Essay corrections

Question 1

B thal symptom explanations

Answer 1

Fatigue and pallor - a globin chain xs causing precipitation within the erythroblasts and damaging them. The alpha globins do not form tetramers. They cause erythroblasts to die and thus depletion of functioning haemoglobin.  + Ineffective erythropoiesis
Jaundice - intravascular haemolysis as well due to abnormal RBC presence in blood. 
Splenomegaly and hepatomegaly - Increased extamedullary haematopoiesis + extravascular haemolysis
Bone marrow hyperplasia -> Hypoxic environment stimulates hypoxic drive and increased EPO production. Erythropoiesis is however ineffective therefore leading to bone deformity, Bone spikules develop and the BM expands, showing up as a hair on end appearance -> osteoporosis and pathological fractures + Enlargement of maxillae other facial bones
Pulmonary HTN - Increased haemolysis means increased Hb in the circulation, this saturates the haptoglobin and then free Hb binds to NO and is oxidised to met haemoglobin . Lack of NO causes vasoconstriction, particularly affecting the pulmonary circulation
Consequences of transfusions – iron loading
Heart – Arrhythmias, cardiomyopathy, cardiac failure
Liver – cirrhosis and also hepatocellular cancer
Pancreas – diabetes
Pituitary – growth interruption and also sexual maturation
Psychosocial of transfusion dependant life (Affects education, activity, integration (Ratip et al. 1992), Anxiety in over half , 58% have difficulty with sexual maturity)

Question 2

PNH mechanism references

Answer 2

PIGA discovery was Takeda 1993
Pathophysiology is BRODSKY 2004
Mx, xs anticoagulation not needed for proph in PNH emadi BRODSKY 2009
Microparticles -> wiedmar 1993
Free Hb - > rother 2005
C5a (IL 6, 8., TNFa) -> Ritis 2006
decreased fibrinolysis (TFPI coreceptor, decreased uro r a and heparan sulfate) -> maroney 2006
chronologically through time but opposite alphabet

Question 3

Stroke prevention reference in blood transfusion

Answer 3

NEJM DeBaun et al. , regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anaemia.
• 3236 transfusions, 4/99 (4%) patients developed 9 alloAbs
• Alloimmunisation rate of 0.278/100 RBCs

Question 4

Cons of blood transufsions

Answer 4

Haemosiderosis Iron overload
Hyperhaemolysis syndrome
Haemolytic transufion reaction (acute and delayed)

Transmission of infectious agents 
TRALI TACO TA-GvHD
TwITCH Trial  - future 
PTP
Recurrent venous access

Question 5

IVH vs EVH in SCD

Answer 5

IV haemolysis = free Hb in circulation = breakdown of NO = vasoconstriction and more platelet activation
ohaptoblobin and haemopexin, two mechanisms by which Free Hb is removed from the blood, are both reduced in SCD
oIV haemolysis = release of arginase = breakdown of arginine = less NO synthesis
Scavegened NO:
•Sickle vasculopathy – SCD can be described as a chronic inflammatory disease!
•Pulmonary HTN, vascular hyperplasia

Extravascular haemolysis
•metHbS is formed via oxidation. it breaks down into hemichromes and releases haem and Fe3+
•Haem and Fe3+ oxidise membrane lipids, cytoskeleton and other HbS molecules
•oxidised HbS precipitates as Heinz bodies which bind to ANKYRIN BAND 3 on inner CSM
othis is seen and removed by the spleen; extravascular haemolysis and chronic HA

Question 6

Malaria essay references

Answer 6

1 Kyes et al. -> PfEMP1 causes Ag variation
2 Eodzien - higher IgG levels in HbAS indviduals
3 Cockburn et al. - CR1 polymorphism is association with alpha thalassemia and confers protection to severe malaria
4 Ayi et al - proposed that oxidative events led to the enhanced phagocytosis of ring staged cells in beta thal, sickle and HbH (the oxidative events were aggregation of band 3, deposition of antibodies and complement C3c frgaments).

