Other Haematological Disorders Flashcards
What is myelodysplastic syndrome?
Myelodysplastic syndrome is caused by the myeloid pluripotent stem cells not maturing properly and therefore not producing healthy blood cells. There are a number of specific types of myelodysplastic syndrome.
The stem cell clone gives rise to intermediate cell types that are defective and are particularly susceptible to apoptosis, resulting in death within the bone marrow before they reach maturity. This, in turn, causes insufficiency in the numbers of mature blood cells, which may affect one or several cell lines - red blood cells (RBCs), white blood cells (WBCs) and/or platelets. Importantly, 30% of patients with MDS eventually progress to AML.
What’s the difference between MDS and AML?
The only difference between myelodysplastic syndrome and acute myeloid leukemia, is that in myelodysplastic syndromes the cells can mature into something, while in acute myeloid leukemia they can’t mature at all. If in myelodysplastic syndromes, maturation stops occurring, the disease becomes the same thing as acute myeloid leukemia.
Who is myelodysplastic syndrome more common in?
- Older pts (>60yrs)
- Previous chemotherapy or radiotherapy
What 3 blood abnormalities can myelodysplastic syndrome lead to?
Low levels of cells that originate from myeloid cell line:
- Anaemia
- Neutropenia
- Thrombocytopenia
How does myelodysplastic syndrome present?
- May be asymptomatic and diagnosed on FBC for something else
- Symptoms of anaemia (SOB, fatigue, pallor)
- Symptoms of neutropenia (frequent or severe infections)
- Thrombocytopenia (bruising, bleeding, purpura)
How is myelodysplastic syndrome diagnosed? Highlight the confirmatory test
- FBC: anaemia, leucopenia, thrombocytopenia
- Blood film: blast cells
- Bone marrow biopsy= confirmatory test: blast cells
Discuss the management of myelodysplastic syndrome
Depending on the symptoms, risk of progression and overall prognosis the treatment options are:
- Watchful waiting
- Supportive treatment with blood transfusions if severely anaemic
- Chemotherapy
- Stem cell transplantation
What may myelodysplastic syndrome progress to?
AML
What are myeloproliferative disorders?
State the 3 myeloproliferative disorders
Chronic conditions in which there is abnormal clonal proliferation of one or more cells lines of myeloid lineage. Considered a type of bone marrow cancer.
Three myeloproliferative disorders:
- Primary myelofibrosis
- Polycythaemia vera
- Essential thrombocythaemia
Proliferation of what cells occurs in polycythaemia vera?
Proliferation of erythroid cells
(Medicine in a minute says can also affect myeloid & megakaryocyte cell lines but mostly affects erythroid)
What mutation is present in ~90% of polycythaemia vera patients?
JAK2 mutation
*JAK2 is a tyrosine kinase protein responsible for cell signalling in bone marrow haematopoietic stem cells. Mutations up-regulate sensitivity towards growth factors such as erythropoietin & thrombopoietin)
State signs & symptoms of polycythaemia vera
May be asymptomatic; pesentation often insidious:
- Hyperviscosity syndrome:
- End-organ congestion: visual disturbance, neurological symptoms (headache, dizziness, tinnitus), cardiac (angina, SOB)
- Blood stasis: thrombosis, bleeding (high shear force through capillaries)
- Splenomegaly
- Pruritis
- Erythromelalgia (burning & erythema in hands & feet. <5%)
- Plethoric appearance (conjunctival plethora & ruddy complexion)
- Hypertension (⅓)
- Systemic symptoms (fatigue, weight loss, night sweats, fever)
What initial investigations should you do in suspected polycythaemia vera?
- FBC: raised haematocrit, ~50% may also have raised neutrophils/basophils/platelets
- U&Es: renal func
- LFTs: liver damage
- Coagulation: liver func
- JAK2 mutation screen
*Bone marrow biopsy usually unnecessary if have raised haematocrit and are JAK2 positive
Threshold for haematocrit when diagnosing polycythaemia vera changes depend on whether JAK2 positive or negative. What is the threshold for men and for women in JAK2 positive patients?
