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Y1 TP2 Metabolism, Endocrinolo, Haemotology > 5. Spherocytosis And Lymphocytosis > Flashcards

5. Spherocytosis And Lymphocytosis Flashcards

1
Q

2 types of haemolytic anaemia

A

Inherited

Acquired

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2
Q

Inherited haemolytic anaemia

A 
--> From parents (defective gene) 
	• Glycolysis defect
	• Pentose p pathways 
	• Membrane protein 
	• Haemoglobin defect
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3
Q

Acquired haemolytic anciemia

A

–> damage to cells
• Microangiopathic haemolytic anaemia (MAHA)
• Antibody damage (Autoimmune haemolytic anaemia)
• Oxidant damage (Exposure to chemicals and oxidants)
• Heat damage (e.g. severe burns)
• Enzymatic damage (e.g. snake venom)

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4
Q

Haemolytic anaemia diagnosis

A

2 main principles
• Confirm that it is haemolysis (haemolytic anaemia) due to acute reaction or chronic disease
• Determine aetiology (cause)

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5
Q

Symptoms of haemolytic anaemia

A 
--> lack of rbc presence or function
	• Low bp
	• Uncontrollable bleeding
	• Increased heart rate
	• Pain
	• Urinary problems
* same like any anaemia (e.g. fatigue, shortness of breath) 
* from haemolysis increase bilirubin (breakdown of rbc releases bilirubin) jaundice gall bladder stones
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6
Q

Definition of haemolytic anaemia

A

Haemolytic anaemia results from the abnormal breakdown (haemolysis) of red blood cells
• RBC have shorter life spans 20-30 days

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7
Q

• Origin of haemolytic anaemia:

A
  • in blood vessels (intravascular haemolysis) - broken down in circulation
    • in the spleen (extravascular haemolysis) - rbc cleared in spleen
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8
Q

Bone marrow

A
  • The bone marrow only has a capacity to increase red cell production by around 5 to 6 fold = not enough to compensate for haemolytic anaemia
  • Increased production by the bone marrow is unable to compensate and anaemia will occur
    • symptoms from relatively harmless to life-threatening
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9
Q

3 types of jaundice

A
  • Prehepatic
    • Hepatic
    • Post hepatic
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10
Q

Haemolytic anaemia causes pre hepatic jaundice

A
  • More rbc broken down
    • More bilirubin released ionto body
    • Jaundice – yellwo skin, brain fog etc
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11
Q

Inherited haemolytic anemias – glycolysis defect

A

—> Pyruvate kinase deficiency (limit ATP production) is an inherited metabolic disorder (typically autosomal recessive but there is also a dominant form) due to:

  • mutations in the PKLR gene
  • Four pyruvate kinase isoenzymes, two of which are encoded by PKLR (isoenzymes L and R expressed in liver and erythrocytes, respectively)
    • Since red blood cells lack mitochondria, pyruvate kinase deficiency inhibits their only metabolic pathway which can supply ATP for cellular processes.
  • Patients with severe deficiency may require regular blood transfusion.
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12
Q

Inherited haemolytic anaemias – pentose – p pathway

—> G6PDH deficiency leads to oxidative damage

A
  • Glucose-6-phosphate dehydrogenase (G6PDH) is an X- linked recessive inborn error of metabolism, risk of haemolytic anaemia
  • G6PDH is the rate limiting enzyme of the pentose phosphate pathway which supplies reducing energy by maintaining NADPH levels.
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13
Q

Inherited haemolytic anaemias – pentose – p pathway

—> increase oxidative damge = increase rbc clearance

A
  • NADPH drives numerous anabolic reactions and is required to protect against oxidative stress by maintaining the level of reduced glutathione
  • The pentose phosphate pathway is the only source of reduced glutathione in red blood cells,
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14
Q

Inherited haemolytic anaemia – hereditary spherocytosis

A

• Hereditary spherocytosis is an inherited autosomal dominant disease
= resulting in abnormalities in erythrocyte membrane proteins

  • Impede the ability of the cell to change shape
  • Causes: Mutations in the genes coding for 4 different proteins necessary to maintain RBC normal shape
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15
Q

Inherited haemolytic anaemia – hereditary spherocytosis

Results in

A
  • Local disconnection of the cytoskeleton and membrane- can’t hold biconcave shape
    • reduction in membrane surface area
    • production of a “spherocyte” shape instead of biconcave shape to the red blood cell lysed by spleen as spleen finds it abnormal
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16
Q