Question 7

HO-1 role?

Answer 7

Sickle Hb induces expression of heme oxygenase 1 in HSC via Nrf2 TF. CO (a by product of heme catabolism) by HO-1, prevents further accumulation of free Hb and limits tissue damage post Plasmodium infection

Question 8

Ayi et al proposed what for malaria

Answer 8

Ayi et al - proposed that oxidative events led to the enhanced phagocytosis of ring staged cells in beta thal, sickle and HbH (the oxidative events were aggregation of band 3, deposition of antibodies and complement C3c frgaments).

Question 9

Duffy antigen explanation + reference

Answer 9

LUTZ et al.
For invasions to occur an interaction between the parasites and antigens of the Duffy Blood Group System is necessary. In Caucasians six antigens are produced by the Duffy locus (Fya, Fyb, F3, F4, F5 and F6). It has been observed that Fy(a-b-) individuals are resistant to Plasmodium knowlesi and P. vivax infection, because the invasion requires at least one of these antigens. The P. vivax Duffy Binding Protein (PvDBP) is functionally important in the invasion process of these parasites in Duffy / DARC positive humans. The proteins or fractions may be considered, therefore, an important and potential innoculum to be used in immunization against malaria.

Question 10

HFE mutation mechanism

Answer 10

The most prevalent disease-causing HFE mutation in the general population is the C282Y mutation, which disrupts the formation of a disulfide bond in the HFE protein and impairs its capability to bind β2-microglobulin. As a consequence, HFE is unable to reach the cell surface and aggregates intracellularly. This causes impaired signaling leading to reduced hepcidin mRNA expression, decreased plasma hepcidin levels, and excessive systemic iron accumulation in adults (aged over 40 years).
Hepcidin binds to FP and degrades it so low hepcidin -> hig FPN -> high absorption means that high fe export in the blood

Question 11

Iron overload management

Answer 11

Primary
Removal of excess iron by phlebotomy
Initially once weekly until transferrin saturation <16% and ferritin <20 mcg/L then maintenance. Keep transferrin saturation <50% and ferritin <50 mcg/L indefinitely
Secondary
Deferoxamine is the drug traditionally used for iron chelation therapy. It is given by a slow subcutaneous infusion overnight through a portable pump:
• Chelation is usually by slow SC deferoixamine 20-60mg/kg/day over 8-24hrs
• Some oral iron chelators (desferiox, deferipone) are available but they have side effects (GI disturbance, neutropenia, agranulocytosis)

Question 12

Lectin pathway

Answer 12

MBL or ficolins bind to carbohydrate moieties on bacterial surface and activate MASPS. MASPS 1 and 2 are mbl associated serine proteases which convert analogous to C1q and split C2 and C4s > C3 convertase

Question 13

Alternative pathway

Answer 13

•C3 undergoes hydrolysis to C3(H20)
•This allows factor D to cleave Factor B into Bb and Ba
•C3(H2O)Bb is a C3 convertase cleaving C3 > C3a+b
•C3b in contact with a FOREIGN surface activates C3 amplification loop.
•C3b does two things:
1 .Opsonisation which surrounds the pathogenic surface enabling phagocytosis ( C3b molecules can attach to the Fc regions of antigen-bound antibodies leading to phagocytosis or movement to the liver, where the C3b-tagged immune complex is then destroyed)
2. C5 activation and formation of MAC

Question 14

What stops complement from attacking our own cells?

Answer 14

This process does not occur on own cells as our cells; FLUID PHASE and MEMBRANE bound regulators to control this process. Dysregulation of these mechanisms leads to pathogenesis:

• Own cell membranes contain sialic acid which is absent from pathogenic cell membranes.
• FACTOR H in the presence of Sialic acid on self-cells regulates C3b amplification. Absence on pathogenic surfaces fails to confer protection leading to C3b accumulation (and clearance of pathogen)
• C3b on self-cells can be inactivated by FACTOR I.