Male: >0.52
Female: >0.48
Discuss the management of polycythaemia vera
- First line to keep Hb in range= venesection
- Aspirin (reduce risk of thrombus formation)
- Chemotherapy (hydroxycarbamide)
State some potential complications of polycythaemia vera
- Thrombotic events (significant cause mortality)
- Progression to myelofibrosis
- Progression to AML
Abnormal proliferation of what cells occurs in essential thrombocythaemia?
Abnormal proliferation of megakaryocytes
What mutations may be present in pts with essential thrombocythaemia? (3)
- Jak2 (50%)
- MPL (35%)
- CALR (~20%)
State some signs & symptoms of essential thrombocythaemia
May be asymptomatic or have:
- Thrombosis
- Bleeding
- Erythromelalgia
- Moderate splenomegaly
What initial investigations would you do if you suspected essential thrombocythaemia?
- FBC: raised platelets
- Blood film: immature precursor cells, large platelets
- Fe panel/haematinics: Fe deficiency can cause reactive thrombocytosis
Discuss the management of essential thrombocythaemia
- Aspirin: reduce risk of clot formation
- Chemotherapy (hydroxycarbamide)
State some potential complications of essential thrombocythaemia
- Thrombus formation
- Transformation to myelofibrosis
- Transformation to AML
What is myelofibrosis?
State some potential causes
Myelofibrosis occurs when proliferation of cells leads to fibrosis of bone marrow.
Can occur as a result of polycythaemia vera or essential thrombocythaemia or due to primary myelofibrosis.
Primary myelofibrosis is rare and characterised by multi-lineage clonal proliferation, in particular abnormal megakaryocytes); these proliferating cells release cytokines, in particular fibroblast growth factor, which causes fibrosis of bone marrow.
What mutations may be found in pts with myelofibrosis?
- JAK2 (60%)
- CALR (25%)
- MPL (8%)
Explain how myelofibrosis can lead to portal hypertension & spinal cord compression
- Proliferating cells produce cytokines; in particular fibroblast growth factor and platelet derived growth factor (PDGF)
- Cytokines cause fibrosis of bone marrow
- Since bone marrow is replaced by scar tissue haematopoiesis is reduced
- Consequently haematopoiesis starts to occur in other organs such as liver & spleen (extramedullary haematopoiesis) leading to splenomegaly & hepatomegaly
- This can lead to portal hypertension and spinal cord compression
State signs & symptoms of myelofibrosis
- B symptoms (fever, night sweats, weight loss)
- Massive splenomegaly
- Hepatomegaly
- Bone marrow failure symptoms
- Anaemia (SOB, fatigue, pallor)
- Neutropenia (frequent/severe infections)
- Thrombocytopenia (bruising, bleeding, purpura)
- Pruritis
- Features of portal hypertension
What initial investigations would you do if you suspect myelofibrosis?
- FBC with differential: a**naemia, leukocyte and platelet counts can be low, normal, or high
- Blood film: leucoerythroblasts, tear drop shaped RBCs, blasts
- Bone marrow aspiration: dry tap
- Trephine marrow biopsy: will show fibrosis
Discuss the management of myelofibrosis
- Mild disease with minimal symptoms may be monitored and not actively treated
- Supportive management (e.g. of anaemia with red cell transfusions, of splenomegaly with splenectomy)
- Chemotherapy with hydroxycarbamide
- Ruxolitinib (JAK2 inhibitor) in some pts
- Allogenic stem cell transplantation potentially curative
State some potential complications of myelofibrosis
- Gout (due to hyperuricaemia due to increased cell turnover)
- Portal hypertension
- AML
State some causes of mild, moderate and massive splenomegaly in adults
Mild
- Connective tissue disorders e.g. SLE
- Infection e.g. infectious mononucleosis
Moderate
- Portal hypertension
- Thalassaemia
- Glycogen storage diseases
Massive
- Myelofibrosis
- Gaucher disease
- CML
- Hairy cell leukaemia
- Polycythaemia vera
- Malaria (hyperreactive malarial splenomegaly)
State some causes of splenomegaly in children
- Infectious mononucleosis
- Sickle cell
- ALL
- Juvenile idiopathic arthritis
- Gaucher disease
- Hereditary spherocytosis
What is graft vs host disease (GVHD)?