Inherited haemolytic anaemia – hereditary spherocytosis

Treatment

A

Treatment: splenectomy (partial or total)

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17
Q

Mechanism of spherocytosis

A

• Spectrin and ankyrin = useful in maintaining membrane shape
• Deficiency of these = unstable membrane
○ Reduced density of membrane skeletion
○ Release micro vesicles
○ Leads to spherocytosis – round rbc which is cleared by spleem

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18
Q

Symptoms of hereditary spherocytosis

A
  • destruction of red blood cells in the spleen
    • their removal from the blood stream (haemolytic anaemia)
    • a yellow tone to the skin (jaundice)
    • an enlarged spleen (splenomegaly) and gall stone development.
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19
Q

Normal haemoglobin structure

A

The haemoglobin molecule consists of a tetramer of:
• four globin polypeptide chains
• two alpha chains and two non-alpha chains (β, δ or γ)

• held together by noncovalent interactions with each globin chain complexed with an oxygen binding haem group (that carries oxygen)

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20
Q

3 types of haemoglobin

A

HbA

HbA2

HbF

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21
Q

Chain compositions of HbA

A
  • 2 alpha chains 2 beta chains

* 95% in adults

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22
Q

Chain compositions of HbA2

A
  • 2 alpha and 2 delta chains

* 2-3.5%

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23
Q

Chain compositions of HbF

A
  • Fetal
    • 2 alpha and 2 gamma chains
    • Less than 2%
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24
Q

Haemoglobinopathies

Definition

A

—> Haemoglobinopathies are inherited disorders where expression of one or more of the globin chains of haemoglobin is abnormal

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25
Q

Haemoglobinopathies

2 main categories:

A

Abnormal haemoglobin variants

Thalassaemias

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26
Q

Abnormal haemoglobin variants

A

from mutations in the genes for α or β globin chains that alter the stability and/or function of haemoglobin (e. g. Sickle cell disease)
• qualitatove – reducction in haemoglobin quality

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27
Q

Thalassaemias

A

result from reduced or absent expression of normal α or β-globin chains. This leads to a reduced level of haemoglobin rather than the presence of an abnormal haemoglobin
• Quantititaitive reduced expression of haemaglobin chaisn

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28
Q

Sickle cell disease - definition

A

—> Most common Hb variant of clinical significance is haemoglobin S (HbS)
• The HbS variant has an uncharged valine instead of a charged glutamic acid at position 6 of β-globin (glutamic acid –> valine)

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29
Q

Sickle cell disease impact on haemoglobin

A

• More prone to polymerise at low oxygen tension.
= Leads to formation of long twisted haemoglobin polymers (more insoluble) causing deformation the red blood cell membrane leading to the sickle shape
• Sickle shape – is stickier (more blockages in vasculature) and less flexible than biconcave disc

  • After repeated episodes of sickling (blocking in vasculature), damage occurs to the red cell membrane causing it to lose elasticity
  • Damaged cells fail to return to a normal shape when normal oxygen tension is restored
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30
Q

HbS variants are found in people of

A

– Black African descent
– Arab
– Mediterranean
– South Asia population

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31
Q

• Two HbS types:

A
  1. Heterozygous individuals for HbS have some resistance to malaria
  2. Homozygous individual develop sickle cell disease – Combinations with other haemoglobinopathies produce sickling syndromes of variable severity such as: sickle-β-thalassaemia, HbS/C or HbS/E.
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32
Q

Symptoms of sickle cell

A

Severe pain is a first-hand symptom of this disease = due to sickleing (blockages in vasculature

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33
Q

4 patterns of the acute sickle cell disease crisis:

A
  1. Bone crisis
  2. Acute chest syndrome
  3. Joint crisis
  4. Impaired organs – (e.g. lungs, eyes, kidneys, genitals, liver, spleen, heart attacks can even occur
    • Enlarged spleen as the spleen works to clear out these defective rbc
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34
Q

Sickle cell crisis treatment

A
  1. Opioid pain medication such as morphine
  2. Antibiotics for infection
  3. Anti inflammatory medicines such as ibuprofen
  4. Oxygen – oxygenated blood
  5. Intravenous or oral fluids
  6. An exchange transfusion:
    – conducted with a special machine
    – with the help of which the abnormal sickle red blood cells are removed and replaced with normal ones
  7. Hydroxyurea can decrease the frequency and severity of crisis
  8. Haematopoietic stem cell transplantation is the only cure (rarely performed – hard to find donor with sufficient genetic match)
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35
Q