Question 15

aHUS mechanism

Answer 15

• Deficiency or polymorphisms in Factor H (which regulates the alternative pathway) confer risk of HUS in response to risk such as infection/pregnancy
• Disorder of complement regulation
• Characterized by: Haemolysis, Thrombocytopenia and Renal failure
• Complex genetic trait – multiple mutation required for manifestation.
• Associated with mutations of Factor I and MCP

Question 16

pathogenesis of VOE in SCA

Answer 16

•VCAM1 is upregulated by the dysfunctional endothelium. it binds to reticulocytes via VLA4
•reversibly sickled cells also bind to dysfunctional endothelium and exposed ECM
o young sickle cells bind to integrins via LW antigen. LW antigen is upregulated by adrenaline so stress/adrenaline = adhesion and may lead to sickling
•The majority of adhesion is believed to occur in post-capillary venules
o RBCs elongate in capillary bed (surface area) and there is slow blood flow in the venule
o adhesion leads to retrograde capillary obstruction = ischaemia/infarction
•Vaso-occlusive disease starts after 6 months of life – HbF protects upto this point
o Painful crises (limbs/chest/abdomen) occur in 40% of patients?
o hand foot syndrome (dactylitis) in the first two years of life leads to growth delay
o adolescent sequelae include delayed puberty and priapism

Question 17

SCA hyposplenism pathogenesis

Answer 17

• Haemolysis → Splenomegaly → recurrent sequestration crises due to infarcts →atrophy and fibrosis of spleen → hyposplenism (Howel Jolly bodies) → recurrent infections occur due to immune dysfunction, particularly malaria, pneumococcus and meningococcus
• splenomegaly usually disappears after 5 years. persistent splenomegaly may indicate thalassaemia or higher HbF

Question 18

How does thrombin’s exosite structure allow its regulation

Answer 18

Thrombin has low affinity for fibrinogen (since fibrinogen is high concn) and once fibrin is formed thrombin remains bound to it with weak affinity so that 1 it can move about on clot surface and @F13 2 it can @PC.
Thrombin’s affinity for fibrin is WEAKER than TM so once fibrin is formed -> anticoagulant fate

Question 19

What two paragraphs do you forget/mess up in thrombin essay

Answer 19

Thrombin’s interaction with platelets:
Thrombin activates platelets using exosite 2 to activate PAR1 and PAR4. PAR4 blocking Ab had no effect on plt @ by thrombin, but when combined with PAR1 Ab it wasn’t activated even in high concn of thrombin
Thrombin’s interaction with TAFI - is PROcoagulant and uses exo 1 (if cs exo 2) Thrombin alongside TM activate TAFI. TAFI removes lysine residues on fibrin meaning that Plasminogen and tpa cannot recognise fibrin using their kringle domains (wang et al.). Removing lysine residues also partially digests fibrin which casues an associated decreased in plasminogen binding and retardation in clot lysis

Question 20

DIC mechanism in APML + reference

Other APML references

Answer 20

Shanshank et al. -> promyelocytes produce a lot of TF which bind to FVII-> Hypercoagulable blood
FALANGA et al. ->
APL also secrete inflammatory cytokines (IL Ib) which induce TF in EC, microparticles are released -> Hypercoaguation
MENELL et al. 15;17 -> really high levels of ANNEXIN which is a cofactor for tPA that increases its formation by 60 fold. This alongside increased elastase production by APML (which degrades fibrin inhibitors) leads to&raquo_space; Hyperfibrinolysis
Pethema Protcol. Frank et al. for DS, ATO gives 72% CR (Sun et al.)

Question 21

APML FMN

Answer 21

• Beaware of other variant translocations 11;17 (resistant to ATRA)
• Mx: ATRA has 90% cure rate for those who survive DS. Platelets are given to keep counts 30-50 and cryo given to keep fibrinogen >1.5g/L. ATO has 72% Sun et al.

