause B12 deficiency?
pernicious anaemia
- autoimmune antibodies against intrinsic factor/parietal cells
gastrectomy
give 6 example of diseases of the small bowel which can cause B12 deficiency
- terminal illeum resection
- crohns
- stagnant loops
- jejunal diverticulosis
- tropical sprue
- fish tapeworm
what are the causes of folate deficiency?
- mainly dietary/malnutrition cause
- also malabsorption/small bowel disease
also if increased usage:
- pregnancy
- haemolysis
- inflammatory disorders
- drugs/alcohol/ITU
what are the signs + symptoms of B12/folate deficiency? 6
megaloblastic anaemia
- can have pancytopenia if more severe (esp in advanced B12 deficiency)
mild jaundice
glossitis (inflammation of tongue)
angular stomatitis (inflammation of lips)
anorexia/weight loss
sterility
what is a severe complication of B12 deficiency? (normally of pernicious anaemia)
what happens?
how can this present? 4
subacute combined degeneration of the cord (SACDC)
- demyelination of dorsal + lateral columns
- peripheral nerve damage
presents as:
- peripheral neuropathy/paraesthesiae
- numbness + distal weakness
- unsteady walking
- dementia
nb may get this before anaemia presents
always think about B12 deficiency when a patient has neuro symptoms
what is the treatment for:
- folate deficiency?
- B12 deficiency?
folate:
- folic acid pills daily
B12:
- 3 monthsly IM injection of B12
(- can have oral B12 if know it’s not pernicious anaemia)
causes of haemolytic anaemia:
- things that are wrong inside RBC? 2
- things that are wrong with RBC membrane? 1
- things that are wrong external to RBC? 4
inside cell:
- haemoglobinopathies (sickle cell, thalassaemias)
- enzyme defects (G6PD)
membrane:
- hereditary conditions (eg hereditary spherocytosis)
external:
- antibodies to RBC membranes
- drugs/toxins
- faulty heart valves
- vascular/vasculitis/microangiopathy
what are the 4 main things to test for in the blood if you suspect haemolysis?
- high MCV (body compensating)
- high reticulocytes (body compensating)
- raised bilirubin
- raised LDH
nb also look at blood film for fragments/spherocytes/etc
what test do you use to test if there are antibodies attacking RBCs?
DCT/DAT
direct coombes test/direct anti-globulin test
tests to see if there are any anti-RBC antibodies in blood
what is the treatment for autoimmune haemolytic anaemia (AIHA)?
managed with steroids/immunosuppression
if severe: transfusion (but hard to reliable crossmatch!)
with what sort of conditions do you normally see ‘anaemia of chronic disease’?
why?
- malignant
- inflammatory
- chronic infectious
- multiple medical diseases
- etc
reduced RBC production due to:
- abnormal iron metabolism
- poor erythropoetin production
- poor erythropoetin response
- blunted marrow response
it’s basically an inflammatory effect on bone marrow - often have raised inflammatory markers
nb this is a diagnosis of exclusion, exclude any other causes of anaemia first
how do you treat ‘anaemia of chronic disease’?
if underlying disease is treated anaemia normally resolves
- but this is often hard
- give erythropoietin and/or iron if they are symptomatic
(can do transfusions if nothing else works)
what sort of things can cause thrombocytopenia? 9
- ITP
- other autoimmune disorders
- drugs/alcohol/toxins
- liver disease and/or hypersplenism
- pregnancy (physiological + complications, eg ITP, preeclampsia)
- haematological/marrow diseases
- infections (eg acute sepsis, HIV, other viral)
- DIC
- range of congenital conditions
nb there are many more
what is ITP?
what conditions can it be associated with? 4
immune (formerly idiopathic) thrombocytopenic purpura
autoimmune condition against antigens on platelets
can be: acute/chronic/relapsing
associated with:
- lymphoma
- CLL
- HIV
- other autoimmune disease
nb kids often have a preceding illness (prodrome) whereas adults tend not to
“12 year old pregnant diver in House had this”
how does ITP present?