Beta thalaseeamia

A
  • β-thalassaemia results from mutation in one or both of the β globin genes
  • Leads to a reduction in the amount or total absence of the β globin polypeptide chain
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36
Q

Heterozygous Beta thalaseeamia

A

• In heterozygous individuals where only one of the two β globin genes are mutated:
– the rate of β globin production is reduced resulting in microcytosis
OR
• Hb level normal (reduced only in pregnancy or infections)

37
Q

What is Beta thalassaemia major

A

—> In Homozygous individuals both β globin genes are mutated, is a lifethreatening condition called β- thalassaemia major.

• Synthesis of the β globin polypeptide chain is totally absent in such individuals

38
Q

Patients with Beta thalassaemia major

A
  • Dependent on blood transfusions from the first few months of life onwards in order to survive since the synthesis of haemoglobin A cannot replace Haemoglobin F due to the lack of β globin
    • Don’t have healthy production of haemoglobin
39
Q

Alpha thalassaemia

A

• α-thalassaemia results from deletion or loss of function of one or more of the four α globin genes

40
Q

Severity of Alpha thalassaemia

A

• The severity of the condition depends on how many genes are malfunctional ranging from:
– mild microcytosis when one or two genes are affected
– to death in utero where malfunction of all 4 genes leads to a complete absence of the α globin chain (HbF can’t switch to HbA)

41
Q

• Haemoglobin H disease

A 
Lack of function in 3 of the 4 α globin genes: 
	• severe microcytosis
	•  Anaemia
	• haemolysis 
	• (enlarged spleen) splenomegaly
42
Q

Severity of thalassemia

A

Different combinations of α and β globin mutations in the same individuals lead to a wide range of thalassaemia phenotypes (differences in the severity of disease):

43
Q

3 types of thalassemia severity

A
  1. Patients can either be transfusion dependent (thalassaemia major),
  2. require transfusion intermittently (thalassaemia intermedia) or
  3. require no transfusion (thalassaemia minor).
44
Q

Acquired haemolytic anaemias

A
  • Microangiopathic haemolytic anaemia (MAHA)
  • Antibody damage (Autoimmune haemolytic anaemia)
  • Oxidant damage (Exposure to chemicals and oxidants)
  • Heat damage (e.g. severe burns)
  • Enzymatic damage (e.g. snake venom)
45
Q

Microangiopathic haemolytic anaemias (MAHA) - cause

A
  • CAUSE: where red cells are damaged by physical trauma.
  • Often trauma results from red cells getting snagged as they try to pass through small vessels (so their shape changes) laden with fibrin strands because of increased activation of coagulation
46
Q
  1. Microangiopathic haemolytic anaemias (MAHA)

Effects

A

Increased activation of coagultaion is caused by

  • Disseminated intravascular coagulation: a condition where bleeding and clotting occur at the same time in the patient (e.g. in malignancy, obstetric complications, trauma, sepsis, haemolytic uremic syndrome (HUS)in children) can cause this
  • Thrombotic thrombocytopenic purpura - (microangiopathic haemolytic anaemia) a syndrome where small thrombi (clots) within the microvasculature.
47
Q

Antibody damage (Autoimmune haemolytic anaemia)

Causes

A

– Infections
– lymphoproliferative disorders such as leukaemia or lymphoma
– Reactions to drugs such as cephalosporins (class of antibiotic)

48
Q

2 types of Antibody damage (Autoimmune haemolytic anaemia)

A
    1. In warm autoimmune haemolytic anaemia (happens in temp <37 degrees)
    1. In cold autoimmune haemolytic anaemia (temp less than 37 degrees)
49
Q

• 1. In warm autoimmune haemolytic anaemia (happens in temp <37 degrees)

A

○ IgG antibodies recognise epitopes on the red cell membrane.
○ This leads to macrophages in the spleen recognising these red blood cell, destroy RBC or can become membrane spherocytes splenomegaly (enlarged spleen)

50
Q

• 2. In cold autoimmune haemolytic anaemia (temp less than 37 degrees)

A

○ IgM autoantibodies recognise red cell epitopes and there is also complement fixed to the patient’s red cells leading to membrane instability and lysis:
○ Results in – numb fingertips, earlobes etc. (peripheral body parts) – pallor (paleness), – blue discoloration or – in extreme cases gangrene

51
Q

Test for autoimmune haemolytic anaemia

The direct Coombs test

A

—> Detect antibodies or complement bound to the surface of red blood cells.