Question 22

APML (physioogical normal molecular stuff)

Answer 22

RARA - RXR binds to RARE at the promoter regions of target genes (normally expressed in haematopoietic cells)
When RA is present, it induces a confromational change in RARA- RXR complex and disrupts the binding of nuclear corepressors and histone deacetylases, instead it binds to histone acetylatses which result in chromatin relaxation and transcription.
PML RARA - dominant inhibition of RARA, therefore RA cannot overcome…

Question 23

ATRA side effect

Answer 23

Typically occurs 1 week after induction therapy is a life threateing side effect called differentiation syndrome.
Frankel etl al. first described DS in 1992 whereby 9 out of 35 apml pnts developed a variety of signs but mostly fever, pleural effusion, peripheral oedema, pericardial effusion, weight gain >5kg, pulmonary infiltrates

Question 24

Alpha thal major, what can and can’t be made?

Answer 24

Alpha thal major -> Can’t make HbA, HbA2 or HbF (alpha and delta). Only physiological haemoglobin that can form in foetus are:
o Hb Gower 1 zeta2 episilon
o Hb Portland zeta2 gamma
At birth there is only gamma tetramers– ( Hb Bart’s ), Hb H (Beta 4) and a little Portland (zeta2beta2)

Question 25

Alpha thal path FMN

Answer 25

THE WHOLE EXCESS CHAIN FUCK UP
Unlike in B-thalassemia, proportions of Hb on HPLC in alpha thal gives us no clues towards diagnosis so you need to diagnose using DNA analysis.
Loss of one gene:
Most common: is deletion of one alpha gene. It can also be due to a fusion of the alpha1 and alpha2 genes on one chromosome.
Loss of two genes: a0 heterozygosity or a+ homozygosity
o In a+ homozygosity the remaining alpha gene on each allele is upregulated so there is a milder pic than ao heterozygosity

Question 26

HbH

Answer 26

• Loss of three alpha genes: this is compound heterozygosity for a+ and a0.
• Excess B-chains form tetramers = HbH. (high O2 affinity)
• Gamma tetramers also form (Hb Bart’s – high O2 affinity)
• Clinical picture: similar to B-thal, ↓MCV ↓MCH ↓MCHC ↓RBC ↓Hb – differentiate by checking HbA2%
• Film: reticulocytosis because the BM is making new RBCs to try and compensate for anaemia; golf ball cells where B-globin has precipitated
• BM erythropoiesis is (relatively) normal so we don’t see nucleated RBCs in peripheral blood and don’t see inclusion bodies in the precusors in the bone marrow.

Question 27

Variant haemoglobins can interact with B-thalassemia, these are:

Answer 27

•HbE (most common cause of B-thal intermedia worldwide; can cause B-thal major)
oNormal affinity for O2 but unstable; reduced synthesis 25%
•HbS (forms HbSC sickle cell disease)

Question 28

Beta thal path

Answer 28

Alpha xs can’t form tetramers -> excess of alpha monomers -> Inclusion bodies form early in erythropoiesis
SEVERE INEFFECTIVE ERYTHROPOIESIS and INCREASED HAEMOLYSIS
There is also increased fragility and substantially less stable mechanical stability when compared to alpha thal
1. Reduced globin synthesis, reduced Hb
2. Ineffective erythropoiesis: Alpha-globin chains are in excess and precipitate in erythroblasts in the BM. This causes ineffective erythropoiesis whereby these cells can’t mature properly.
3. Haemolysis – of those RBCs that do enter the circulation
o Haemolysis → jaundice, gallstones
o Anaemia → extramedullary haemopoesis in the BM, spleen, liver
o Pulmonary HTN: there free Hb leads to NO depletion (scavenging) causing vasoconstriction
o Haemochromatosis from transfusions
o Psychosocial effects: regular hospital visits, fatigued → missing school, developmental problems etc

Question 29

Beta thal and sickle overlap?

