Haem Flashcards
Define antiphospholipid syndrome
Characterized by the presence of antiphospholipid antibodies (APL) in the plasma, venous and arterial thromboses, recurrent foetal loss and thrombocytopenia.
Explain the aetiology / risk factors of antiphospholipid
syndrome
Difference between primary and secondary
Which individuals are susceptible
What is the genetic and environmental factors leading to the disease
What is the name of the main antiphospholipid antibody?
What is the effect of this antibody
Name another anti-phospholipid antibody
What other condition are these antibodies present in, and what is the implication of this?
What leads to -clotting -thrombocytopenia -anaemia in APS
AUTOIMMUNE
Antiphosholipid antibodies attack phosphilipids in the cell membrane, or plasma proteins bound to those anionic phospholipids.
Primary=happens by itself
Secondary=occurs with other AI diseases
APL may develop in susceptible individuals (e.g. those with rheumatic diseases e.g. SLE) following exposure to infectious agent –> secondary APS
Associated with mutated HLA-DR7 gene, allows production of APL antibodies
Once APL antibodies are present, second hit needed for development of syndrome (an environmental trigger)
Environmental triggers:
- Infections (syphilis, HIV, hep C, malaira)
- Drugs (CVS: procainamide, quiniine, propanalol, hydralazine; antipsychotics: phenytoin, chlorpromazine)
Main antiphospholipid antibody anti-beta2-glycoprotein I
This antibody targets anti-beta2-glcoprtein I, aka Apolipoprotein H. This lipoprotein usually inhibits agglutination
The procoagulant actions of APL is explained by their effect on b2 glycoprotein-I (clotting and platelet aggregation inhibitor), protein C, annexin V, platelets and fibrinolysis.
(remember that one of the key features of APS is arterial and venous thromboses)
Another anti-phospholipid antibody is anti-cardiolipin which targets the cardiolipin phospholipid in the inner mitochondrial membrane. This Ab is also present in syphilis, so having APS may lead to a false positive result for syphilis
See above for clotting, but autoantibodies targeting platelets and RBCs leads to thrombocytopenia and anaemia respectively.
Complement activation critical for pregnancy complications
Summarise the epidemiology of antiphospholipid syndrome
More common in young women
Accounts for 20% of strokes in < 45-yearolds and 27% of women with > 2 miscarriages.
Recognise the presenting symptoms of antiphospholipid syndrome
What is catastrophic antiphospholipid syndrome
Recurrent miscarriages (due to thrombosis leading to placental infarction),
history of arterial thromboses (stroke),
venous thromboses (DVT, pulmonary embolism),
renal failure (due to small capillaries, and the effects of clots here)
headaches (migraine),
chorea,
epilepsy
catastrophic antiphospholipid syndrome= rapid organ failure due to generalised thrombosis
Recognise the signs of antiphospholipid syndrome on physical examination
typical skin finding?
Livedo reticularis (swelling of venules due to obstructing clot).. appears as a mottled, purplish discolouration of skin
Signs of SLE (malar flush, discoid lesions, photosensitivity).
Signs of valvular heart disease (libman sachs endocarditis, see card below!)
Identify appropriate investigations for antiphospholipid syndrome and interpret the results
Diagnosis requires 1 clinical and 1 lab diagnosis criteria
Clinical criteria: 1. Hx thrombosis 2. Pregnancy complications
FBC (reduced platelets), ESR (usually normal), U&Es (APL nephropathy), clotting screen (raised APTT).
Presence of APL may be demonstrated by:
- ELISA testing for anticardiolipin and antib 2-GPI antibodies.
- Lupus anticoagulant assays: Clotting assays showing effects of APL on the phospholipiddependent factors in the coagulation cascade.
False-positive VDRL test for syphilis may be a clue to the presence of any type of APL.
Define haemolytic uraemic syndrome
Characterised by triad of:
- Microangiopathic haemolytic anaemia (it is one of the 3 causes, the other 2 are TTP and DIC)
- Thrombocytopenia
- Acute renal failure
The condition is categorised by whether it is associated with diarrhoea (D+, typical) or not (D-, atypical)
Epidemiology of HUS
Mainly children < 5 years of age
What causes haemolytic syndrome
1) Bacterial infection with E Coli O157:H7 (due to shiga like toxin), or shigella. This initially causes bloody diarrhoea too (D+). Infected from outbreaks after eating uncooked contaminated meat.
2) D negative form include pneumococcal lung infection, drugs (ciclosporin, some chemo agents), bone marrow transplant and pregnancy
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How does bacterial infection cause haemolytic uraemic syndrome
E Coli O157:H7 or shigella bind to intestinal wall and are picked up by white cells.
The kidneys have Gb3 receptor which picks up the antigens on the white blood cell. This causes death of the endothelial cells in the renal vasculature.
These dead endothelial cells are replaced by primary haemostasis with platelet plug, which then gets held together by fibrin.
Lots of endothelial cells die so there are lots of clots in the kidneys which consumes platelets. The deposited fibrin then slices RBCs up leading to MAHA.
There is also acute kidney injury
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Recognise the presenting symptoms of haemolytic uraemic syndrome
GI: severe abdominal colic, watery diarrhoea that becomes blood stained (due to the E Coli/shigella infection)
General: malaise, fatigue, nausea, fever <38 (in D+ form)
Renal: oliguria/anuria, haematuria
Recognise the signs of haemolytic uraemic syndrome on physical examination
General: Pallor (anaemia), slight jaundice (haemolysis), bruising (severe thrombocytopaenia), generalised oedema, HTN and retinopathy
GI: Abdo tenderness
Identify appropriate investigations for haemolytic uraemic syndrome and interpret the results
1st investigations:
FBC: anaemia, thrombocytopaenia
Peripheral blood smear:
To identify schichtocytes and to confirm the thrombocytopaenia
Renal function: Raised creatinine
Electrolytes: Abnormalities due to diarroeah or AKI. Include hyperkalaemia, hyponatraemia, acidosis etc.
PT, PTT: Both must be normal (if not, may suggest DIC)
Raised LDH from broken down RBCs
Low serum haptoglobin (it takes up haemolysed RBCs and then is removed by the liver/spleen)
Stool culture (SORBITOL-MACCONKEY AGAR) to detect shiga toxin producting E. Coli (needs to be done early in the course of diarrhoea though)
PCR to detect shiga toxin 1/2
Complement: abnormal levels of complement in familial and some cases of atypical HUS
The most common cardiac manifestation of SLE is
Pericarditis most common
Libman sacks endocarditis also common (this is also associated with antiphospholipid syndrome)
In antiphospholipid syndrome, who are arterial and venous thromboses more common in
What are the complications of each, generally and in APS
In APS there is a hypercoagulable state, causing thromboses in arteries and veins
Arterial thromboses more common in males.
Complications: heart attach, stroke, limb ischaemia
AND
(in APS) Libman Sacks endocarditis (vegetations (mixture of immune cells and blood clots) can affect the mitral valve)
Venous thrombosis more common in females. Typically present as DVT,
Complications: pulmonary embolism
Define vitamin B12
Which foods contain b12
Outline the normal absorption of b12
How much can the body store of b12
What is the job of b12
Reduced levels of vit b12 in the body
Present in egg, meat, milk but NOT in plants,
The protein containing the b12 is broken down using pepsin. It is then bound to IF (produced by gastric parietal cells). The b12-IF complex is recognised by the enterocytes lining the terminal ileum. Once absorbed, b12 is bound to transcobalamin
Body can store 4yrs of b12
Jobs:
- Allows conversion of dUMP to dTMP which is then converted into thymidine (essential for cell division)
- Also allows for conversion of homocysteine to methionine (too much homocysteine is harmful)
- Also helps to reduce methylmalonic acid
Explain the aetiology / risk factors of vitamin B12 deficiency
b12 deficiency results in reduced cell division and a build up of homocysteine and methylmalonic acid
BLOOD:
Macrocytes are produced which are destroyed in the spleen leading to anaemia, after which megaloblasts are released into the blood. Leads to macrocytic megaloblasic anaemia
Hypersegmented nuclei (>5 lobes)
Reduced production of megakaryocyte.
Can lead to pancytopenia (as can folate deficiency)
TONGUE:
Old epithelial cells aren’t replaced, reducing ability to heal when there is wear and tear of the tongue. This leads to inflammation= GLOSSITIS
ATHEROSCLEROSIS:
Homocysteine can bind to endothelial cells leading to proinflammatory cytokine release attracting immune cells. Narrowing of arteries and ischaemia. Homocysteine also increases increases platelet aggregation. So you are at increased risk of heart attack and stroke!