Positive test
• The patient’s red cells are mixed with anti-human globulin antibody
• If the red cells are coated with antibodies the anti-human globulin will attach to those antibodies making the red cells clump together suggesting the patient’s haemolytic

52
Q

4 Other causes of haemolysis

A
  • Oxidant damage (Exposure to chemicals and oxidants) e.g. lead poisoning
  • Heat damage (e.g. severe burns)
  • Enzymatic damage (e.g. snake venom) and
  • even “foot strike haemolysis” in runners
53
Q

Myeloproliferative Neoplasms (MPNs)

Definition

A

—> Group of diseases of the bone marrow in which excess cells are produced

54
Q

Myeloproliferative Neoplasms (MPNs)

Cause

A
  • Specific point mutation in one copy of the Janus kinase 2 gene (JAK2) - a cytoplasmic tyrosine kinase on chromosome 9, which causes increased proliferation and survival of haematopoietic precursors
    • Increase of precursors in circualtion
55
Q

TPO – thromboperitin

A

• Stimulates platlets

56
Q

EPO – erythropoietin

A

• Stimulates rbc

57
Q

4 major types of Myeloproliferative Neoplasms (MPNs)

A
  • Polycythaemia vera – looking at rbc
  • Essential thrombocythemia – looking at platlets
  • Primary myelofibrosis – looking at bone marrow
  • Chronic myeloid leukaemia
58
Q

Production of platelets

A
  • Stimulation of TPO thromboperitin

* Increase in megakaryocyte = increase in platlets

59
Q

Polycythaemia - definition

A

—> Increase in circulating red cell concentration typified by a persistently raised haematocrit (Hct).

60
Q

Polycythaemia - 2 types

A

Relative

Absolute

61
Q

Relative polycythaemia

A

○ Decrease in plasma volume

○ Makes it appear that ratio of rbc is higher

62
Q

Absolute polycythaemia

A

• Increase in number of erthrythrocytes
○ Primary = abnormality originates in bone marrow, polycythaemia vera only example
○ Secondary = caused by increased levels of erythropoietin due to:
▪ Physiological response to hypoxia e.g. high altitude, chronic lung disease
▪ Abnormal production e.g. renal carcinoma, renal artery stenosis

63
Q

Polycythaemia vera

A

–> increase in rbc in circulation

  • Disease in which the volume percent of erythrocytes in the blood (the haematocrit) exceeds 52% (males) or 48% (females).
  • Most (~95%) cases are caused by mutation of the gene coding for Janus Kinase 2 (JAK2)
64
Q

Clinical features of polycythaemia vera

A
  • Thrombosis = increase in rbc, increase viscosity, abnormal blood flow
  • Haemorrhage
  • Headache
  • Burning pain in the hands or feet
  • Pruritus
  • Splenic discomfort, splenomegaly
  • Gout = uric acid is a breakdown product of rbc
  • Arthritis
  • May transform to myelofibrosis or acute leukaemia

Extra rbc stimulate histamine = itchy

65
Q

Management of polycythaemia

A
  • Phlebotomy = blood letting, remove some rbc
  • Aspirin = reeduce blood viscosity
  • Cytoreduction using agents such as hydroxycarbamide (oral antimetabolite that inhibits DNA synthesis)- slows down cell production
66
Q

Thrombocytosis

A

—> An increase in the platelet count compared to the normal range of a person of the same gender and age

67
Q

3 types of thrombocytosis

A

Primary
Secondary
Redistribution

68
Q

Primary Thrombocytosis

A

○ Originates in bone marrow = essential thrombocythemia

69
Q

Secondary Thrombocytosis

A

○ Normal bone marrow resposne to extrinsic stimulus (e.g. infection, inflammation)

70
Q

Redistribution Thrombocytosis

A

○ Platelets redistributed from splenic pool into bloodstream

71
Q

Essential thrombocythaemia (primary)

Causes

A

• Around half the cases are caused by JAK2 mutations
• Mutations in the thrombopoietin receptor can also result in the disease
= continuously active = more platlets

72
Q

Essential thrombocythemia (primary) - clinical feature

A
  • Numbness in the extremities
  • Thrombosis
  • Disturbances in hearing and vision (related to microvascular complications)
  • Headaches
  • Burning pain in the hands or feet (Erythromelalgia)