Answer 29

B-thal/HbS
• If BO, no HbA is produces, only HbS – this is like SCD, but slightly less severe because there is a lower MCH so the cell is slightly less prone to sickling and haemolysis
• If B+, there is some HbA produced

Question 30

Alpha and beta combined thal reference

Answer 30

Despite the fact that they appeared to have the genotype of hemoglobin H disease, their cells contained no hemoglobin H and had a normal lifespan presumably because excess β-chain production was inhibited by the β-thalessemia gene. These family studies suggest that the α:β imbalance observed in thalassemia may be favorably influenced by combinations of α- and β-thalassemia genes. Kan et al., 1970

Question 31

TACO vs TRALI

Answer 31

SKEATE + EASTLUND
TACO is felt to be similar to other
causes of acute congestive heart failure: an increase in
central venous pressure & pul. blood volume > increase in HYDROSTATIC pressure leading to fluid extravasation into the alveolar space. > respiratory distress, tachycardia, and hypertension & some pnt have JVP DISTENSION or S3.
TRALI results from neutrophil-mediated damage to the
pulmonary microvasculature. The current proposed
model is a ‘two-hit hypothesis’ wherein a primary
stimulus causes neutrophil SEQUESTRATION in the pulmonarycapillaries, and a secondary stimulus causes the
neutrophils to ‘activate’, damaging the endothelial layer
such that fluid and PROTEIN LEAKS into the alveolar space. Neutrophils can be first ‘primed’ and subsequently
‘activated’ by pro-inflammatory stimuli present
either in patients with certain disease states, or infused
with blood products. Patient exposures that can lead to neutrophil priming include surgery, tissue injury, and infection. Pro-inflammatory stimuli that can be infused with blood productsinclude neutrophil-specific or anti-human leukocyte antigen (HLA) antibodies, or bioactive lipids
TRALI - fever, exudative oedema fluid and can have transient leucopenia
Treatment of TACO starts with discontinuing any
ongoing transfusion. Respiratory distress is treated with
the degree of respiratory support needed to maintain the
patient’s oxygenation. Diuretics are administered to
remove excess fluid. TRALI - aggressive respiratory support

Question 32

Other cons of blood transfusion which you forget

Answer 32

PTP - post transfusion purpura (occurs 5-12 days after transufion) due pnt producing allo-antibody to the donor’s plt antigen and this causes thrombocytopenia (anti-HPA-1a being the most frequent antibody). The RBC units must be washed to avoid exposure to platelet membranes and recurrence of thrombocytopenia. In future transfusions, washed RBCs or HPA1bb blood products should be used.
Hyperhaemolysis syndrome occurs when there is a drop in Hb and Hct lower to than that before of the transfusion. It is believed to be due to hyperactive macrophages which consume peripheral reticulocytes (donor and pnt) and results in mass IVH with haemoglobinuria post transfusion.

Question 33

Blood transfusion references

Answer 33

Skeate and eastlund for TRALI and TACO
SHOT 2013 - infection risk has fallen substantially and greatest risk fo clearlical error
NEJM DeBaun et al -> reduced cerebral infarct in SCA children with regular transufsions
Vlachos - DBA (require transufsions 3-5 weeks to maintain Hb above 80g/L)
Schmalzer 1987> becareful of giving simple transfion to SCD pnts without severe anamia due to hyperviscoity syndrome (as Hb is marginally raised without lowering HbS % by much)

Question 34

HbE

Answer 34

o BETA globin variant: change from 26th AA from glutamic acid → lysine; leads to reduced mRNA production
• Is produced at a reduced rate because 2/3 of the mutant transcript is nonsense and doesn’t make any protein; 1/3 makes HbE
oThe mutation is located near to the junction between exon1 and intron1 and it unmasks a cryptic splice site, which is not normally used. this site competes with the normal splice site. Some mRNAs are correctly processed however, a large amount of mRNA is wrongly processed and reaches an early stop codon.
otrait is prevalent in N. India and SE asia
ohomozygosity and carrier status have a mild microcytic anaemia
oneed to rule out compound heterozygosity with B0thal – which resembles b.thal
otravels with C on alkaline electrophoresis and A on acid electrophoresis
olies in the A2 band on HPLC; suspect if A2 rises to 25-30%