NEUROPATHY:
Methylmalonic acid can build up and accumulate in myelin sheaths, which causes it to degenerate. Can slow conduction in nerves and muscles. Subacute combined degeneration of the spinal cord
Reduced intake:
-(see above)
Reduced absorption:
-Crohn’s the enterocytes in terminal ileum might be damaged (so the b12 cannot bind to transcobalamin),
- Pernicious anaemia (IgA antibodies against IF OR the parietal cells),
- Gastric bypass (food passes through stomach quickly so IF can’t get to food to bind b12 fast enough) or gastric atrophy (reduced stomach acid production so not enough b12 is released)
- Diphyllobothrium latum (fish tapeworm) infestation/bacterial overgrowth
Risk factors:
Being long term vegan and not taking vit b12 supplements
What is subacute combined degeneration of spinal cord
Mix of UMN and LMN signs
UMN sign: symmetrical corticospinal tract loss, so causes UMN motor sign
LMN: Dorsal column loss causing LMN and sensory signs
Joint position and vibration affected first leading to ataxia followed by stiffness and weakness if untreated.
Classic triad: Extensor plantars (UMN), absent knee jerks (LMN) and absent ankle jerks (LMN)
Can present with falls at night time due to a combination of ataxia and reduced vision, which is also seen in b12 deficiency.
Pain and temperature may remain intact even in severe cases, as the spinothalamic tracts are preserved.
Recognise the presenting symptoms/signs of vitamin B12 deficiency
Anaemia:
-Pallor, SoB, easy fatigue
Soreness of tongue due to glossitis
Symptoms of IHD:
-chest pain, slurred speech, paralysis
Impaired neurological function:
-loss of memory function, reduced reflexes, psychosis
Identify appropriate investigations for vitamin B12 deficiency and interpret the results
Blood film (hypersegmented neutrophils, large RBCs)
MCV>100fL suggests macrocytosis
Bone marrow sample to look at megaloblastic changes in RBC precursors
Homocysteine and methylmalonic acid elevated
Look for anti-intrinsic factor antibodies for pernicious
Endoscopic or imaging if they could have crohn’s disease
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High homocysteine, normal methylmalonic acid
Folate.
B12 is required for homocysteine to metionine conversion AND
methamalonyl coA to succinyl CoA
Whereas Folate (b9) is only required for homocysteine to metionine conversion, so MMA is normal if there’s only a deficiency of folate
Define folate deficiency
=vitamin B9 deficiency
essential coenzyme that enables critical biochemical reactions (it makes purines and pyramidines)
What are the causes of folate deficiency
REDUCED DIETARY INTAKE
-Tea and toast diet
REDUCED ABSORPTION
- DRUGS: Phenytoin (inhibits intestinal conjugase which allows absorption), trimethoprim (inhibits dihydrofolate reductase), methotrexate, sulfasalazine and alcohol (sulfasalazine and alcohol inhibit the transporter which moves folate from the entereocyte into the portal vein)
- COELIAC, IBD
INCREASED REQUIREMENT:
-pregnancy, severe haemolytic anaemia
Which foods contain folate.
How does folate deficiency cause issues?
Dietary sources include naturally folate-rich foods such as leafy green vegetables, fruit and liver, but also supplements and fortified foods.
Malnutrition and excessive alcohol use are the most common causes of deficiency.
Folate deficiency causes impaired DNA synthesis, which leads to megaloblastic anemia. The clinical picture of anemia is similar to that of vitamin B12 deficiency, although folate deficiency is generally not associated with neurological manifestations.
Where is folate absorbed, where is it stored?
What is the active form of folate
Storage: liver (can store for up to 3 months)
Absorption: in the jejunum
Active form: tetrahydrofolate (THF), obtained after reduction of folate by dihydrofolate reductase.
Reduced THF due to reduced folate causes reduced DNA synthesis, megaloblastic erythropoiesis and anaemia.
Reduced methionine and increased homocysteine leads to endothelial damage and INCREASED RISK OF CARDIOVASCULAR DISEASE AND THROMBOEMBOLIC EVENTS
INCREASED RISK OF CANCER
Recognise the presenting symptoms of folate deficiency
Signs of anemia (e.g., fatigue, pallor)
Sore tongue (glossitis )
Recognise the signs of folate deficiency on physical examination
Glossitis
Fatigue, pallor
Identify appropriate investigations for folate deficiency and interpret the results
Diagnosis is based on laboratory findings such as macrocytosis, hyperhomocysteinemia, and normal levels of methylmalonic acid.
Folate serum levels not reliable
Hypersegmented neutrophils and pancytopenia may be present
What is the most definitive test of iron deficiency
The most definitive test of iron deficiency is a bone marrow biopsy. The bone marrow is part of the iron storage pool, and if a patient is truly iron-deficient, it will contain no stainable iron.
However, Serum iron is one of the key markers of iron depletion, and can therefore be used in the diagnosis of iron deficiency anemia, along with the serum ferritin level and total iron binding capacity.
Differentiate acute and chronic leukaemia
Acute leukaemia involve a proliferation of white cells that don’t mature at all, and these cells are usually in the blast form. Acute leukaemias come from less mature cells
(in the cell lineage tree, the higher up blast cell’s job physiologically is just to rapid divide to produce as many cells as possible that will later all differentiate, so a mutation in a gene in this cell type will result in a much more rapidly dividing leukaemia than the more mature precursor cells, which are more differentiated, and physiologically their function is to become a certain cell type, rather than just divide all the time)
Whereas chronic leukaemias involve proliferation of immature white cells, which have similar appearance to mature cells but lack functionality
(CLL is mature cells, CML is mixed mature and immature cells)
Outline the 3 types of genetic aberration that can result in leukaemia
1) Chromosomal deletions, where part of a chromosome is missing;
2) Trisomies, where there’s one extra chromosome; and
3) Translocations, where two chromosomes break and swap parts with one another.
How can you differentiate a leukaemia from a lymphoma
In leukaemia, the abnormal cells accumulate in the bone marrow or blood.
This differentiates them from lymphomas which can also arise from white blood cells, but they typically form solid tumors in lymphatic tissue such as lymph nodes, thymus, or spleen.
What causes anaemias, thombocytopaenia and leukopaenia in leukaemia
As these abnormal cells keep proliferating in the bone marrow, they take up a lot of space and this means that the other normal blood cells growing in the bone marrow get “crowded out”, resulting in cytopenias, including anemia, thrombocytopenia, and leukopenia.
Outline sites for deposition of leukaemia cells in the body
Some of them can deposit in organs and tissues throughout the body, like:
1) The liver and spleen causing hepatosplenomegaly, or
2) Lymph nodes causing lymphadenopathy, or
3) Skin causing purple or flesh colored plaques or nodules called leukemia cutis.
Differentiate the common age of presentation of AML vs ALL
AML is more common in older adults with a median age of 65 years, where as ALL is more common in children
What genetic abberation is AML usually caused by
AML is usually caused by chromosomal translocations, like translocation of chromosomes 15 and 17.
What genetic abberation is ALL usually caused by
ALL is also due to chromosomal translocations, like:
-translocation of chromosomes 12 and 21, or
!!!-translocation of chromosomes 9 and 22, also called the Philadelphia chromosome.
(note that the philadelphia chromosome is more known with CML but also occurs in CLL!)
Which genetic condition is associated with AML and ALL
A condition often associated with both AML and ALL is Down syndrome, which is caused by an extra chromosome 21.
A specific subset of AML is called acute promyelocytic leukaemia.
What is the genetic abnormality here and what are the effects
What is the treatment
Translocation between 15 and 17.
This disrupts the retinoic acid receptor alpha gene, which is needed for normal cell divsion
The treatment is all-trans retinoic acid, or vitamin A, and arsenic which induces the differentiation of promyelocytes.
What is AML with myelodysplasia
It’s a specific subtype of AML.
It happens when there is more than 20% blast cells.
It has poor prognosis
Risk factors for acute leukaemia
Finally, there are also some risk factors for acute leukemia like:
1) exposure to radiation, and
2) alkylating chemotherapy, which may have been used as a treatment for certain types of cancer.
In a pre-T cell ALL, where might the abnormal cells deposit
In the thymus or lymph nodes!
What is a haematological emergency that can result from acute promyelocytic leukaemia
The promyelocytes can activate the clotting process, further reducing platelets and leading to disseminated intravascular coagulation
What are the symptoms of ALL and AML
Which symtpoms are noted more in ALL?
What symptom is noted in the monocytic variety of AML
What symptom is noted in T-ALL
Fatigue (anaemia)
Easier bleeding (thrombocytopenia)
Increased infection (leukopenia)
Bone paina nd tenderness due to increased production
Abdominal fullness (hepatosplenomegaly)
Pain in lymph nodes (lymphadenopathy)
In ALL, these 2 are particularly noted:
Abdominal fullness (hepatosplenomegaly)
Pain in lymph nodes (lymphadenopathy)
In the monocytic variety of AML:
Swelling of gums due to monocytic enlargement
In t-ALL:
Mediastinal mass due to thymus enlargment
How are ALL and AML diagnosed
- Start with peripheral blood smear
- Myeloblasts in AML
- Lymphoblasts in ALL - Bone marrow biopsy
- Shows raised blast cells
What happens to the proportion of mast cells in acute leukaemia compared to normal person
Increases from 1-2% (normal) to >20% (acute leukaemia)
How can you differentiate AML from ALL?
