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Haematology > General questions > Flashcards

General questions Flashcards

1
Q

List 2 causes of lymphopenia

A

Usually reactive to viral illness

Drugs (immunosuppressants e.g. steroids)

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2
Q

List 4 causes of neutropenia

A

Drugs - AEDs, thyroid inhibitors, abx, antipsychotics, antiarrhythmics, immunomodulators, NSAIDs

Infection - acute or chronic viral

Autoimmune neutropenia

Underproductive bone marrow - e.g. MDS, aplastic anaemia, leukemia

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3
Q

List 4 causes of neutrophilia

A

Infection
Inflammation
Smoking
Myeloproliferative neoplasm e.g. CML

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4
Q

List 5 causes of lymphocytosis

A 
Infection
Inflammation
Smoking
Splenectomy
Lymphoproliferative disorder
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5
Q

List 4 causes of monocytosis

A

Infection
Inflammation
Splenectomy
Chronic monomyelocytic leukemia (CMML)

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6
Q

List 5 causes of eosinophilia

A

Parasite
Allergy/drug reaction
Eosinophilic granulomatous with polyangiitis (EGPA)
Primary hypereosinophilic syndrome

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7
Q

Basophilia is always pathological. What do you worry about?

A

Myeloproliferative neoplasm

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8
Q

At what platelet count do you get spontaneous bleeding?

A

Body can cope quite well until platelets drop below 50. Usually don’t get spontaneous bleeding until platelets <30

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9
Q

When do you transfuse someone in ITP?

A

<30 usually

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10
Q

What do you see on blood film in TTP/HUS?

A

Schistocytes (red cells have jagged edges), red cell fragments

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11
Q

TTP/HUS is caused by a deficiency in protein called adamts13. Its function is ….

A

Chops up von Willebrand factors –> accumulation of vWF fibers –> breakdowns down red cells, catch all the platelets –> thrombocytopenia, haemolytic anaemia

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12
Q

List 5 features of TTP

A 
Thrombocytopenia 
Haemolytic anaemia
ARF
Fever
Neurological abnormalities (usually fluctuating)
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13
Q

List causes of thrombocytopenia

A

1) Infective - viral, sepsis/consumptive especially if DIC
2) Drugs - abx e.g. Bactrim, thiazide diuretic, heparin = HITS, immunomodulators
3) Hypersplenism - hep C, cirrhosis, HIV
4) Malignancy
5) Autoimmune - ITP (diagnosis of exclusion), TTP, HUS

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14
Q

When do you get heparin induced thrombocytopenia (HIT)?

A

Day 5-10 of heparin exposure

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15
Q

What is the HIT screen?

Hint: 4 Ts

A

Thrombocytopenia
Timing of platelet count fall
Thrombosis and other sequelae
HIT in the most likely cause

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16
Q

List causes of thrombocytosis

A

Primary
- Essential thrombocythaemia (JAK 2)

Reactive

  • Infection/inflammation
  • Iron deficiency anaemia
  • Splenectomy
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17
Q

What investigations are important in pancytopenia?

A 
Blood flim
Raised LDH, bilirubin (destruction)
Reticulocyte count (appropriate response)
Low haptoglobin
Urine haemosiderin
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18
Q

What is acquired aplastic anaemia?

A

Autoimmune destruction of pluripotent hematopoietic stem cells (HSC) by T lymphocytes

  • Impaired regulatory T cell function
  • Increased activity of IL17
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19
Q

What do you expect to see on blood film and bone marrow aspirate/biopsy in acquired aplastic anaemia?

A

Blood film: reduced/absent reticulocytes, macrocytic RBCs

BM: reduced cells, absence of fibrosis and malignant cells, cytogenetics/directed next-generation sequencing panel

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20
Q

How do you treat idiopathic acquired aplastic anaemia?

A

<50 years: HSCT

>50 years: triple immunosuppressive therapy: anti-thymocyte globulin (ATG), cyclosporin, methylprednisolone

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21
Q

Which drugs causes an underproductive bone marrow?

