Sickle Cell disease: Introduction Flashcards
Heterozygous or Homozygous?
Heterozygous state called sickle cell trait/carr…… (SCT);
Homozygous form = Sickle cell a………………;
Sickle cell disease is associated with compound heterozygosity:
Hb …./…
Hb …./…. thal
Hb …../… thal
SCT is associated with benign clinical course with 30-40% HbS;
SCT: Only in exceptional circumstances does sick………. occur
Sickle Hb causes right shift in ………….
Heterozygous or Homozygous?
Heterozygous state called sickle cell trait/carrier (SCT);
Homozygous form = Sickle cell anaemia;
Sickle cell disease is associated with compound heterozygosity:
Hb S/C
Hb S/β thal
Hb S/α thal
SCT is associated with benign clinical course with 30-40% HbS;
SCT: Only in exceptional circumstances does sickling occur
Sickle Hb causes right shift in ODC
Homozygous state
Approaching 100% HbS;
Induction of Hb… improves symptoms;
Chronic haem……… anaemia;
Recurrent, intermittent va……-occlusion:
- Severe ……….
- ………. failure;
Early death
- Life expectancy - Median life expectancy for males and females with HbSS is 42…. and 4… years
Homozygous state
Approaching 100% HbS;
Induction of HbF improves symptoms;
Chronic haemolytic anaemia;
Recurrent, intermittent vaso-occlusion:
- Severe pain;
- Organ failure;
Early death
- Life expectancy - Median life expectancy for males and females with HbSS is 42 and 48 years
Lab findings
Hb ~ ….g/L
Retics ~ .-….%
WBC~…-… x 109 /L
Plts > ….. x 109 /L
Beyond ….yrs of life Hb stabilises with episodic lowering (hyperhaemolysis, sequestration, aplasia);
Red cell lifespan reduced to ~ 12 days.
Lab findings
Hb ~ 85g/L
Retics ~ 5-20%
WBC~10-12 x 109 /L
Plts > 400 x 109 /L
Beyond 5yrs of life Hb stabilises with episodic lowering (hyperhaemolysis, sequestration, aplasia);
Red cell lifespan reduced to ~ 12 days.
Effects of Chronic haemolysis
Range of ECHb varies during the course of the disease:
- Steady state = ….-…….ug/ml
- VOC - >…….ug/ml
Maximum capacity of haptoglobin …..-…….ug/ml;
ECHb binds haptoglobin is cleared by macrophages via CD…..;
Excess ECHb consumes endo………….. …..;
Release of Arg………… I;
Vasocon……….., syst…..and pulm….. hyper……. follows.
Effects of Chronic haemolysis
Range of ECHb varies during the course of the disease:
- Steady state = 20-330ug/ml
- VOC - >410ug/ml
Maximum capacity of haptoglobin 70-150ug/ml;
ECHb binds haptoglobin is cleared by macrophages via CD163;
Excess ECHb consumes endogenous NO;
Release of Arginase I;
Vasoconstriction, systemic and pulmonary hypertension follows.
Nitric Oxide and arginine
NO is synthesised by vas………… end………….. cells;
NO deficiency enhances end…………….-……. production;
Substrate is ….-argi…….;
Patients have increased asymmetric dimethyl…………. which inhibits argi……… transport = vascular dysfun………..;
Association between circulating AD…… levels and all-cause mor………….
Nitric Oxide and arginine
NO is synthesised by vascular endothelial cells;
NO deficiency enhances endothelin-1 production;
Substrate is L-arginine;
Patients have increased asymmetric dimethylarginine which inhibits arginine transport = vascular dysfunction;
Association between circulating ADMA levels and all-cause mortality
L-arginine is converted citrulline and NO via the action of end………….. nit…… oxi…… synt…………
Within the cyt………. of smo……… mus……. cells the conv……….. of GT… to cG……. (facili………. by N…. binding to the haem moi……. of gua……… cyc……..) leads to decre…….. [Ca(2+)] and….. relax…….. of smo….. mu. cells
L-arginine is converted citrulline and NO via the action of endothelial nitric oxide synthase.
Within the cytoplasm of smooth muscle cells the conversion of GTP to cGMP (facilitated by NO binding to the haem moiety of guanylate cyclase) leads to decreased [Ca(2+)] and relaxation of smooth muscle cells
Downstream effects
N.. inhibits plat………. adhe…….. & activ…….;
Renal impa…….. lea……… to fail……..;
Activated endot………… se………… ULv…..;
EC….. int………… wit. ULv…… prev……….. clea……… by ADAMT………..
Downstream effects
NO inhibits platelet adhesion & activation;
Renal impairment leading to failure;
Activated endothelium secretes ULvWF;
ECHb interacts with ULvWF preventing cleavage by ADAMTS13
Platelet activation
Rel……… of Thrombos……….-1 from activated plat……….