AML:
- Myeloblasts are large
- Nuclei contain FINE chromatin with large nucleoli
- Can contain auer rods (particualry in acute promuyelocytic leukaemia) which are crystallised aggregates of the myeloperoxidase enzymes
ALL:
- Lymphoblasts are relatively smaller cells
- Nuclei containe COARSE chromatin which squash together to form small nucleoli
- Very little cytoplasm, which contains glycogen granules
What immunophenotyping markers suggests:
- ALL
- Specifically pre b cell
- TdT (which is a DNA polymerase ONLY in lymphoblasts)
- CD10 (surface marker)
Treatment for acute leukaemia
Reduce number of blast cell to allow other cells to develop normally
-AML and ALL treatmnet based on type and stage
Generally involves
-Chemo, biological, stem cell transplant, bone marrow transplant
Remember acute promyeloctic leukaemia can be treated with all-trans-retinoic-acid (ATRA)
It binds to the disrupted retinoic acid receptor and causes the blast to mature into neutrophils which go on to die, therefore cleaning out a lot of the blasts from the blood
How would you distinguish presentation of immune thrombocytopenia with AML? What about myeloma.
Immune thrombocytopenic purpura typically presents with bruising and bleeding with an isolated low platelet count.
Acute myeloid leukaemia frequently presents with bone marrow failure (which can be excess bleeding and bruising but with low plt Hb etc) with circulating blast cells in the peripheral blood.
In myeloma again pancytopenia can be part of the presenting picture but blast cells would not be seen in the peripheral blood
2 types of polycythaemia
Polycythaemia vera (a rare type of bone neoplasm resulting in a clonal proliferation of myeloid cells) and
Secondary polycythaemia (secondary to, for example, chronic hypoxia, renal tumours and erythropoietin abuse in athletes).
There is a strong association between polycythaemia vera and which other condition?
Myelofibrosis
What is the difference between TTP and HUS
Thrombotic thrombocytopaenic purpura (TTP) has the same features as HUS : 1) Acute renal failure, 2) Thrombocytopaenia and 3) MAHA)
With the addition of:
1) Fever and
2) Fluctuating neurological signs.
Define polycythaemia
Normal haematocrit is 45%. Polycythaemia is when there is increased concentration of RBCs in the blood (increased haematocrit)
Explain the aetiology / risk factors of polycythaemia
How is RBC production in the marrow usually controlled
Which mutation in which cells
- Polycythaemia vera: Increased blood cell levels due to overproduction by bone marrow
- Appropriate increase in erthyropoietin (chronic hypoxia e.g. high altitude, COPD, cyanotic heart disease
- Inappropriate increase in erythrypoietin (renal cell carcinoma/cysts, hepatoma, cerebellar haemangioblastoma, fibroids)
POLYCYTHAEMIA VERA:
Usually begins with mutation in haematopoietic stem cell.
90% of the time it’s a mutation in the janus kinase 2 (JAK2 gene).
RBC production is usually controlled by erythropoietin which activates JAK2 to switch on RBC production in HSC.
JAK2 is always on in the mutated version, leading to constant RBC production even without erythropoietin.
Eventually, the HSCs die out, and scar tissue forms. The bone marrow can no longer produce blood cells. This is known as a spent phase of polycythaemia vera. And at this point it’s really myelofibrosis.
Summarise the epidemiology of polycythaemia
.
Recognise the presenting symptoms of polycythaemia
What are they more prone to
Fatigue, dizziness, increased sweating, headaches, redness in the face, tinnitus, blurred vision,
and, perhaps the most memorable symptom, pruritus after a hot
bath.
MORE PRONE TO BLOOD CLOTS and their sequalae:
-stroke, heart attack, DVT, budd-chiari syndrome (when liver veins are blocked by a bloodclot)
Recognise the signs of polycythaemia on physical examination
Splenomegaly (excess RBCs build up in the spleen)
GOUT and KIDNEY STONES: due to to increased uric acid due to high turnover of RBCs
Identify appropriate investigations for polycythaemia (specifically vera here) and interpret the results
Blood test:
Increased Hb, haematocrit, increased WCC, increased platelet count
Decreased erythropoietin (but sometimes normal or elevated)
Bone marrow tissue examination/biopsy: look for fibrosis
Genetic testing: JAK2 testing
Brief treatment of polycythaemia
Phlebotomy (remove blood) every few months when there is lots of production
Myelosuppression:
- Hydroxyurea
- Ruxolitinib (JAK2 inhibitor)
In the spent phase may need blood transplants! (note these can actually come from autologous donation from their own blood previously removed and frozen after phlebotomy treatment)
Define myelofibrosis
The depletion of HSC and the formation of fibrotic/scar tissue in the bone marrow, in association with extramedullar haematopoiesis and splenomegaly
Explain the aetiology / risk factors of myelofibrosis
Primary:
A gene mutation within haematopoietic cells, usually JAK2 (gain of function, oncogene). Leads to proliferation of megakaryocytes in the bone marrow, which release cytokines including fibroblast growth factor which activates fibroblasts within the bone marrow. This is a myeloproliferative neoplasm
Secondary:
Essential thrombocythaemia
Polycythaemia vera
These are both also myeloprliferative neoplasms
*IMPORTANT! PLEASE NOTE THAT THE JAK2 MUTATION IS ACTUALLY COMMON TO PRIMARY MYELOFIBROSIS AND BOTH CAUSES OF SECONDARY MYELOFIBROSIS (ESSENTIAL THROMBOCYTHAEMIA AND POLYCYTHAEMIA VERA)
These both result in fibrosis which replaces normal bone marrow tissue, leading to pancytopaenia
The HSCs migrate to liver, spleen and lungs, and try to kick out blood cells, but often cannot compensate for the failure of medullary haematopoiesis, resulting in pancytopaenia
RISK FACTOR:
Long-term exposure to high levels of benzene or very high doses of ionising radiation may increase the risk of primary myelofibrosis in a small number of cases.
Summarise the epidemiology of myelofibrosis
.
Recognise the presenting symptoms of myelofibrosis
Asymptomatic: diagnosed following abnormal blood count
Systemic symptoms:
Common- fatigue, weight loss, anorexia, itching, fever, night sweats
Uncommon: LUQ abdo pain, indigestion (caused by massive splenomegaly)
Bone pain, bleeding and gout are less common complaints
Recognise the signs of myelofibrosis on physical examination
Signs of extramullary haematopoiesis:
Splenomegaly is main finding (massive in 10%)
Hepatomegaly
Pulmonary HTN
Signs of pancytopaenia:
Leukopaenia –> frequent infections
Anaemia –> fatigue
XS platelets –> DVTs and pulmonary thomboembolisms
Identify appropriate investigations for myelofibrosis and interpret the results
What type of cells are seen in blood film
FBCs:
Initial increase in blood cells (in primary, especially platelets. Be careful to differentiate this from essential thrombocytopaenia, which is a secondary cause of myelofibrosis)
BUT there is then a drop due to pancytopaenia (as the fibrosis reduces medullary function)
LFT abnormal
Blood smear (i.e. the following cells are in the peripheral circulation, not bone marrow):
Abnormal, tear drop shaped RBCs (CALLED DACROCYTES);
Circulating immature, nucleated RBCs;
Immature WBCs and platelets
MARROW ASPIRATION/BIOPSY:
Early: increase in HSC numbers
Late: reduced HSC numbers and fibrosis
Aspiration usually unsuccessful (‘dry tap’). Trephine biopsy shows fibrotic hypercellular marrow, with dense reticulin fibres on silver staining
What are the features of multiple myeloma
hyperCalcaemia (stones, bones, abdominal groans and psychiatric overtones)
Renal failure
Anaemia
Bone pain
=CRAB
What finding is seen on blood film in multiple myeloma
Rouleaux are stacks of red cells seen on a blood film,
which form due to the high concentration of plasma proteins (e.g. immunoglobulins)
and give rise to the high ESR.
In which type of disease are each of these cells seen on blood film:
Schistocytes
Granulocytes with absent granulation/hyposegmented neutrophils
Dacrocytes
Smear cells
Schistocytes, also known as red cell fragments, are an indicator of intravascular
haemolysis.
Granulocytes with absent granulation and hyposegmented nuclei are
found in myelodysplastic syndrome.
Dacrocytes are teardrop-shaped cells seen in
myelofibrosis.
Smear cells are seen in chronic lymphocytic leukaemia.
Hx in ALL
Symptoms of bone marrow failure:
Anaemia (fatigue,dyspnoea)
-Bleeding(spontaneous bruising, bleeding gums, menorrhagia),
-Opportunistic infections (bacterial, viral, fungal, protozoal).
