Week 2 - E - Pancytopenia - Reduced production - Inherited (fanconi's), Acquired (primary and secondary), Increased destruction - Hypersplenism

Question 1

https://s3.amazonaws.com/classconnection/403/flashcards/11907403/png/paella-recipedocxpngjpgpngjpg-162292820CB01D09A8E.png

Answer 1

This man shows that he his anaemic, thrombocytopenic and neutropenic - he has a pancytopenia

Question 2

Define pancytopenia?

Answer 2

This is a deficiency of all the blood cell lineages - red blood cells, white blood cells and platelets The deficiency in WBCs usually refers to neutrophils and not lymphocytes

Question 3

Pancytopenia is NOT a diagnosis (it reflects a diagnosis) Pancytopenia does NOT always mean bone marrow failure In the steady state, what is the difference between cell production and cell destrcution?

Answer 3

In the steady state - the rate of cell production = the rate of cell destruction and therefore homeostasis is kept

Question 4

In the steady state, cell loss is balanced by cell production For example: - State the lifespan of platelets, red cells and neutrophils? Also state how many are produced and lost per second?

Answer 4

Red cells * Lifespan is ~120 days * 2.5million are produced and lost per second Neutrophils * Life span is 7-8hours * 1.2 million are produced and lost per second Platelets * Life span is 7-10 days * 1 million are produced per second

Question 5

Which blood cell is usually the first to decrease in a pancytopenia? Why may this be?

Answer 5

Platelets are usually the first blood lineage to decrease in pancytopenia This may be because in terms of marrow stress,the small cells are fighting to leave the marrow whereas the big megakaryocytes are large and therefore may be unable to - as megakaryocytes contain many platelet for budding, this can cause a vast decrease

Question 6

Redcued production is caused by bone marrow failure This can be separated into inherited syndromes that cause failure or acquired failure Inherited causes of bone marrow failure are very uncommon Can you name an inherited condition causing failure?

Answer 6

An inherited condition that can cause bone marrow failure leading to reduced production of cells is Fanconi’s anaemia

Question 7

What causes Fanconi’s anaemia to arise?

Answer 7

Fanconi’s anaemia arises due to an impaired response to DNA damage It is specifically the inability to correct inter-strand cross links

Question 8

As said fanconis anaemia arises due to the impaired ability to repair damaged DNA - specifically inter-strand cross links What is the inheritcance of anconi’s syndrome? What age does it usually present?

Answer 8

Fanconis anaemia - arises due to gene mutations causing the inability to repair inter-strand cross links that have damaged the DNA The inheritance of the condition is autosomal recessive and usually presents around age 7 of childhood development

Question 9

What haematological abnormalities can result from fanconis anaemia?

Answer 9

There is usually bone marrow failure due to aplastic anaemia There is also a greatly increased risk of acute myeloid leukaemia

Question 10

Fanconis anaemia also can cause multiple abnormalities in the child, what are these?

Answer 10

SHort stature Hypogenitalia Microcephaly Cafe-au lait spots The child may also have absent or small thumbs Can also affect multiple systems, endocrine, cardio, renal, GI, already talked about haem

Question 11

Fanconi anaemia It can cause aplastic anaemia in the bones, WHat is usually the order of the anaemia in these children?

Answer 11

Causes a macrocytic anaemia followed by thombocytopenia followed by neutropenia

Question 12

What does fanconi syndrome greatly increase the risk of? (haematological disorder)

Answer 12

Greatly increases the risk of acute myeloid leukaemia (and breast cancer)

Question 13

Now we have talked about the inherited cause of decreased production (pancytopenia) due to bone marrow failure, will now talk about acquired - primary and secondary - causes leading to pancytopenia In acquired primary bone marrow failure, there is an intrinsic bone marrow failure with no obvious cause usually due to a stem cell defect What are the three main types of acquired primary bone marrow failure?

Answer 13

Idiopathic aplastic anaemia Myelodysplastic syndrome Acute leukaemia

Question 14

What happens in idiopathic aplastic anaemia?

Answer 14

There is an autoimmune attack against the haemopoietic stem cells leading to pancytopenia

Question 15

What is the pathogenesis of the aplastoc anaemia?

Answer 15

There is an autoimmune reaction where auto-reactive T cells produce TNFa and IFNy which then attack the HSC causing reduced reduction of the lineages causing pancytopenia

Question 16

Bone marrow biopsy is required for diagnosis What does the patients bone marrow biopsy show here? Name an inherited cause of reduced production of cells in the bone marrow

Answer 16

Patients marrow here shows the absence of any haematopoietic activity as only trabeculae (the bone) is seen on the biopsy - no red or yellow marrow is visible Fanconi’s anaemia is an inherited condition resulting in aplastic anaemia which causes pancytopenia

Question 17

3 causes of acquired primary bone marrow failure Aplastic anaemia MYELODYSPLASTIC SYNDROMES Acute leukaemia What is myelodysplastic syndrome?

Answer 17

Myelodysplastic syndromes (MDS) are a group of cancers in which immature blood cells in the bone marrow do not mature and therefore do not become healthy blood cells. Like the other two causes of primary bone marrow failure, there is no obvious cause and it is thought to be due to a haemopoietic stem cell defect

Question 18

What is seen in the marrow biopsy in myelodysplastic syndromes? What are types of cells that may be seen on biopsy?

Answer 18

There is increased cells - hyercellularity as there is increased proliferation but as erythropoiesis is ineffective, there is also increased apoptosis The cells on the film/aspirate/biopsy are also dysplastic Ringed sideroblasts are often seen in the marrow with this condition

Question 19

What are ringed sideroblasts? What are the crystals of granules that collect to form needle like shapes in the marrow that may be seen with myelodysplastic syndromes? What are they a poor prognostic sign of?