Interacts with CD…….
Pro………… eryp………..
Enha………. RBC clearance via P….
Prom……… RBC Ca2+ incr……
Ca2+ dependent K+ cha……… affected = RBC dehyd………
Release of Thrombospondin-1 from activated platelets
Interacts with CD47
Promotes eryptosis
Enhances RBC clearance via PS
Promotes RBC Ca2+ increase
Ca2+ dependent K+ channels affected = RBC dehydration
Sickle-endothelial Interactions
Involves polymerisation dependant and independant processes;
Oxy-deocy cycles in vi… do not cause V……:
- delay time for H….. polyerissation > capillary transit time.
Hbs polymerisation changes oxyHb to deoxyHb
Factors increasing transit time= increase risk of V….;
- R…. and leuc………..
Sickle-endothelial Interactions
Involves polymerisation dependant and independant processes;
Oxy-deocy cycles in vivo do not cause VOC:
- delay time for Hbs polyerissation > capillary transit time.
Hbs polymerisation changes oxyHb to deoxyHb
Factors increasing transit time= increase risk of VOC;
- RBS and leucocyte.
Sickle heterogeneity 1
Fabry and Nagel (1982) – four fractions of RBC in sickle patients
1 lighter than fraction 2 mainly reticu…………..
2 MC….. - ……….g/L
- same as HbAA
3 dense irregularly shaped RBC - ……….. MCHC
- Irreversibly sickled ce……..(ISC) MCHC > ………g/L
Sickle heterogeneity 1
Fabry and Nagel (1982) – four fractions of RBC in sickle patients
1 lighter than fraction 2 mainly reticulocytes
2 MCHC - 300g/L
- same as HbAA
3 dense irregularly shaped RBC high MCHC
- Irreversibly sickled cells (ISC) MCHC > 450g/L
Two step model suggest reticul………… and defo……….. cells bind first followed by trapping of dense disc………. and irre………… sickled cells
Two step model suggest reticulocytes and deformable cells bind first followed by trapping of dense discocytes and irreversibly sickled cells
Leucocyte recruitment
Raised WBC found in sickle patients;
VOC often follows in………….;
Can lead to repe………. injury;
End…….. activation follows;
Inflammation follows; increasing infla……………. cyto……….;
….-selectin expressed;
Leu………. recruit………… decre……… micro……….. flow;
Enhances …….. binding;
Leucocytes and red cells bind = ………..
Leucocyte recruitment
Raised WBC found in sickle patients;
VOC often follows infection;
Can lead to reperfusion injury;
Endothelial activation follows;
Inflammation follows; increasing inflammatory cytokines;
E-selectin expressed;
Leucocyte recruitment decreases microcirculatory flow;
Enhances RBC binding;
Leucocytes and red cells bind = VOC.
Summary: Vaso-occlusive crisis
Top branch only: During inflammation ….-selectin expressed on endo…………….. Neutrophil ESL-…. binds promoting leu………. rolling. Leucocytes, such as this neu……… express αM…… integrin in response to ESL-… liga……, binding to sic……. cells
Summary: Vaso-occlusive crisis
Top branch only: During inflammation E-selectin expressed on endothelium. Neutrophil ESL-1 binds promoting leucocyte rolling. Leucocytes, such as this neutrophil express αMβ2 integrin in response to ESL-1 ligation, binding to sickle cells
GLU–6-val
Osteomyelitis,
Osteonecrosis& skin
- Skeletal deformity
- Leg ulcers
Cardiovascular
- cardiomegaly
- Pulmonary artery hypertension
Stroke & TIA
- Cognitive impairment
- Physical disability
- Death
Acute chest syndrome
- Resp failure
- cough
- Pleuritic chest pain
- dyspnoea
- haemoptysis
GI
- Intra-hepatic sickling
- Pigment gallstones
Splenic sequestration
- Death
- hyposplenism
- Obstructive sleep
apnoea#
- Hypertrophy of
lymphoid tissue
Anaemia
- Aplastic crisis
Renal failure
Genitourinary
- Priapism
GLU-g-6-val
Osteomyelitis,
Osteonecrosis& skin
- Skeletal deformity
- Leg ulcers
Cardiovascular
- cardiomegaly
- Pulmonary artery hypertension
Stroke & TIA
- Cognitive impairment
- Physical disability
- Death
Acute chest syndrome
- Resp failure
- cough
- Pleuritic chest pain
- dyspnoea
- haemoptysis
GI
- Intra-hepatic sickling
- Pigment gallstones
Splenic sequestration
- Death
- hyposplenism
- Obstructive sleep
apnoea#
- Hypertrophy of
lymphoid tissue
Anaemia
- Aplastic crisis
Renal failure
Genitourinary
- Priapism