Symptoms of organ infiltration:
- Tender bones, enlarged lymph nodes, mediastinal compression (in T cell ALL)
- Headache, visual disturbance, nausea (meningeal involvement)
Examination in ALL
Signs of BM failure:
- Pallor
- Bruising, bleeding
- Infection (fever, GI, skin, resp problems)
Signs of organ infiltration:
Lymphadenopathy, hepatosplenomegaly, cranial nerve palsies,
retinal haemorrhage or papilloedema on fundoscopy,
leukaemic infiltration of the anterior chamber of the eye (mimics hypopyon),
testicular swelling.
Investigations for ALL.
What would be seen on:
Blood tests
Blood film
Bone marrow aspirate?
Immunophenotyping?
Cytochemistry?
Bone radiograph?
Bloods:
- Normochromic, normocytic anaemia
- Reduced platelets
- Variable WCC
- Raised uric acid
- Raised LDH
Blood film:
-Lymphoblasts (in the periphery)
Bone marrow aspirate: hypercellular with >30% lymphoblasts
Immunophenotyping:
Using antibodies for cell surface antigens e.g. CD20.
Cytochemistry:
PAS stain positive: B cell lineage
Acid phosphatase positive: T cell lineage
Bone radiograph:
Mottled appearance with ‘punched-out’ lesions (e.g. skull caused by leukaemic infiltration
What is the morphologic classification of ALL
L1: Small lymphoblasts, scanty cytoplasm.
L2: Larger, heterogenous lymphoblasts.
L3: Large lymphoblasts with blue or vacuolated cytoplasm.
Why might you do a chest x ray in ALL
May show mediastinal lymphadenopathy, thymic enlargement (in T cell lineage ALL), lytic bone lesions.
Which conditions is ALL assocaited with
Environmental (radioation viruses)
Genetic (down syndrome, neurofibromatosis type 1, fanconi’s anaemia, achondroplasia, ataxia telangiectasia, xeroderma pigmentosum)
How is AML classified
Into 8 morphological variant using the FAB systems.
M0: Myeloblastic. No Maturation
M1 Myeloblastic with little maturation.
M2 Myeloblastic with maturation.
M3 Promyelocytic with coarse cytoplasmic granules.
M4 Granulocytic and monocytic differentiation (myelomonocytic).
M5 Monoblastic differentiation.
M6 Erythroblastic differentiation.
M7 Megakaryoblastic.
Which morphologic variant contains Auer rods
What is this variant associated with
M3 Promyelocytic with coarse cytoplasmic granules. Characteristic Auer rods (crystallisation of granules resembling bundle of sticks or ‘faggots’).
Associated with DIC and IC haemorrhage
Symptoms of AML
Symptoms of bone marrow failure:
- Anaemia (lethargy, dyspnoea)
- Bleeding (thrombocytopaenia OR DIC)
- Infections
Symptoms of tissue infiltration:
- GUM SWELLING OR BLEEDING (in M4)
- CNS involvement (headache, nausea, diplopia) in M4 and M5 especially
What is the cause of bleeding in AML
Thrombocytopaenia due to bone marrow failure
OR
DIC, especially in M3 variant
AML on examinaion
Signs of bone marrow failure:
- Pallor, cardiac flow murmur
- Ecchymoses and bleeding
- Infections
Signs of tissue infiltration
- Skin rashes, gum hypertrophy,
- Deposit of leukaemic blasts may rarely be seen in the eye (chloroma), tongue and bone–in the latter may cause fractures.
AML investigations:
What would be seen on:
Blood tests
Blood film
Bone marrow aspirate?
Immunophenotyping?
Immunocytochemistry?
Blood tests
- Low Hb and platelets, variable WCC.
- High uric acid and LDH
- May do fibronigen and d dimers when DIC is suspected in M3.
Blood film
- AML blasts with cytoplasmic granules
- Auer rods in M3
Bone marrow aspirate
Hypercellular with >30 % blasts (immature cells)
Immunophenotyping
Antibodies against surface antigens to classify lineage of abnormal clones.
Immunocytochemistry:
- Myeloblast granules are positive for Sudan Black, choroactetate esterase and myeloperoxidase
- Monoblasts are positive for non-specific and butyrate esterase
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Define Von Willebrand’s disease
Bleeding disorder of PRIMARY HAEMOSTASIS
Explain the aetiology / risk factors of Von Willebrand’s disease
Genetics ?
What does vWF do?
Abnormalities in expression or function on von Willebrand Factor, a plasma glycoprotein involved in blood clotting.
It acts as an adhesive bridge between platelet receptor (GP-1b) and damaged subendothelium (collagen IV) of vessels.
Also binds to factor VIII and prevents its degradation
Usually autosomal dominant, occasionally recessive
Type 1: Autosomal dominant, partial quantitative deficiency
Type II: Autosomal dominant, qualitative deficiency
Type III: Autosomal recessive, severe quantitative defi cien
Summarise the epidemiology of Von Willebrand’s disease
.
Recognise the presenting symptoms/signs of Von Willebrand’s disease
Most common symptoms include:
nosebleeds,
bruising,
gum bleeding
and prolonged bleeding from minor wounds
Spontaenous ucocutaneous bleeding (mouth, epistaxis, menorrhagia)
Increase bleeding after minor trauma or easy bruising.
Surgery and trauma provoke clinical manifestation
Identify appropriate investigations for Von Willebrand’s disease and interpret the result
Increased bleeding time
NORMAL platelet count
Increased PTT
Reduced factor VIII
Reduced platelet aggregation in the presence of ristocetin
Reduced vWF
Define haemophilia
Bleeding diatheses resulting from inherited deficiency of clotting factor
A: (most common). Deficiency factor VIII.
B: Deficiency factor IX.
C (rare): Deficiency factor XI.
Explain the aetiology / risk factors of haemophilia
A and B exhibit X-linked recessive.
30% of cases are new mutations.
Summarise the epidemiology of haemophilia
Incidence of haemophilia A is” 1 in 5– 10,000 males and for haemophilia B is 1 in 25–30,000 males.
Haemophilia C is more common in Ashkenazi Jews.
Recognise the presenting symptoms of haemophilia
From early childhood
Swollen painful joints occurring spontaneously or with minimal trauma (haemarthroses)
Painful bleeding into muscles
Haematuria
Excessive bruising or bleeding after surgery of trauma.
Female carriers usually asmptomatic (but may have low enough levels to cause excess bleeding after trauma)
Recognise the signs of haemophilia on physical examination
Multiple bruises. Muscle haematomas.
Haemarthroses.
Joint deformity.
Nerve palsies (nerve compression by haematoma).
Signs of iron-deficiency anaemia.
Identify appropriate investigations for haemophilia and interpret the results
Clotting screen: Increased APTT (reflects activity of intrinsic and common pathway)
Normal PT and normal platelets
Coagulation factor assays (reduced factor VIII, IX or XI depending on type)
Deficiency of which coagulation factor is asymptomatic
Factor XII
T/F factor VII causes abnormality in the PT
F
What is a prolonged PT. What about prolonged PTT
prolonged PT (>16–18 s)
prolonged APTT (>30–50 s)
What does prolonged TT indicate
What about abnormal bleeding time
A
prolonged TT suggests fibrinogen deficiency while abnormal bleeding
times suggest platelet deficiencies
What would liver disease cause in a clotting screen
In liver disease (B) the PT, APTT,
bleeding time and platelet counts would be abnormal alongside peripheral
stigmata of liver disease.
What would DIC cause in a clotting screen
Disseminated intravascular coagulation (C) causes
abnormalities of PT, APTT, bleeding time and platelets
What is Glanzmann’s thombaesthenia
What would it show in a clotting screen
Glanzmann’s thrombaesthenia
(E), a platelet abnormality whereby glycoprotein IIb/IIIa is absent preventing
platelet bridging with fibrinogen, the bleeding time is significantly
prolonged while PT, APTT and platelet counts are normal.
What would congenital
afibrogenaemia show on clotting screen
In congenital
afibrogenaemia (D), the PT, APTT, TT and bleeding times would be abnormal
while the platelet count would be normal.
What clues are seen with the following conditions: AML ALL CML CLL Hodgkin's Non-hodgkin's Myelodysplasia Myelofibrosis Multiple myelpma
AML: auer rods, sudan black stain
ALL: occurs in children
CML: philadelphai chromosome (between 9 and 22) + massive splenomegaly
CLL: smear/smudge cells, warm agglutinins (AIHA)
Hodgkin’s: painful lymph nodes after alcohol ingestion
Non-hodgkin’s: B symptoms (fever, weight loss, night sweats). Painless enlarging cervical lymph nodes
Myelodysplasia: ringed sideroblasts, no splenomegaly. Granulocytes with absent granulation and hyposegmented nuclei
Myelofibrosis: MASSIVE splenomaegaly. Dry tap (failure of bone marrow aspirate). Dacrocytes! Associated with polycythaemia rubra vera
Multiple myeloma: CRAB symptoms (calcium, renal impairment, anaemia, bone pain)
Which anaemia is a complication of myelodysplasia
What does iron testing show
Sideroblastic anaemia
Iron testing shows high serum iron, low TIBC and high ferritin
(Immature red cells in the bone marrow, called sideroblasts, cannot utilise iron for the synthesis of haem, so iron accumulates in the mitochondria surrounding the nucleus, and then spills out into the blood, causing high serum iron and high ferritin)
What is the diagnosis of sideroblastic anaemia
BM biopsy (shows ringed sideroblasts with prussian ble)
t/f myelodysplastic syndrome is the only cause of sideroblastic anaemia
F. Can be congenital or Acquired: -MDS -Excessive alcohol abuse -Copper deficiency -Vit B6 def
What is the inheritance of G6PD
X-linked!