bruising, petechiae and/or bleeding
low platelet count (but can vary hugely)
nb this is a diagnosis of exclusion! no definitive test
what is the treatment for ITP? 4
steroids (first line)
IV immunoglobulin (2nd line)
other immunosuppressives or splenectomy (3rd line)
newer thrombo-mimetics (eltrombopag, romiplostin)
- stimulate platelet production (mimic thrombopoetin)
nb usually rapid response to treatmetn but can relaps + commonly recurrent (though rarely life-threatening)
why do you give someone IV immunoglobulins if they are suffering from ITP/how do they work?
if you saturate spleens (and other lymphatics) with exogenous Igs then spleen ‘chews up’ them instead of platelets (so fewer platelets destroyed)
- however this is a temporary solution as, once Igs are ‘chewed up’, spleen wil go back to destroying platelets instead
what is TTP?
why does it occur?
what are the signs/symptoms?5
thrombotic thrombocytopenia purpura (TTP)
extensive microclots throughout circulation (damaging organs, incl kidneys, heart + brain)
autoimmune anitbodies against enzyme ADAMTS-13 (this normally reduces the action of vWF) increasing potency of vWF so any slight endothelial injury results in lots of clots
- so basically have too much vwf
signs/symptoms:
- thrombocytopenia (all used up in clots)
- fever
- neurological symptoms
- haemolysis (retics/LDH)
- bleeding
nb this is a lot rarer than ITP but is a lot more serious
what is the treatment for TTP?
- plasma exchange with FFP/plasma
- steroids
(monitor ADAMTS-13 level in case of relapse)
what is acute leukaemia?
what are the 2 main subgroups?
result of accumulation of early myeloid or lymphoid precursors in the bone marrow, blood and other tissues
may arise de novo or be the terminal event of a pre-existing blood disorder
- acute myeloid leukaemia (AML)
- acute lymphoblastic leukaemia (ALL)
what histological feature do blast cells have that mature ones do not?
nucleoli
- appear a small white circles in the nucleus
what are the main symptoms of acute leukaemia? 3
which organs may leukaemia cells infiltrate? 5
- anaemia
- infections
- easy bruising + haemorrhage
- spleen
- liver
- meninges
- testes
- skin
which type of leukaemia is most likely to infiltrate the meninges?
why is this important?
acute lymphoblastic leukaemias (ALL)
because of the blood-brain barrier, once the cancer has spread to CNS it’s harder to get drugs to the cancer cells via normal route (eg IV) so have to do spinal injections which are higher risk
name 3 examples of common infections in leukaemia patients.
what type of leukaemias are most likely to lead to each one?
staphylococcus aureus infection of the orbit (around eye)
- AML
mixed perianal infection with strep faecalis + E. coli
- AML
oral candida
- ALL
what are haemorrhagic ecchymoses?
how are they different from purpura?
in what type of leukaemia do you tend to get this? why?
a sub-cutaneous spot of bleeding not caused by trauma but by underlying cell pathology (ie clotting problems)
same as purpura, but larger
AML
- as platelets are derived from the myeloid lineage
at what level of platelet count do you get spontaneous bruising and bleeding?
platelet count below 10
what specific type of leukaemia often causes gum infections and hypertrophy?
monocytic leukaemia
- a type of AML
what tests are done to confirm a leukaemia diagnosis? 4
- blood smeer (morphology of cells)
- immunological markers
- cytogenetics, FISH
- molecular techniques (PCR - polymerase chain reaction)
what was the ‘old’ and what is the ‘new’ classification of AMLs?
old: FAB classification = ‘morphological’
new: WHO classification = ‘risk adapted’
ie new one is about working out the likely prognosis of the cancer and using that to guide appropriate treatment decisions
what is the normal process of myeloid cell maturation (to a neutrophil)?
(ie what are the 6 intermediate cell types)
myeloblast -> promyelocyte -> myelocyte -> metamyelocyte -> band -> neutrophil
nb shape of nuclei:
- metamyelocyte = kidney
- band = horseshoe
- neutrophil = lobed
what feature is typically of promyelocytic leukaemia?
what is the treatment?