A

Benzene, chemotherapy, NSAIDs, AEDs, steroids, chloramphenicol

Biologics - e.g. rituximab, TNFi, IL6i

ETOH

Radiation therpay

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22
Q

Fluoropyrimidines (e.g. flurouracil and capecitabine) can cause severe and sometimes fatal BM toxicity particularly in those with … deficiency

A

Dihydropyrimidine dehydrogenase enzyme deficiency

Can do genetic testing but not routinely done

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23
Q

Which infections commonly cause pancytopenia/bone marrow failure?

A

Commonly viral

  • Hep A, B, C
  • CMV
  • EBV
  • HHV-6
  • HIV
  • Parvovirus B19 - directly attacks proerythroblasts, commonly causes anaemia only
  • Hepatitis associated aplastic anaemia (HAA) - occurs after an episode of acute hepatitis
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24
Q

List 4 inherited BM failure syndromes

A

Fanconi’s anaemia
Dyskeratosis congenita
Shwachman-Diamond syndrome
GATA2-associated syndromes

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25
Q

List 4 bone marrow infiltrate disorders that can cause bone marrow failure?

A

Myeloproliferative disorder

Systemic diseases infiltrating BM - leukaemia, lymphoma, myeloma, amyloidosis, hairy cell leukemia

Solid tumours - prostate, breast, lung ca

Granulomatous disease
TB
Sarcoidosis
Gaucher disease (type of bone disease)

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26
Q

What nutritional deficiencies cause bone marrow failure?

A

Folate
B12
Copper

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27
Q

What causes folate deficiency?

A

Malnourish/inadequate dietary intake

ETOH

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28
Q

What causes B12 deficiency?

A

Bariatric surgery

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29
Q

What causes copper deficiency?

A

Gastric surgery
Malabsorption syndrome
Excessive zinc intake

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30
Q

What accumulates in both B12 and folate deficiency and what only accumulates in B12 deficiency?

A

Homocysteine accumulates in both B12 and folate deficiency

Methylmalonic acid accumulates only in B12 deficiency

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31
Q

What are the two main groups/ways you can get peripheral destruction of cells leading to pancytopenia?

A
  1. Spleen sequestration

2. Autoimmune mediated pancytopenia

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32
Q

What are some examples of autoimmune mediated pancytopenias?

A

CLL
SLE
Common variable immunodeficiency disease (CVID) - autoimmune haemolytic anaemia and ITP more common; get splenomegaly (differentiate if autoimmune or hypersplenism)

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33
Q

Paroxysmal nocturnal haemoglobinuria is an acquired stem cell disorder resulting in absent glycosylphophatidylinositol (GPI), renders cells……

A

Susceptible to destruction by complement

Absence of GPI –> absent DAF (decay accelerating factor is linked to the cell by GPI; it protects cells against complement) –> renders cells susceptible to complement mediated damage

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34
Q

What happens in paroxysmal nocturnal haemoglobinuria?

A

Intravascular haemolysis occurs especially during sleep

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35
Q

Intravascular haemolysis in paroxysmal nocturnal haemoglobinuria leads to…

A

Pancytopenia (cells are lysed)
Haemoglobinemia and haemoglobinuria (especially in the morning); haemosiderinuria is seen days after haemolysis (Hb taken up by tubules in the kidney –> collects as haemosiderin –> slough off into urine)

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36
Q

Why does intravascular haemolysis occur during sleep or at night in paroxysmal nocturnal haemoglobinuria?

A

Sleep –> shallow breathing –> respiratory acidosis –> activates complement

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37
Q

How do you test for paroxysmal nocturnal haemoglobinuria?

A

Confirmatory test is flow cytometry with FLAER (to detect lack of CD55 ie DAF or CD59 on blood cells)

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38
Q

Rx for paroxysmal nocturnal haemoglobinuria

A

Eculizumab or HSCT

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39
Q

How do people die from paroxysmal nocturnal haemoglobinuria?