Heinz bodies are seen in which condition
G6PD!
They are removed by splenic macrophages resulting in bite cells
This can lead to hemoglobinuria and back pain hours after exposure to oxidative stress .
Spherocytes indicate which condition
AIHI: Antibody mediated
destruction of red blood cells is known as immune
hemolytic anemia
Spherocytes are a common manifestation due to the consumption of antibody-coated red blood cells.
Also, hereditary spherocytosis (diagnosed with osmolality fragility test)
Activation of complement is associated with which haemolytic anaemia
Activation of complement can be caused by an absent glycosylphosphatidylinositol (GPI), which can also manifest as anemia symptoms and hemoglobinuria
This defect is known as
paroxysmal nocturnal hemoglobinuria
.
Which tumour marker is POOR prognostic indicator for B cell CLL
ZAP-70 positive
(ZAP-70 is usually expressed as part of the TCR! So it if’s seen on B cells you know it’s bad)
CD38 +ve
(presence associated iwth less mature clonal B lymphocytes)
What is CD23 used for
CLL cells are CD23+ve
Mantle cell lymphoma (i.e. a NHL) is CD23 negative
It’s use to distinguish them
Tumour lysis syndrome presents how
Patients are at greatest risk for
acute kidney injury which usually presents as
anuria.
TLS is characterized by nausea, vomiting, diarrhea,
lethargy,
heart failure,
seizures, muscle cramps, or sudden death.
What are the electrolyte abnormalities associated with tumour lysis
The metabolic abnormalities include elevated potassium,
phosphate
, and
uric acid
Most common type of tumour for TLS to be associated with
Although
tumor lysis syndrome has been reported with virtually every type of tumor, it is typically associated with acute leukemias
and
high-grade non-Hodgkin lymphomas, such as
Burkitt lymphoma
Which skin condition is a type of T cell lymphoma
Mycosis fungoidesis a type of cutaneous T-cell lymphoma which can be difficult to diagnose in the early stages. Non- Hodgkins
Manigests as red patches, and can prgoress slowly to plaque like lesions.
Can be indistinguishable from eczema.
The cause is unclear and it is most commonly seen in male adults. It may or may not be itchy, and may or may not progress. In some cases, it can spontaneously resolve.
What are the AIDS defining malignancies
Kaposis
Primary central nervous system lymphoma
Cervical carcinoma
What is inheritence of pyruvate kinase deficiency
his autosomal recessive disorder is caused by a deficiency of PK in erythrocytes, which lack mitochondria and depend on PK for glucose metabolism and energy production.
What proteins can be found in the urine in multiple myeloma
Bence-Jones
proteins, which are monoclonal immunoglobulin light chains, can be detected in the
urine of patients with multiple myeloma.
Biochemical features of pagets?
Normal
Biochemical features of multiple myeloma
Raised calcium and ESR
Note multiple myeloma is also associated with lytic bone lesions
Types of acquired and inherited haemolytic anaemias
INHERITED:
1) Membrane defects: hereditary spherocytosis, elliptocytosis
2) Enzyme defects: pyruvate kinase deficiency
3) Metabolic defects: G6PD deficiency
4) Haemaglobinopathies: sickle cell, thalassaemia
ACQUIRED:
1) Autoimmune haemolytic anaemia
2) Isoimmune (transfusion, haemolytic disease of the new born)
3) Drugs (penicillin, quinine)
4) Trauma: MAHA e.g. due to HUS, DIC), artifical heart valves
5) Infection: malaria and sepsis
6) Paroxysmal noctural haemoglobinura: increased complement- mediated lysis caused by reduced sythesis of portein cellular anchor or complement degrading proteins
History and signs of haemolytic anaemia
Jauncie, haematuria, anaemia, hepatosplenomegaly
What does intrinsic vs extrinsic haemolysis mean compared to intravascular vs extravascular
Intrinsic haemolysis is when there are problems with the red blood cell itself that’s causing it to break down (G6PD, PK deficiency etc.)
Extrinsic haemolysis is when healthy red blood cells are destroyed for other reasons.
Intrinsic and extrinsic equate quite well with heredistary and acquired.
Intravascular is when the haemolysis happens within vessels, whereas extravascular is when they are destroyed, for example, in the spleen
What can haptoglobin tell you about the type of haemolysis
Haptoglobin binds free haem, and then gets removed from the circulation by the liver with the bound haem.
So if there is free haem in the blood stream (i.e. intravascular haemolysis) then haptoglobin will bind it, and therefore HAPTOGLOBIN IS REDUCED IN INTRAVASCULAR HAEMOLYSIS.
In extravascular haemolysis the haptoglobin is normal
What is the inheritance of hereditary spherocytosis
Autosomal dominant.
This condition results in chronic, mild, extravascular haemolysis
What type of haemolysis occurs in paroxysmal noctural haemoglobinuria
Genetic abnormalities in myeloid stem cell (PIG-A mutation) means that complement is not properly inactivated, so there is INTRAVASCULAR haemolysis with activated complement destroying RBCs.
T/F paroxysmal noctural haemoglobinuria causes isolated haemolytic anaemia only
F. It can cause anaemia by a different mechanism too (aplastic anaemia) because it affects myeloid cells.
And it can cause pancyopaenia too for the same reason
T/F PNH has no effect on platelets
F.
It also affects platelets and can form them to activate and cause thrombosis
The patient has thrombosis, haemolytic anaemia, reduced RBC and leukaemia
PNH
G6PD causes haemolytic anaemia by what mechanism
It makes cells vulnerable to oxygen free radicals.
Low levels of G6PD mean that NADP+ isn’t converted to NADPH, which is required to reduce glutathione via glutathione reductase enzyme.
Glutathione can make the oxygen free radicals less harmful by converting them to water
What type of haemolysus occurs with pyruvate kinase dificiency
What cell types
Extravascular haemolysis.
PK deficiency means there is less ATP, meaning that K+ leaves the cell, and the cells shrivel to form BURR CELLS (ECHINOCYTES)
Cholelithiasis from an early age and haemolysis?
Hereditary spherocytosis (likely to have been chronic haemolysis since birth)
Anaemia usually mild
Paroxysmal noctural haemoglobinuria
1st morning urine is dark since it collects during the night
Venous thrombosis, Budd chiari syndrome
Jaundice in a newborn and splenomegaly
PK deficiency
Most common cause of osteomyelitis in somebody with sickle cell disease
Salmonella
Splenic complications of sickle cell
Splenic sequestration can lead to sudden reduction in haemoglobin and hypovolaemic shock
Splenic infarcts can cause autosplenectomy (fibrosis and atrophy on biopsy)
Which infections is someone with sickle cell with autosplenectomy prediscoposed to
S pneumoniae
H influenza
N meningitidis
What is a feature of sickle cell trait
Asymptomatic unless exposed to high altitude or dehydration.
HOWEVER,
They can have isothenuria (inability to concentrate urine) due to papillary necrosis in the renal medulla
How do symptoms of HbSC compare to sickle cell
Less frequent and less severe
What might the following factors show in hereditary spherocytosis:
MCV
MCH
MCHC
MCV normal or slightly reduced
MCH, normal (RBC has correct amount of haemoglobin)
MCHC increased (because smaller volume of each cell so concentration is increase)
T/F the osmotic fragitlity test is specific for hereditary spherocytosis
F, it’s also positive in autoimmune haemolytic anaemia
Positive osmotic fragility test, how can you distinguish hereditary spherocytosis from AIHA
Coombs test positive in AIHI but not in hereditary spherocytosis
What is the gold standard test for paroxysmal noctural haemoglobunura
Flow cytometry (reudced CD55 AND CD59)
Diagnosis of G6PD deficiency
Heinz bodies in cells
Bite cells
DEFINITIVE TEST: enzyme assay to test for levels of G6PD
6 WEEKS AFTER THE HAEMOLYSIS EPISODE
Diagnosis of PK deficiency
Echinocytes
DEFINITIVE TEST: enzyme assay to test for levels of G6PD
6 WEEKS AFTER THE HAEMOLYSIS EPISODE
When are howell jolly bodies present
In sickle cell, when there is a dysfunctional spleen which cannot remove these cells
When does intravascular and extravascular haemolysis occur, out of the intrinsic haemolytic anaemias
Intravascular: PNH
Extravascular: hereditary spherocytosis and PK deficiency
Both: G6PD deficiency and SCA
When must you be careful about interpreting haptoglobin
It’s an acute phase protein, so will be increased in infection, possibly masking an intravascular haemolysis
General symptoms and lab findings in haemolytic anaemia
Increased LDH (general)
Increased haptoglobin (intravascular)
Increased reticulocytes (reactive)
In extreme haemoysis: Increase free haemoglobin (—> brown coloured urine)
Glutamate replaced by lysin vs glutamate replaced by valine
These disease represent sickle cell and haemoglobin C disease respectively
Primary vs secondary causes of cold and warm agglutinin disease
These are both types of AIHI.