Multi-system complication most commonly as a result of allogenic bone marrow transplantation (can also less frequently occur as a complication of blood transfusions in immunocompromised pts and solid organ transplants)
Briefly outline the pathophysiology of a GVHD
T cells in donor tissue (graft) form immune response against recipient (host) cells
What criteria is used to diagnose GVHD?
Billingham criteria:
- Transplanted tissue contains immunologically functioning cells
- Recipient & donor are immunologically different
- Recipient is immunocompromised
There are two types of GVHD; acute and chronic. Discuss for acute GVHD:
- Within how many days of transplantation it occurs
- What organs it usually affects
- Signs & symptoms
- 100 days
- Affects skin (>80%), liver (50%) and GI tract (50%)
- Symptoms:
- Itchy skin rash
- Sickness
- Diarrhoea
- Abdo pain
- Jaundice
There are two types of GVHD; acute and chronic. Discuss for chronic GVHD:
- When it occurs
- What organs it usually affects
- Signs & symptoms
- Usually >100 days after transplantation; may occur after acute disease or de novo
- Involves more organs than acute GVHD but common organs include lung, eye, skin, GI
- Symptoms:
- Skin changes inlcuding dryness, flaking, discolouration
- Dry gritty eyes
- Mouth ulcers
- Diarrhoea
- Sickness
- SOB & wheezy
- Muscle weakness & joint pain
What can be given as prophylaxis against GVHD?
Immunosuppressive drugs following transplantation to try and stop donor’s T cells attacking recipients tissues
Discuss the management of GVHD
Options differ for acute & chronic and depend on the organs involved, but options include:
- Topical corticosteroids
- Systemic corticosteroids
- Immunosupressive agents e.g. calcineurin inhibitors
*NOTE: haematology LOs specify must know very basic pathological & clinical features of primary amyloidosis
- What is amyloidosis
- State 3 types
- Amyloidosis is classified by the abnormal deposition of fibril protein in tissues of body. The names of these classifications start with the letter ‘A’ (for amyloid) followed by an abbreviation of the fibril protein involved.
- Types:
- AL (known as primary amyloidosis)
- AS
- ATTR (inherited form)
AL amyloidosis is most common type of amyloidosis, discuss:
- Pathophysiology
- How it presents
- Management
- Abnormal plasma cells produce abnormal forms of light chain proteins, which enter the bloodstream and can form amyloid deposits. Closely associated with multiple myeloma but often not malignant
- Presentation varies:
- Commonly includes dyspnoea & weakness
- Kidney failure (oedema, fatigue, weakness, loss appetite)
- Heart failure (SOB, oedema, fatigue)
- Treated with anti-myeloma therapy but there is no standard treatment; it is tailored to pts
- First line often combination chemotherapy regimes commonly including dexamethasone
State some DVT risk factors, consider:
- Generic
- Conditions
- Medications
General
- increased risk with advancing age
- obesity
- family history of VTE
- pregnancy (especially puerperium)
- immobility
- hospitalisation
- anaesthesia
- central venous catheter: femoral >> subclavian
Underlying conditions
- malignancy
- thrombophilia: e.g. Activated protein C resistance, protein C and S deficiency
- heart failure
- antiphospholipid syndrome
- Behcet’s
- polycythaemia
- nephrotic syndrome
- sickle cell disease
- paroxysmal nocturnal haemoglobinuria
- hyperviscosity syndrome
- homocystinuria
Medication
- combined oral contraceptive pill: 3rd generation more than 2nd generation
- hormone replacement therapy: the risk of VTE is higher in women taking oestrogen + progestogen preparations compared to those taking oestrogen-only preparations
- raloxifene and tamoxifen
- antipsychotics (especially olanzapine) have recently been shown to be a risk factor
Which cancers have a:
- Very high risk
- High risk
…of VTE?
Very high
- Stomach
- Pancreas
- Brain
High
- Lung
- Haematological
- Gynaecological
- Renal
- Bladder