- how does it work?
when you give chemo:
- get DIC
because cellular contents are very procoagulant so when the cells are broken down (due to chemo) these are released -> DIC (+ related clotting problems)
treatment:
- give chemo AND all trans retinoic acid (ATRA)
ATRA makes premyelocytes mature to neutrophils (fewer procoagulant contents) so when chemo breaks cells down, DIC doesn’t occur!
what histological findings are often present in the blast cells found in AML?
auer rods
small linear red lines (of crystalised granules)
what is the philadephia translocation?
in which leukaemias is this found?
exchange of material between C22 + C9
(9 becomes longer, 22 shorter)
BCR-ABL fusion gene created on C22 –> tyrosine kinase
- CML - 95%
- ALL - 25%
(- AML - occasionally)
what is the treatment for AML in:
- favourable risk groups?
- intermediate risk groups?
- poor risk groups?
give chemo to all first
favourable risk groups
- chemo
intermediate risk groups
- depends
poor risk groups (or younger patients)
- bone marrow transplant
what are poor prognostic risk factors in ALL? (2 major, 4 minor)
major risk factors:
- increasing age (kids do very well)
- high white cell count (at presentation)
minor risk factors:
- male
- certain cytogenetic abnormalities
- poor response to treatment
- T-ALL and null-ALL (ie if B-cell then best prognosis)
what is the treatment for ALL? 3
all patients:
- intensive chemo
- intrathecal methotrexate (prophylaxis of meningeal leukaemia)
- cranial irradiation (prophylaxis of meningeal leukaemia)
then:
- good risk patients = maintenance chemo
- bad risk patients = bone marrow transplant
what is the main complication of treatment of acute leukaemia?
what is the treatment?
neutropenic sepsis
all patients w acute leukaemia will become neutropenic during treatment
puts at high risk of BACTERIAL infection -> sepsis
treatment:
- IMMEDIATE broad-spectrum antibiotics (within an hour) - eg tazocin + gentamicin
nb given before get results of cultures, then can make treatment more specific
what is done to prevent neutropenic sepsis? (incl drug names) 5
- protective isolation (sterile hospital room)
- prophylactic antibiotics (LEVOFLOXACIN)
- use of granulocyte colony stimulating factors
- strict hand hygiene
- patient education
what are the large cells characteristic of hodgkins lymphoma called?
reed sternberg cells
“popcorn cells”
inflammatory cells almost always found with them
“hodgkins sounds like a hedge, and both hedges and reeds are plants, so with hodgkins you get reed sternberg cells”
name a NOAC which is a direct thrombin inhibitor
dabigatran
what is the most common type of non-hodgkins low-grade lymphoma?
follicular lymphoma
called because the abnormal b lymphocytes cluster in lymph nodes to form, what are called, follicles
what is the suffix of lmwh’s?
give an example
-parin
“like hePARIN”
enoxaparin
a transfusion related lung injury (TRALI) is a reaction against which cells?
leucocytes
what are the two main functions of vwf?
- to transport factor 8 in the blood (factor 8 degrades rapidly when not bound)
- it binds to exposed collagen (ie when endothelium is damaged) and then binds to platelets
(effectively forming a bridge between damaged endothelial wall and platelets) + activating the platelets in the process
-> degranulation of platelets
platelets secrete:
- more vwf
- fibrinogen
- serotonin -> vasocomstriction
- ADP -> activates platelets
- Ca2+ -> secondary haemostasis
- thromboxane -> vasoconstriction, activates platelets + causes activation
where is vwf produced/stored? 2
- in granules in platelets
- in granules in endothelial cells
why does aspirin have an anti- platelet effect?
becuase it is a COX inhibitor
COX is the enzyme which (among other things) synthesises thromboxane in platelets
so without thromboxane, have less vasocnstriction, activation + aggregation of platelets
what is the mechanism of clopidogrel (another anti-platelet)?
interferes with ADP receptor
another way that platelets are activated
what clotting time is used to monitor anticoagulation with warfarin? aka? why?
prothrombin time
INR
because this measures the EXTRINSIC pathway which is the one in whick the vit K dependent factors are in
“1972”
what is the sickle cell mutation?
when the 6th amino acid is mutated from glu -> val
what ethnic group are thalassaemias particularly common in?
greeks
esp greek cypriots
what globin chains do you have an excess of in:
- alpha thalassaemia?
- beta thalassaemia?
alpha thalassaemia:
- excess of beta chains
beta thalassaemia:
- excess of alpha chains
why do thalassaemias lead to skeletal deformities?
because increased activity in bone marrow to compensate for the haemolytic anaemia
so messes up structure of bone thus changing the morphology and reducing the strength