COLD. Primary: idiopathic. Secondary: Infection (mycoplasma, EBV), cancer (NHL, CLL)
WARM. Primary: idiopathic. Secondary: lymphoma, CLL, SLE, drug reaction
Causes of microangiopathic haemolytic anaemia
DIC, HUS, TTP, malignant HTN, SLE
Causes of macropathic haemolytic anaemia
Moderate and severe AS (heart valve replacement solves the anaemia)
Prosthetic heart valve
Extracorporeal circulation (dialysis)
Exertional haemoglobinura (destruction of RBCs during hard exercise)
Define lymphoma. Hodgkin’s vs non-hodgkins
Lymphoma is neoplasm of LYMPHOID cells originating in LYMPH NODES or LYMPHOID TISSUE.
Hodkin’s: presence of Reed-Sternberg cells (a cell of B lymphoid lineage)
Non-hodkin’s: diverse range of lymphoma, 85% are B cell (non-reed-sternberg), 15% are T cell and NK cell.
Aetiology of Hodgkin’s and non Hodgkin’s
-HTLV1 and HHV8 are associated with what
Hodgkin’s. RFs:
- EBV,
- immunosuppression (HIV),
- autoimmune conditions (rheum arthritis, sarcoid)
NHL: RFs:
- EBV in Burkitt’s and AIDS associated lymphomas.
- HTLV1: Implicated in adult T cell lymphma/leukaemia
- HHV8 (herpes kaposi sarcoma virus) detected in body-cavity-based lymphoma.
- H. Pylori (gastric lymphoma)
- Autoimmune conditions (Hashimoto’s, rheum arthritis)
Other risk factors:
- Radiotherapy,
- Immunosuppression
- Chemo
- HIV, HBV, HCV
- Connective tissue diseases
Epi of hodgkins and non hodgkins
Hodkins: bi-modal. th peaks 20–30 years and >50 years. More common in males
NHL: incidence increases with` age. More common in males. More common in the West.
Symptoms of hodkins and non hodkins lymphoma
- Which are systemic symptoms more prevalent in
- Which is extra-nodal involvement more common in
Hodgkins.
- Painless enlarging mass (neck, ocassionally axilla/groin). WORSE AFTER ALCOHOL.
- B symptoms: fevers, night sweat, weight loss >10% body mass in 6 months
- PRURITIS (due to cytokines), cough, dyspnoea
NHL.
- Painless enlarging mass (neck, axilla/groin)
- Systemic symptoms are LESS frequent compared to Hodgkins, but include fever, night sweats, weight loss, hypercalcaemia)
- EXTRANODAL DISEASE (more common in NHL than hodgkins: skin rash, headache, sore throat, abdo discomfort, testicular swelling.
NOTE: Non-Hodgkin lymphoma may arise in lymph nodes anywhere in the body, whereas Hodgkin lymphoma typically begins in the upper body, such as the neck, chest or armpits.
Signs of hodgkins vs NHL
Hodgkins:
- Non tender, firm, rubbery, lymphadenopathy.
- Splenomegaly, skin excoriations, signs of intrathoracic disease (pleural effusion, SVC obstruction)
NHL:
- Non tender, firm, rubbery, lymphadenopathy.
- Skin rash: MYCOSIS FUNGOIDES/Sezary syndrome
- Bone marrow involvement: Anaemia, infections, purpura
What does mycosis fungoides look like
Well-defined indurated scaly plaque-like lesions with raised ulcerated nodules caused by cutaneous T-cell lymphoma
What does sezarys syndrome look like
Widespread red rash all over the skin. Also T cell.
Think of this when there’s lymphadenopathy too.
Investigation for lymphoma
Most common histological subtype?
CD3 +ve?
CD 20 +VE
A surgically excised tissue biopsy is widely accepted as the gold standard for the diagnosis of lymphoma
FBC:
- Elevated or reduced WBC
- Anaemia
- Thrombocytopaenia
Serum chemistry:
-Raised LDH hypercalcaemia
CONFIRMATORY TEST: excisional lymph node biopsy .
NHL: monomorphous, lymphocytic proliferation
Hodgkin’s: Reed-Sternberg cells (RSCs), CD15/CD30-positive
Staging: Xray and CT scan. Brain MRI for neurologic
Bone marrow aspirate and trephine biopsy (BM involvement in very avanced disease only)
Imaging: CXR, CT CAP, PET
STAGING: ANN ARBOR
Most common histological subtype is Reed-Sternberg.
For NHL:
B-cell lymphomas: CD20 positive
T-cell lymphomas: CD3 positive
What does reed-sternberg cell look like
It is a large cell with abundant pale cytoplasm and two or more oval lobulated nuclei containing prominent ‘owl-eye’ eosinophilic nucleoli (can appear as lacunar or ‘popcorn’ cells).
Causes of DIC
Gram -ve sepsis, acute promyelocytic leukaemia, severe pre-eclampsia
Complications of sickle cell disease
1) Vaso-occlusive crisis
2) Autosplenectomy
3) Sequestration crises (responsible for acute chest syndrome and priapism)
4) Haemolytic crisis
5) Aplastic crisis (triggered by parvovirus B19 infection)
Methotrexate causes which kind of anaemia
Macrocytic!
What is the cause of target cells
Codocyte = Target cell (associated with liver disease and hyposplenism)
What are dacrocytes
Dacrocyte = Tear-drop cell (associated with myelofibrosis)
What are spherocytes assocaited with
Spherocyte = a small, spherical red blood cell (associated with hereditary
spherocytosis and autoimmune haemolytic anaemia)
What are reticulocytes and when are they increased
Reticulocyte = an immature red blood cell showing a basophilic reticulum when
stained (a high reticulocyte count indicates increased red blood cell production
activity in response to, for example, blood loss or haemolytic anaemia)
What are schistocytes
Schistocyte = red cell fragment (sign of intravascular haemolysis e.g. due to artificial
heart valves or MAHA)
Difference between reactive lymphadenopathy and lympohoma presentaiton
In reactive lymphadenopathy due to an infection, the lymph node is typically tender and mobile.
If the lymph node is due to lymphoma or from a metastasis from another malignancy, the lymph node is typically non-tender and non-mobile or fixed.
In malignancy, lymphadenopathy can also be accompanied by “B” symptoms, which are caused by cytokine release, and include a fever, drenching sweats, and an unintentional 10% weight loss within six months.
Commonest haemotpoietic neoplasm
NHL is the most common hematopoietic neoplasm
Approx. 85% of lymphomas
Chromosomal transolcation for NHL
Chromosomal translocations: most commonly t(14;18)
NHl associatied with which AI diseases
Hashimoto thyroiditis, rheumatic disease
What is immune thrombocytopenic purpura
Syndrome characterized by immune destruction of platelets resulting in bruising or a bleeding tendency.
How are you differntiating it from cancers of the blood etc.
It has an isolated low platelet count and that is it
Cause of immune thrombocytopenic purpura
When is actue ITP seen
Often idiopathic
ACUTE ITP: Following viral infection in children (vs HUS, which is more commonly due to E. Coli!!)
CHRONIC: More often seen in adults assocaited with infection, autoimmune disease, malignancies and drugs
Which infections assocaited with ITP
Malaria, EBV, HIV
Which autoimmune associated with ITP
SLE, thyroid
Which drugs associated with ITP
Quinine
Hx of ITP
Easy bruising, mucosal bleeding, menorrhagia, epistaxis
Children typically present with sudden onset of mucocutaneous bleeding with extensive bruising and petechiae
Examination of ITP
Visible petechiae, bruises (purpura or ecchymoses).
Typically, signs of other illness (e.g. infections, wasting, splenomegaly) would suggest other causes.
Investigation of ITP
IT IS A DIAGNOSIS OF EXCLUSION.
-Exclude myelodysplasia, acute leukaemia, marrow infiltration
1st investigations are:
FBC (+clotting) and peripheral blood smear (to rule out pseudothrombocytopenia, caused by clumping together of platelets in EDTA tube… so a blood smear can reveal that the platelet count may actually be normal. It can also look for unusual cells)
You can do bone marrow aspirate if the cells look abnormal on peripheral blood smear
What will FBC and clotting screen show in FBC
FBC: reduced platelets
CLOTTING SCREEN: nnormal PT, APTT and fibrinogen
Which antibodies may be present in ITP
(antiplatelet antibody may be present but not used routinely for diagnosis, anticardiolipin antibody, antinuclear antibody
Complications of ITP
Mucosal bleeding. Major haemorrhage is rare (<1 %).