Answer 19

Ringed sideoblasts are erythroblasts with iron loaded mitochondria presenting as a ring Also seen in sideroblastic anaemia The granules of crystals that can collect are known as Auer rods and are a poor prognosctic sign as it highlights acute myeloid leukaemia

Question 20

3 causes of acquired primary bone marrow failure * Aplastic anaemia * Myelodysplastic syndromes * ACUTE LEUKAEMIA How can acute leukaemia cause pancytopenia?

Answer 20

In acute leukaemia there is the abnormal proliferation of cells (Blasts) from leukaemic stem cells which cause the failure of these cells to differentiate into more mature forms Pancytopenia in AML arises from The failure of cells to differentiate / mature and The abnormal cells preventing normal HSC development

Question 21

Acquired Secondary bone marrow failure can be for a number of reasons Eg drugs, deficiencies, infiltration disorders and viral diseases What drugs can cause secondary failure? What do they cause? What deficiencies can cause pancytopenia?

Answer 21

Chloramphenicol, chemotherapy and alcohol can all lead to pancytopenia as they cause aplasia B12/folate affect all lineages and therefore deficiencies in these can lead to bone marrow failure as the nuclea division of all the lineages is impaired and therefore undergo apoptosis

Question 22

Do B12 / folate deficiencies result in a hypo or hyperceullar state? What is increased destruction causing pancytopenia due to?

Answer 22

B12/folate deficiencies result in a hyperceullar state Increased destruction causes pancytopenia due to hypersplenism

Question 23

What are the primary lymphoid organs? What are the secondary lymphoid organs?

Answer 23

Primary lymphoid organs - bone marrow and tonsils Secondary lymphoid organs - lymph nodes, spleen, tonsils (Waldeyer’s ring) and lymphoid tissue found along the alimentary canal

Question 24

In hypersplenism there is an increased splenic pool -ie more blood is flowing through the spleen than is meant to What is the main cause of hypersplenism? Hypersplenism is basically when the spleen is overactive What does the hypersplenism cause?

Answer 24

Hypersplenism is caused by splenomegaly When the spleen enlarges there is incresed flow of blood through the spleen (Splenic pool) and therefore the spleen destroyed more blood cells than the bone can compensate for resulting in pancytopenia

Question 25

Any cause of splenomegaly can potentially result in hypersplenism Splenic size alone may not always correlate with hypersplenism What are different causes of hypersplenism? (remember the circulatory causes)

Answer 25

Portal hypertension - ie due to liver failure, spleen cant drain blood via splenic vein properly leading to splenomegaly Congestive cardiac failure Rheumatoid arthritis Thalassemia, splenic lymphoma

Question 26

What is the rare autoimmune disease characterised by the triad of arthritis, splenomegaly and neutropenia? What type of arthritis is associated with this condition as it causes an auto-immune response?

Answer 26

This would be Fely’s syndrome Rheumatoid arthritis is the type of arthritis associated with Felty’s syndrome

Question 27

Felty’s syndrome can be remembered by the acrnym santa WHat are the different components of Felty’s syndrome?

Answer 27

Splenomegaly Anaemia Neutropenia Thombocytopenia Arthriris (Rheumatoid)

Question 28

Signs and symptoms of pancytopenia can reflect: * the lack of circulating blood cells * the cause of the pancytopenia What are the symptoms of the lack of circulating blood cells? The cause of the pancytopenia symptoms have been discussed

Answer 28

Anaemia * Paleness, fatigue, short of breath Neutropenia * Infection - longer and more severe Thrombocytopenia * Bleeding, bruising, purpura

Question 29

What is chromosome fragility testing?

Answer 29

This is where the DNA is exposed to damaging agents and we are able to visualise the chromosomes inability to repair themselves

Question 30

Marrow cellularity is variable depending on the causes What is the cellularity in each of the conditions? Aplastic anaemia? B12/folate deficiency? Myelodysplastic syndromes? Hypersplenism?

Answer 30

Hypocellular - aplstic anaemia Hyperceullular - B12/folate deficiency, myelodysplastic syndromes (increased proliferation and apoptosis), hypersplenism - EPO increase due to decrease in oxygen

Question 31

Treatment for pancytopenia is Supportive - treat the symptoms of low blood cells Specific – Dependent on cause (eg pancytopenia due to B12/folate deficiency) What is the supportive treatment of pancytopenia?

Answer 31

Treat the anaemia with Red cell transfusions Treat the thrombocytopenia with platelet transfusions Neutrophil transfusion not common as they die in transit so consider antibiotic use and prophylactic treatment

Question 32

Treat neutropenic fever promptly based on local unit antibiotic policy without waiting for (microbiology) results What is neutropenic sepssis defined as? What is the treatment?

Answer 32

Neutropenia - when neutrophils are below 1.5 Neutropenic sepsis is defined as neutrophil count below 1 or 0.5 if chemo in the last 21 days + sepsis Give piperacillin +tazobactam

Question 33

What is the treatment of idiopathic aplastic anaemia? What is the treatment of a B12/foate deficiency?

Answer 33

Idiopathic aplastic anaemia - immunsuppression is important here to stop the auto-reactive Tcells releasing TNFa and IFNy which attack the HSC - give ciclosporin and anti-thymocyte globulin B12 deficiency - give 1mg IM hydroxycobalmin injection 6 times in 2 weeks to replenish stores and the 1mg IM every 3 months for life (if its due to pernicious anaemia) If due to folate deficiency then 5mg folate daily for 4 months