Numbness and burning due to high platelets count reduces blood flow to the area

73
Q 
Essential thrombocythaemia (primary) 
Management
A
  • Aspirin = blood viscosity

* Return the platelet count into the normal range with drug such as hydroxycarbomide

74
Q

Thromobcytopenia

A

• An abnormally low level of platelets - either be inherited or acquired.
Not a myloproliferative disorder as the platlet number is low

75
Q

Types of Thromobcytopenia

A

Inherited (rare syndromes)

Acquirred
○ Decreased platelet production due to:
○ Increased platelet consumption (platelets are used more) due to:
○ Increased platelet destruction due to:

76
Q

Acquired thrombocytopenia

	○ Decreased platelet production due to:
A

▪ not enough B12 or folate deficiency
▪ Acute leukaemia or aplastic anaemia
▪ Liver failure (decreased thrombopoietin production)
▪ Sepsis
▪ Cytoxic chemotherapy

77
Q

Acquired thrombocytopenia

○ Increased platelet consumption (platelets are used more) due to:

A

▪ Massive hemorrhage
▪ Disseminated intravascular coagulation – abnormal blood clotting
▪ Thromotic thrombocytopericpurpura – blood clots form in small blood vessels

78
Q

Acquired thrombocytopenia

	○ Increased platelet destruction due to:
A

▪ Autoimmune response
▪ Drug induced – heparin
▪ Hypersplenism resulting in increased destruction and splenic pooling of platlets

79
Q

Thrombocytopenia clinical features

A
  • Patients generally not symptomatic until the platelet count < 30
  • Easy bruising
  • Petechiae – small spots on feet/forarms
  • Mucosal bleeding
  • Severe bleeding after trauma
  • Intracranial haemorrhage

Females have heavier periods
Heavier nose bloods

80
Q

Management – thrombocytopenia

A
  • Corticosteroids
  • Intravenous pooled human Immunoglobulin
  • Splenectomy
  • Thrombopoietin receptor agonists
81
Q

Primary myelofibrosis

A

—> A myeloproliferative neoplasm where the proliferation of mutated hematopoietic stem cells
= results in reactive bone marrow fibrosis eventually leading to the replacement of marrow with scar tissue (collagen deposition)
• Due to fibrosis bone marrow can’t make enough normal blood cells

• Mutations in the JAK2 gene are often associated with the disease.

82
Q

Primary myelofibrosis – clinical features

A
  • Hepatosplenomegaly – production of hematopoietic stem cells from spleen or liver
  • Bruising
  • Fatigue (and other symptoms related to anaemia)
  • Weight loss
  • Fever
  • Increased sweating
  • Portal hypertension
83
Q

Management primary myelofibrosis

A
  • Hydroxycarbamide
  • Folic acid – stimulate platelet function
  • Allopurinol – gout symptoms
  • Blood transfusions – anaemia
  • Splenectomy
  • Ruxolitinib, an inhibitor of JAK2 has been shown to significantly reduce spleen volume and improve symptoms of myelofibrosis.
84
Q

Chronic myeloid leukaemia (CML)

A
  • Characterized by the unregulated growth of myeloid cells in the bone marrow
  • Specific chromosomal translocation called the Philadelphia chromosome involving a reciprocal translocation between chromosomes 9 and 22. This translocation causes an oncogenic gene fusion (BCR-ABL)
85
Q

Chronic myeloid leukaemia (CML)

2 types

A
  • Acute = lots of immature cells (faster)

* Chronic = lots of immature and mature (diferentiated) cells (slow)

86
Q

Pancytopenia

A

–> reduction in all blood cells

• Reduction in white cells, red cells and platelets

87
Q

Pancytopenia causes

A
  • B12/folate deficiency – required in dna synthesis
  • Drugs
  • Infections - Viruses
  • Bone marrow infiltration by malignancy
  • Marrow fibrosis
  • Radiation
  • Idiopathic aplastic anaemia
  • Congenital bone marrow failure
88
Q

Aplastic anemia

A
  • A rare disease resulting in damage to bone marrow and hematopoietic stem cells
  • Pancytopenia
89
Q

4 proteins that are the most common causes of hereditary spherocytosis

A
  • Spectrin
  • ankirin
  • band 3
  • protein 4.2

Y1 TP2 Metabolism, Endocrinolo, Haemotology (5 decks)

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