Question 35

HbD

Answer 35

HbD
o change from 121st AA from glutamic acid → glutamine
o carrier status common in Punjab/ los angeles
o target cells abundant

Question 36

Sepsis mechanism

Answer 36

Bacteria bind to TLR on macrophages or dendtitic cells and cause the activation and release of cytokines and comeplment. This results in endothelial “membrane shedding” (loss of EPCR, TM and TFPI). It also causes increased vwf release. Decreased plasminogen + tpa and increased PAI-1 reducing fibirnolysis. EC reduce cell to cell contact which allows extravasation of cells but also increases vascular leakage and oedema -> exacerbated by thrombin activating PAR 1 on EC increasing the extravsation. Adheson molecules presen ton EC which binds and activate monocotyes -> TF MP (800%) and neutrophils are also receruited tot he endothelium -< NETS
THIs al leads to consumption of platelets and DIC

Question 37

PNH essay plan

Answer 37

Background
Pathophysiology (intravascular, extravascular-increased opsonisation by compleemnt fragment C3d due to lack of CD55, chronic)
Thrombosis intro + epi
Thrombosis mechanism
1. Prothrombotic microparticles providing a catalytic surface for the assembly of prothrombinase (mostly produced by plt, but by also lysed rbc)
2. Free Hb-> NO scavenge
3. Complement @ (C5a) activates pro inflam and prothrombotic => IL6, IL8, TNFa
4. Defective fibrinolysis due to deficiency in gp1 upa, heparan sulfate and co-receptor of TFPI
Diagnosis -> CD55 and CD59 flowcyto, although Wang et al. showed using CD16/CD66b is better as it detects a large clone size and is less subjective to analytical interference (he also recommneded that we should screen everyone with MDS and bone marrrow disease due to sizeable association.) Also misdiagnosis of haematuria can delay PNH diagnosis (veerreddy et al.)
First line is eculizumab -> monoclonal ab for C5 (and inhibits c5 convertase)

Question 38

HL ref

Answer 38

McNally -> EBV in 40-50% + 3-4 fold increase
Spinar -> HIV has high proportion of RS and 10fold risk of HL
Siddon -> HHV6 in 49% of RS cells
Strus et al. 2001 - > ALPS Fas
Joos 2002 - > REL is usually amplified and expressed in up to 55% of cases.
Joos 2000 - CGH of 50% loss of gain in 2p 7q 16 q
Franke 2001 - CGH of 50% loss of gain of 1q 3p 5q Xq
Bauger et al. -> REL targets anti apoptic genes and control growth promoting CKs eg IL13

Question 39

HL fmn

Answer 39

FMN: Tumour cells (Hodgkin and RS cells) are a minor component of the tumour mass, the bulk of which is mixed cellular infiltrate
FMN: BCL6 and 3q translocations occur in Nodular
Peripheral Lns and enarlged in NODULAR LP HL, and it can relapse as large B cell as well. Nodular is GC B cell but classical is heterogeneous (can be GC or nonGC)
Brentuximab anti cd30 for CHL - 22% CR (Rothe et al.)
Rituximab anti cd20 in NLPH
FMN: LMP1 upregreulated ahesio moecules eg ICAM1 and protect against cell death by upregulating antiapoptici genes eg bcl2 and @nfkb.
REL explanation too

Question 40

Complement pathway classical

Answer 40

IgG anibody-antigen complexes enabled C1q to bind tot he FC REGION OF THE ANTIBODY

Question 41

Complement pathway higher marks stuff (background, higher marks and onclusion)

Answer 41

BAckground: The complement system is a part of the immune system that enhances, or complements, the ability of antibodies and phagocytic cells to clear pathogens. It can also directly kill pathogens itself. It is part of the innate system but can be stimulated by antibodies generated from the adaptive immune system

1. 4th pathway OOOh AHHHHH
   Using ELISA, Selander et al, showed that ML can bind to SEROGROUP O ANTIGEN-SPECIFIC SALMONELLA OLIGOSACCHARIDE. This binding can activate C3 in the absence of C2, C4 and even MASP2.