Define aplastic anaemia
Characterized by diminished haematopoietic precursors in the bone marrow and deficiency of all blood cell elements (pancytopaenia).
Causes of aplastic anaemia
1) Idiopathic (most common): Autoimmune destruction of the haematopoietic stem cells
2) Acquired: Drugs chemicals, radiation, viral infection, paroxysmal nocturnal haemoglobinuria
3) Inherited
What drugs cause aplastic anaemia
Chloramphenicol, gold, alkylating agents, antiepileptics, sulphonamides, methotrexate, nifedipine
Thyroid meds like PTU and methomazole
What viral infection causes aplastic anaemia
Which toxins
B19 parvovirus,HIV,EBV
Toxins like benzene
What are the inherited causes of aplastic anaemia
Fanconi’s anaemia (most common)
Dyskeratosis congenita
How does dyskeratosis congenita present
(associated with reticulated hyperpigmented rash, nail dystrophy and mucosa leukoplakia
Symptoms associated with aplastic anaemia
From anaemia: Tiredness, lethargy, dyspnoea.
From low platelets: Easy bruising, bleeding gums, epistaxis.
From leukopaenia: Increased frequency and severity of infection
Examination of aplastic anaemia
Anaemia: pale
Thrombocytopaenia: Petechiae, bruises
Leukopaenia: Multiple bacterial or fungal infections. NO hepatimegaly, splenomegaly or lymphadenopathy
What is fanconi’s syndrome
Short stautre, microcephaly, cafe au lait skin lesions, absent or hypoplastic thumbs
Predisposed to malignancy
Inherited cause of aplastic anaemia
Blood results for aplastic anaemia
Reduced RBCs, WCC and platelet count.
INCREASED epo
REDUCED reticulocyte count
Definitive diagnosis of aplastic anaemia
Reduced haematopoietic stem cells
Normal cellular morphology
Absence of infiltrative disorder (like malignancy or fibrosis)
It would have a dry tap
How would you differentiate aplastic anaemia from myelofibrosis from bone marrow aspirate
They would both be a “dry tap”
In myelofibrosis there would be fibrosis in the bone marrow are low HSC
In aplastic anaemia there is no fibrosis, there are just low HSC
Which drugs can cause HUS
: Oral contraceptive pill, ciclosporin, mitomycin, 5-fluorouracil.
What is TTP and how does it differ in cause from HUS
In both cases clots are formed in the kidney vessels
In HUS this is most commonly caused by shiga producing/E.Coli
In TTP, clots form inappropriately when vWF is NOT broken down.
vWF is normally cleaved by ADAMTS13, breaking it down and stopping platelets binding.
In TTP there is defective ADAMTS13, so there is excess vWF floating around binding platelets and forming clots in many places throughout the body. So it uses up platelets too
Epidemiology
The incidence of TTP and haemolytic uraemic syndrome is higher in women and in black people
Why might a patient with TTP be fine until a certain incident
An additional stressor (such as infection, pregnancy) may need to be placed on the patient before TTP manifests
Symptoms/signs of TTP
Typically same as HUS (i.e. MAHA, thrombocytopaenia and AKI) PLUS neurological manifestations and fever
Investigations for TTP
1st investigations:
FBC: anaemia, thrombocytopaenia
Peripheral blood smear:
To identify schichtocytes and to confirm the thrombocytopaenia.
Reticulocytosis
Urinalysis (proteinuria)
Urea and creatinine increased
Coomb’s will be negative (rules out AI haemolytic anaemia)
MAY do:
ADAMTS-13 activity assay.
There is debate over whether the von Willebrand factor cleaving enzyme (ADAMTS-13) activity assay can help in the management of patients with TTP. It does not appear to predict who will respond to plasma exchange
What is disseminated intravascular coagulopathy
2 forms
A condition in which there is excessive clotting disproportionate to the vascular injury
- ACUTE form: bleeding and depletion of platelets and clotting factors
- CHRONIC: non-overt form , where thromboembolism is accompanied by generalised activation of the coagulation system
What causes disseminated intravascular coagulopathy
Sepsis (esp gram +ve)
Maliganancy: AML (acute DIC), lung, breast, GI (chronic DIC)
Obstetric complications: missed miscarriage, severe pre-eclampsia etc.
Haemolytic transfusion reaction, burns, severe liver disease, aortic aneurysms, haemangiomas.
What can disseminated intravascular coagulopathy lead to
Microangiopathic haemolytic anaemia (along with HUS and TTP)
Outline the pathology of acute DIC
There is endothelial damage and increase release of granulocyte/macrophage procoagulant substances.
There is therefore lots of thrombin production, which depletes clotting factors and platelets, but also then activates the fibrinolytic system.
This causes bleeding into subcutaneous tissues, skin and mucous membranes.
Occlusion of blood vessels by fibrin in the microcirculation results in microangiopathic haemolytic anaemia and ischaemic organ damage.
Outline the pathology of chronic DIC
The process is identical to acute DIC, but at a slower rate with time for compensatory responses, which diminish the likelihood of bleeding but give rise to a hypercoagulable state and thrombosis can occur.
Hisotry of DIC
The patient is severely unwell with symptoms of the underlying disease, confusion, dyspnoea and evidence of bleeding.
What is seen on examination of acute DIC
Petechiae, purpura, ecchymoses, epistaxis, mucosal bleeding, overt haemorrhage. Signs of end organ damage (e.g. local infarction or gangrene), respiratory distress, oliguria caused by renal failure.
What is seen on examination of chronic DIC
Signs of deep venous or arterial thrombosis or embolism, superficial venous thrombosis, especially without varicose veins.
Investigations for DIC
FBC: reduced platelets, reduced Hb (MAHA).
Clotting:
Raised APTT/PT/TT, reduced fibrinogen, raised fibrin degradation products and d dimers
Peripheral blood film:
RBC gradments
T/F alcohol commonly results in a macrocytic anaemia
F.
Alcohol misuse is associated with high MCV but rarely anaemia.
Which two features from hisotry point towards hodgkins lymphoma
Painful lymph nodes after alcohol and Pel-Ebstein fevers (cyclical fever with periods of both high and normal temperature)
What does Ann Arbor classification take into account
For lymphomas
based on both the localization of the lymphoma with respect to the diaphragm and on the presence of systemic symptoms (i.e. whether confined to one side of the diaphragm or not)
Infectious lymphadenopathy vs malignant lymphadenopathy. Exception
Infectious is usually tender (EXCEPT TB!!)
Malignancy usually non-tender (EXCEPT HL when alcohol)
Most common types of low grade NHL
The most common low-grade B-cell lymphoma is follicular lymphoma, while the most common low-grade T-cell lymphomas are the cutaneous T-cell lymphomas such as mycosis fungoides.
Lymphoma more common in young people
Certain subtypes of NHL are more common in children and young adults, such as Burkitt lymphoma.
Cytopenia and massive splenomegaly. Cytoplasmic projections of lymphocytes under microscopy.
Further test?
Hairy cell leukemia (type of NHL)
Usually positive tartrate-resistant acid phosphatase (TRAP) stain and CD11c marker
Histology pattern of burkitts
Starry sky pattern
A microscopic finding that resembles a starry sky: Tingible body macrophages (containing many phagocytized tumor cells) are scattered diffusely within a sheet of uniform neoplastic cells.
Translocation for burkitts
8;14
Where is burkitts usually found
Maxillary and mandibular bones
Most common NHL in adults
Diffuse large B cell lymphoma
What are the myelodysplastic syndromes
A series of haematologic conditions characterized by chronic cytopaenia (anaemia, neutropaenia, thrombocytopaenia) AND abnormal cellular maturation
Here are the 5 subgroups of myelodysplastic syndrome, what is the % blasts in the bone marrow
Refractory anaemia
Refractory anaemia with ringed sideroblasts
Refractory anaemia with excess blasts
Chronic myelomonocytic leukaemia
Refractory anaemia with excess blasts in transformation
<5 <5 5-20 Up to 20 21-30
Cause of myelodysplastic syndromes
there are just 2 causes really
Primary (90%): unknown
Secondary (10%): Patients who have received chemo or radio
May be chromosomal abnormalities
Age of diagnosis of myelodysplastic syndromes
Mean age diagnosis is 65–75 years, more common in males. Twice as common as AML.
Compare MDS to aplastic anaemia
In aplastic anaemia, there is destruction of HSC (can be autoimmune or by drugs, viruses etc), so they no longer produce RBCs, WBCs or platelets.
In myelodysplastic syndrome, there is damage to the HSC so that they produce faulty blood cells, which DO NOT MATURE, and instead persist as immature cells called blasts
THE IMMATURE BLASTS USUALLY DIE IN THE BONE MARROW, OR WHEN THEY ENTER THE BLOOD, SO THEY DON’T DO THE JOB THEY ARE SUPPOSED TO.