A

Main cause of death is thrombosis of hepatic, portal or cerebral veins
- Destroyed platelets release cytoplasmic contents into circulation –> activates coagulation cascade –> thrombosis

Other complications: iron deficiency anaemia (due to chronic loss of Hb in the urine) and AML (10% transformation)

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40
Q

Whats haemophagocytic lymphohistiocytosis?

A

Life-threatening disease
Cytokine storm syndrome
Uncontrolled Proliferation of activated lymphocytes (T + NK cells) and macrophages that secrete high amounts of inflammatory cytokines.

There are inherited or non-inherited causes.

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41
Q

What happens in haemophagocytic lymphohistiocytosis?

A

It is a life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages, characterised by proliferation of morphologically benign lymphocytes and macrophages that secrete high amounts of inflammatory cytokines. It is classified as one of the cytokine storm syndromes.

Fever (cytokine storm)
Cytopenia (suppresses haematopoiesis)
Splenomegaly (extramedullary haematopoiesis)

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42
Q

What are some secondary causes or non-inherited causes of haemophagocytic lymphohistocytosis?

A
  • Infection (mainly viruses such as EBV, CMV, HIV)
  • Malignancy mainly lymphoma
  • Macrophage activation syndrome in autoimmune conditions
  • Organ or stem cell transplant
  • Immunosuppression, vaccination
    Lots more!
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43
Q

Rx for haemophagocytic lymphohistocytosis

A

Corticosteroids
Etoposide (high specificity against T cell proliferation and cytokine secretion)
Primary HLH may need ASCT

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44
Q

Patients with high grade lymphomas (Burkitts and T lymphoblastic) and leukemias (ALL) are prone to tumour lysis syndrome. What would you expect in your blood?

A

Hyperuricaemia
Hyperuricosuria
Hyperkalaemia
Hyperphosphatemia –> secondary hypocalcaemia

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45
Q

What’s a major complication of tumour lysis syndrome?

A

Renal failure

Precipitation of uric acid, xanthine and/or phosphate in renal tubules –> obstructive nephropathy –> renal failure

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46
Q

How do you prevent hyperuricaemia to prevent obstructive nephropathy in tumour lysis syndrome?

A

Urate oxidase (rasburicase)

  • Oxidises uric acid to molecules more soluble and less toxic to kidneys
  • Achieves rapid decrease in serum uric acid
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47
Q

List causes of thrombocytoepnia

A

TTP/HUS
ITP

Secondary causes

  • Infection - viral, HIV, hep C, sepsis (DIC)
  • Hypersplenism - cirrhosis
  • Meds - Bactrim, thiazide, heparin (HIT), immunomodulators
  • Malignancy
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48
Q

How is ITP diagnosed?

A

Diagnosis of exclusion

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49
Q

Pathophysiology of ITP

How does it cause thrombocytopenia?

A

Splenic plasma cells make IgG –> antibodies coat platelets –> platelets are consumed by splenic macrophages –> thrombocytopenia

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50
Q

List causes of ITP

Split answer up into acute and chronic forms of ITP

A

Acute form

  • After viral infection or immunisation
  • Self-limiting
  • Children

Chronic form

  • Adults
  • Primary or secondary (e.g. SLE)
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51
Q

Rx for ITP

A 
Steroids 
IVIG (spleen macrophages consume IVIG instead of ab coated platelets; effects are short lived) 
Splenectomy (eliminates source of ab and site of platelet destruction; only done in refractory cases)
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52
Q

Is heparin induced thrombocytopenia serious?

A

YES

Can be life-threatening

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53
Q

How does HIT present?

A

90% thrombocytopenia
50% thrombosis venous > arterial
- Skin necrosis, limb gangrene, organ infarction

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54
Q

What is the 4Ts score used in HIT?