Conclusion:
Although complement research has been in the center of interest for many years, our understanding and insight into the cascade mechanisms and their complex interaction with other protein cascades such as the coagulation cascade is still in its nascent phase. Currently, complement activation is not divisable into three canonical pathways with separate activation patterns. The exact role of complement in many diseases needs to be further clarified because successful complement interventions need to be matched to the individual patient and be as specific as possible.

Question 42

Beta thalassemia symptom references

Answer 42

Morris et al 2005 -> arginase in pulmonary hypertension
Circulation journal May 2010 -> two types of beta thal cardiomyopathy
Hazmi et al. 1994 -> stats about pancreas 6% vs 2% in thal minor compared to normal . 24% vs 2% vs 0% for IGTT. Due to a combo of liver damage + iron overloading -> damageds Beta cell and causes IGT
Pignatti et al. > super sad pituitary statistics -> 83% M 75% F had delayed skeletal growth, only 19% of females had experieces menarch and 67% M 39%F had lack of puberty
Eshragi et al -> 14.6% had hyopthyrdoisim Caspian trop med
Ratip et al > affects edugcation activity adn integration 58% difficult with sexual maturity and over half have anxiety.

Question 43

Splenectomy essay references

Answer 43

De Montalembert -> partial splenectomy preserves immune function
Pringle 1982 - > emobilisation
Casale et al -> HS benefits (relieves symptomatic anaemia, reduces bilirubinaemia and prevents gall stones, reverses growth retardation and possibile improvemenn tin CO and LV remodelling)
Santos et al > painful splenomegaly infarction has shown to improve anaemia and thrombocytopenia and relieve pain and discomfort .
Kristinsson et al. 2014 -> 2 fold inrease in DVT and PE and 4.5 and 1.4 fold increase nin irks of death from PE and CAD. Immediate AND LIFE LONG suspectibiltiy
Porter et al. 2017> spontaneous iron overloading
(Other cons -> surigcal risk and 10% sepsis, in malaria it can result in slower clearance of the parasite )

Question 44

Pros of splenecomty in beta thal and MPN

Answer 44

In beta thal -> indicated in hypersplenism as it can raise Hb by 20g/L and reduce pain from splenomegaly, and it eliminates the haemolysis of donor cells as well. Can make pnt transufion independent
Myelofibrosis conditions e.g. P vera -> hypersplenism due to extramedullary haematopoiesis. If teh hypersplenism is PAINFUL, splenectomy can be indicated to reduce pain or in splenic infartions(but not actually treat the disease). Santos et al, examiend this and showed that pain and discomfort were relieved, as well as anamiea nd thrombocytopenia were imrpoved. Howeer, there was leukocytosis and thrombocytosis

Question 45

Complement implicated in disease + ref

Answer 45

aHUS - factor H def/polymorphism -> Kavanagh 2011
PNH - WIedmar…
Catatrophic APL renal transplant - MolMedJ 2010
C3 deficiecny -> G+and G-ve - Sjöholm 2006
C5-c8 - Tedesco 2008 - meningoocial
C1q - Hoffman and Hoffman2010 - lupus
Alzeimers -> beta amyloid plaques activate c1 Cr3 and Cr4- Heneka et al. 2010

Question 46

Pure red cell aplasia. Define it? Name an inherited cause of PRCA.

Answer 46

Normocytic normochromic anaemia with severe reticulocytopenia with marked reduction/absence of erythroid precursors from bone marrow
Can be congenital (DBFA- congenital eryhtroid asplasia, congenital abrnomalities and cancer predisposition. In more than 50% , the syndrome appearst to result form haploinsufficiency of either small or large subunit associated ribosomal protein. )
acquired (B19 parovirus)