This then crows out the healthy cells in the bone marrow and you get reduction in cell counts (chronic cytopaenia)
Outline how MDS is a spectrum of disease
It generally gets worse as you get older.
Ultimately 40-50% of people with MDS progress to having acute myeloid leukaemia (AML)
It is classified as AML when there are more than 20% blasts
What are the symptoms/signs of myelodysplastic syndrome
Asymptomatic, diagnosed after routine blood count (50%)
Symptoms of bone marrow failure:
- Anaemia (fatigue, dizziness, pallor, cardiac flow murmur)
- Neutropaenia (recurrent infections)
- Thrombocytopaenia (easy bruising, epistaxis, purpura, ecchymoses).
SPLEEN NOT ENLARGED (except in CMML, one subtype)
Gum hypertrophy and lymphadenopathy
T/F deficiencies in all RBCs, WBCs and platelets are required for a diagnosis of myelodysplastic syndrome
F
MDS is diagnosed when bone marrow demonstrates significant dysplasia, clonal cytogenetic abnormality, quantitative changes in at least one of the blood cell lines, and blasts <20%.
What investigations would you do if you suspected myelodysplastic syndrome
FBC- (one or more cytopenias) with differential. OVAL MACROCYTIC RED CELLS AND GRANULOCYTES
Reticulocyte count- inappropriately normal or low
Blood film: Normocytic/macrocytic red cells, ovalomacrocytosis, reduced granulocytes, granulocytes display reduced or absent granulation and biloped (PELGEROID) nucleus, myeloblasts
Serum b12, folate, iron studies should all be normal
HIV test
Bone marrow aspiration with iron stain. Prussian blue iron staining of bone marrow aspirate can show ringed sideroblasts - abnormal erythroid precursor cells which have granules around the nucleus. 10% may show marrow fibrosis
Bone marrow core biopsy- hypercellular marrow
What conditions can involve into MDS
Aplastic anaemia and fanconis anaemia
CD5 +ve cells
Chronic lymphocytic leukaemia
Previous gastrectomy. SoB and tingling fingers. High MMA and low ferritin.
What would MCV show, and what would red blood cell distribution width show?
Patient's who underwent a Roux-en-Y bariatric surgery are at risk for combined vitamin B12 and iron deficiency , which manifests as a macrocytic / megaloblastic anemia superimposed on a microcytic anemia which appears as a normal range mean corpuscular volume and an elevated red blood cell distribution width .
Where might target cells appear
Target cells (E) can be indicative of obstructive jaundice, liver disease, haemoglobinopathies and hyposplenism.
Tissue related lung injury? Symptoms?
This can be a life-threatening
complication whereby within 2–6 h after transfusion an inflammatory
process causes sequestration of neutrophils within the lungs and antibodies
that form against the donor’s white blood cells and then attack the patient’s
lungs which share the HLA antigens.
Patient symptoms can include fever,
hypotension, cyanosis and pulmonary oedema on x-ray.
When does an immediate haemolytic transufsion reaction occur and why
An immediate
haemolytic transfusion reaction (A) occurs due to the immune destruction
of transfused cells by the patient’s immune system. Symptoms include
hypotension, tachycardia, nausea, abdominal pain and loin pain with 24 h
of transfusion.
These symptoms are similar to a delayed haemolytic
reaction (C), but this typically occurs more than 24 h after transfusion.
What is IgA deficiency in relation to transfusions
IgA deficiency (D) patient’s develop antibodies to IgA during their first
exposure to a blood transfusion, an anaphylactic-type reaction then occurs
if the patient is retransfused with bronchospasm, laryngeal oedema and
hypotension occurring. In febrile non-haemolytic transfusion reaction occurs due to white cell antibodies reacting with the leukocytes present in
the blood transfusion
Patients usually present with fever, rigors and discomfort.
What effect would vWF have on clotting profile
Platelet count itself would be normal, as would PT
aPTT would be increased (because vWF affects stability of factor VIII)
Bleeding time would be increased (because platelet aggregation takes longer)
What effect would factor V deficiency have on clotting profile
PT and PTT are both increased
Bleeding time and platelet count are normal
Note that these findings are also found in Factor X deficiency, vitamin K deficiency
and warfarin therapy
What is Glanzmann’s thrombasthenia and what effect on clotting profile
Platelets
lack glycoprotein IIb/IIIa therefore fibrinogen bridging between platelets is
disrupted, bleeding time is therefore the only abnormal result.
This is the same for Bernard Soulier syndrome
39 degrees with neutropaenia
Septicaemia
Following translocations happen in which cancers:
t(15;17) t(8;21) t(9;22) t(14;18) t(8;14)
t(15;17)- acute promyelocytic leukaemia, a subtype
(M3) of AML.
t(8;21)- acute myelogenous leukaemia disorders (M2 variant)
t(9;22)- occurs in CML
(Philadelphia chromosome). Also occurs in ALLA
t(14;18)- follicular lymphoma, a tumour of follicles
consisting of centrocytes.
t(8;14)- abnormality occurs in Burkitt’s
lymphoma secondary to a latent Epstein–Barr (EBV) infection and usually
affects the maxilla or mandible.
T/F infectious mono is associated iwth massive splenomegaly
F
Infectious mononucleosis (A), secondary to EBV, is usually an acute limited
disease which is asssociated with fever, weight loss and malaise giving rise
to mild splenomegaly only.
What is multiple myeloma
Haem malignancy resulting from clonal proliferation of a particular plasma (antibody producing) cell.
This results in bone lesions and production of monoclonal immunoglobulin (paraprotein- usually IgG or IgA)
What are the causes of multiple myeloma
Viral trigger?
Chromosomal aberrations are frequent, certain cytokines (e.g. IL-6) act as potent growth factors for plasma cell proliferation
Associated with ionizing radiation, agricultural work or occupational chemical exposures (benzene).
Who is multiple myeloma most common in ethnicity
AfroCaribbeans > white people > Asians.
History of multiple myeloma
Calcium raised (stones, abdominal moans, psychic), polyuria
Renal failure
Anaemia
Bone pain (back and ribs)
Recurrent infections
Hyperviscocity: Bleeding, headaches, visual disturbance.
Examination of multiple myeloma
Pallor, tachycardia, flow murmur, signs of heart failure, dehydration.
Purpura, hepatosplenomegaly, macroglossia, carpal tunnel syndrome and peripheral neuropathies.
Investgiations for myeloma
Bloods?
Best initial test?
Best confirmatory test
Normochromic normocytic anaemia
Raised ESR, normal or raised CRP
Creatinine and calcium raised, normal Alk Phos
Serum electrophoresis (1st test): serum paraproteins (2/3 IgG, 1/3 IgA)
Urine electrophoresis: Bence-Jones protein (free light chain, lamda or kappa in 70% cases)
Bone marrow aspirate and trephine (bone marrow biopsy): Increased Plasma cells (identified as large cells with a perinuclear halo, eccentric nuclei, blue cytoplasm) – usually >20%.
X rays. Osteolytic lesions WITHOUT surround sclerosis. Pathological fractures
Staging used for multiple myeloma
Durie–Salmon staging: Based on serum Hb, immunoglobulin, Ca2þ, creatinine levels and number of radiographical bone lesions on the skeletal survey.
What causes hypercalcaemia in multiple myeloma
ultimately caused by bone destruction from osteolytic tumor lesions and is most commonly observed in patients with extensive bone involvement by neoplastic plasma cells.
What is the impact of mulitple myeloma on other cells in the bone marrow
Proliferating plasma cells suppress normal bone marrow function, which leads to clinical findings of anemia, bleeding and/or infection
What are the complications of multiple myeloma
Often affect kidneys:
myeloma cast nephropathy, light chain deposition disease, amyloid light-chain (AL) amyloidosis with renal involvement, and nephrocalcinosis
What is the most common symptom for multiple myeloma
Back pain
Bence Jones myeloma causes what kind of urine
Foamy urine, caused by Bence Jones proteinuria
t/f myeloma is associated with lymphadenopathy
F.
Enlarged lymph nodes are not a typical finding!
What RBC finding can be seen in peripheral blood smear of myeloma
Rouleaux formation
Bone marrow finding for multiple myeloma
clusters of plasma cells
Clockface nuclei: Chromatin in the periphery of the nucleus resembles a cartwheel or clock face arrangement.
t/f prophylactic splenectomy is not indicated in sickle cell disease, unless there is splenic sequestration.
T.
If vaso-occlusive crises do occur, hydration and analgesia are the mainstays of treatment. Other treatment options, such as folic acid
supplementation , prophylactic penicillin , or hydroxyurea may be considered to lower complication rates and thus improve the quality of life .
Splenectomy in sickle cell disease is reserved for patients who have had splenic sequestration crisis or hypersplenism (in which large amounts of blood pool in the spleen , causing massive splenomegaly , severe anemia , hypovolemia and possibly even shock).