A

4Ts screen is used to calculate the probability of HIT

  • Thrombocytopenia
  • Time of platelet count fall
  • Thrombosis
  • HIT is the most likely diagnosis
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55
Q

How to treat HIT?

A

Stop heparin
Anticoagulation for at least 4/52 (3/12 if thrombosis)
- DOAC
- Not warfarin due to transient prothrombotic state. Can be used later when the patient is stably anticoagulated and the platelet count has recovered

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56
Q

What is primary and secondary haemostasis?

A

Primary: weak platelet plug is formed
Secondary: stabilises the platelet plug by activating the coagulation cascade

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57
Q

Which factor is deficient in haemophilia A?

A

Factor 8

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58
Q

How do patients present with haemophilia A and B?

A

Deep tissue, joint and post-surgical bleeding

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59
Q

What coagulation factors are measured in INR, PT and APTT?

A

PT and INR: extrinsic pathway (VII) and common pathway (II, V, X)

APTT: intrinsic pathway (all factors except XIII and VII)

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60
Q

Rx haemophilia

A

‘Prophylaxis’ with regular infusions of factor concentrates to prevent bleeding episodes

Clinical trials:
Emicizumab in haemophilia A (ab mimics factor VIII)
Fitusiran in haemophilia A and B (RNA molecule that acts on antithrombin production by the liver)
Gene therapy

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61
Q

What factor is deficient in haemophilia B?

A

Factor 9

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62
Q

What is a coagulation factor inhibitor?

A

Acquired ab against a particular coagulation factor –> impaired function
Anti factor VIII is most common

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63
Q

Explain mixing study

A

To determine if there is a coagulation factor inhibitor

If you mix normal plasma with patient’s plasma which contains coagulation factor inhibitor, PTT will not correct

If you mix normal plasma with the plasma of a patient with haemophilia A, PTT will correct

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64
Q

What is von willebrand disease?

A

Genetic vWF deficiency (autosomal dominant)

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65
Q

How do patients with von willebrand disease present?

A

Mild mucosal and skin bleeding

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66
Q

Rx for von willebrand disease

A

Desmopressin (ADH analogue) - releases endogenous vWF through stimulation of endothelial cells

Human plasma-derived VWF (Biostate)

Tranexamic acid

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67
Q

Vitamin K deficiency affects which coagulation factors?

A

Factors II, VII, IX, X, protein C and S

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68
Q

How do people get vitamin K deficiency?

A

Long-term abx therapy - disrupts vitamin K producing bacteria in the GIT
Malabsorption of fat soluble vitamins
Liver failure - liver activates vitamin K

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69
Q

How does liver failure affect bleeding?

A

Liver makes coagulation factors and activates vitamin K

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70
Q

How do we monitor the effects of liver failure on coagulation?

A

PT

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71
Q

How does bleeding pattern differ between platelet function disorder and coagulopathy?

A

Platelet disorder: mucosal bleeding, petechiae, prolonged bleeding from skin cuts

Coagulopathy: deep hematomas, hemarthrosis

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72
Q

What does vWF do?

A

1) Binds platelets to site of vascular injury

2) Stabilises factor VIII in the circulation (prevents premature degradation)

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73
Q

What are the problems with using factor concentrates in haemophilia?

A

Short t/12
Frequent IV injections
Ports - infection risk, occlusion
Factor 8 antibodies (body produces ab towards exogenous factors –> need to use bypassing agents)

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74
Q

What is DIC?

A

Activation of the coagulation cascade everywhere –> widespread microthrombi –> ischaemia and infarction

At the same time use up all the platelets and coagulation factors –> bleeding especially from orifices, mucosal surfaces, IV sites

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75
Q

How do you get DIC?