Question 47

Pick 2 mechanisms of APRCA and explain their pathophysiology

Answer 47

Parovirus The B19-associated damage of erythroid lineage cells is due to cytotoxicity mediated by viral proteins NS1 which cause cell cycle arrest in G1 and G2. B19-infected erythroid-lineage cells show apoptotic features. In a patient who has a concurrent disease that results in a shortened life span of RBC, TAC (transient aplastic crisis) can occur and this can be fatal, e.g. beta thal (Arabzadeh, 2017)
T-cell CLL showed that blood lymphocytes inhibited normal marrow CFU-E growth. T cell receptors for the Fc portion of IgG molecule (Ty) were shown to have an inhibitory effect on CFU-E. CFU-E growth markedly increased after removal of the Ty cells by E-rosetting

Question 48

Pathogensis of VOE in SCD

Answer 48

VCAM1 is upregulated by dysfunctional endothelium and it binds to reticulocytes via vla4.
Young sickle cells bind to integrins via LW antigen (which is upregulated by adrenaline)
Increased ahdesion in post cap venules -> RBC elongate in capillary bed which reduces blood flow and increaes the chance of shcaemia infarcton
Vasoocclusive disease starts at 6 months of life (HbF protects until this point)

Question 49

ACS mechanism and pulhtn

Answer 49

Years 3 →
microthrombi in pulmonary vessels = lung infarcts
vasoconstriction due to less NO due to free Hb is another
rib infarcts = less deep breathing (pain) = hypoxia = sickling
importantly, ACS → hypoxia → sickling → ACS
oexacerbated by infection and BM emboli
•clinical features include fever, CP, cough, SOB, wheeze, cyanosis and LOC due to hypoxia
PUL HTN:
•recurrent Episodes of ACS can lead to this because it causes thrombosis, vasoconstriction and thickening of vascular walls/fibrosis
oLow NO (free Hb) also contributes to thrombosis and vasoconstriction
•can lead to right heart failure and death

Question 50

Priapism

Answer 50

priapism is an unwanted, painful, persistent erection (acute emergency)
Poor venous drainage from corpus spongiosum is the cause
odecreased NO synthesis (arginase release from RBCs) = vasoconstriction
ofree Hb = NO scavenging
oIncreased reticulocyte adhesion = slow flow = sickling

Question 51

Why does SCD cause anaemia? Consequence of this?

Answer 51

red cell life is reduced 10 fold due to intra- and extravascular haemolysis
EPO response means that erythropoiesis is increases 3-6fold = increase in plasma volume
oexpansion of BM increases need for folic acid. folic acid deficiency can contribute to anaemia in Africa
HbS has a lower affinity for O2 in the first place – this impairs the EPO response

Question 52

Stomatocytosisa and ovalocytosis

Answer 52

Hereditary stomatocytosis - AD disease where high cytoplasmic cation content gives overhydrated cells that appear as stomatocytes (increased viscosity = loss of deformability)
Hereditary Ovalocytosis
oSingle mutation in band 3 cofners loss of deformability; common in SE Asians
oOvalocytes differ from spherocytes because they are paler and some appear as ellipses

Question 53

Features of HA on blood film

Answer 53

Features of haemolysis on film; heinz bodies
Direct coombs (tells you if its immune or not)
Thick and thin blood film for someone whose just been to a malaria endemic area; dipstick test is an alternative
Film - hypersplenism signs (peripheral cytopenia), low number of malarial parasites
Marrow - hypercellular
Film - Anaemia, reticulocytosis, polychromasia
Bloods - high BR, LDH & low (used up) haptoglobins in intravascular haemolysis
Urine - haemoglobinuria (red)/ haemosiderinuria (brown) in intravascular haemolysis

Question 54

Presence in managing HA

Answer 54

Conservative - avoiding triggers in G6PD, monitoring complications, folate
Medical - transfusions for severe anaemia, immunization against HepB
Surgical - cholecystectomy for recurrent gallestones. Splenectomy is good for:
oPk deficeicny, HS, severe HE and sometime in thalassaemia
oPatients who are between 3-10, transfusion dependent, have poor growth and chronic Hb<8
•Watch for encapsulated bacteria sepsis; give prophylactic penicillin