A

1) Sepsis
2) Adenocarcinoma especially metastasis
3) Acute promyelocytic leukaemia (subtype of AML)
4) Obstetric complication - amniotic fluid leaking into mother’s circulation
5) Rattlesnake bite

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76
Q

Lab findings for DIC

A 
Low platelets
Low fibrinogen 
High PT/APTT
Microangiopathic haemolytic anaemia
Elevated d-dimer (best screening test)
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77
Q

Rx DIC

A

Cryoprecipitate (contains coagulation factors, fibrinogen)

Blood products

78
Q

Rx TTP

A

MEDICAL EMERGENCY
Treatment must be initiated within hours

Daily plasma exchange
Steroids
Rituximab

When the platelet count recovers, can stop plasma exchange

20-30% relapse - ab can come back again

79
Q

How does HUS happen?

A

Shiga toxin producing ecoli –> toxin enters bloodstream –> gets to kidney and damages glomeruli and endothelium

80
Q

How does HUS present?

A

Bloody diarrhoea after eating something wrong
Severe ARF
Microangiopathy (glomeruli gets destroyed and RBCs that go through get sheared)

Anyone that presents with MAHA picture –> send stool for shiga toxin

81
Q

Pathophysiology of atypical HUS

A

Not triggered by bacteria

Atypical hemolytic uremic syndrome (aHUS) is a disease that causes abnormal blood clots to form in small blood vessels in the kidneys. These clots can cause serious medical problems if they restrict or block blood flow, including hemolytic anemia , thrombocytopenia , and kidney failure.

Inherited problem in the complement system –> complement system is unchecked and just continues –> MAC formation

82
Q

Rx atypical HUS

A

Eculizumab (C5 inhibitor) –> stop MAC formation

Weekly for a month then monthly for a year ($7000 per injection)

No investigation to confirm this

Prior to this, people used to die from ARF, anaemia

83
Q

Investigations if suspecting TMA/MAHA

A 
Haemolytic screen
Stool shiga toxin 
FBC
Blood flim
Coags (normal)
ADAMTS13 (takes ages to come back)
84
Q

If someone comes in with anaemia + thrombocytopenia, what’s the next important investigation?

A

Blood film
Haemolytic screen

Think of TMA/MAHA!

85
Q

What’s plasmic score for TTP?

A

7 criteria

Probability of TTP

86
Q

What’s the difference between TMA and MAHA?

A

TMA is the disease process

MAHA is what you see under the microscope - haemolysis

87
Q

Eltrombopag for ITP

When do you use it?

A

TPO mimetic
For refractory ITP at high risk of infection (rituximab and splenectomy are reasonable options but high risk of infection)

88
Q

What is GVHD?

A

Most common life threatening complication of allograft

Competent T cells in the donated tissue (the graft) recognise the recipient (the host) as foreign (non-self) -> attacks it

89
Q

Risk factors for acute GVHD

A
  • More foreign antigen (when the donor and hosts are enemies)
    > Degree of HLA mismatch
    > Unrelated donors
    > female donors for male recipients (especially multiparous; lots of foetal exposure)
  • Abundance of mature immune cells in the mix (when there are guns out)
    > Peripheral blood stem cell grafts
    > Conditioning regimen intensity
    > Administration of anti-T-lymphocyte globulin (to turn down T cell response, to make the graft less active)
90
Q

Graft vs host disease prophylaxis

A

Thymoglobulin

Inject human T lymphocytes into rabbits –> rabbits makes antibodies against these T lymphocytes –> take the antibodies and make them into thymoglobulins –> inject thymoglobulin into humans –> humans can use thymoglobulins to slow down/stop the T lymphocytes (graft) from attacking their own body

91
Q

Some patients with severe haemophilia A develop inhibitors to factor VIII. Which of the following scenarios carries the highest risk of developing inhibitors?

A

Patient factors

  • Type of gene mutation (certain variants are associated with increased risk of inhibitors, especially large deletions and nonsense mutations)
  • African and/or Hispanic ethnicity
  • FHx of inhibitor development

Disease/treatment factors

  • Increased severity of disease
  • Use of recombinant (non-plasma derived) products
  • Prolonged intensive factor replacement >5 days
  • On-demand treatment (compared to regular prophylaxis)

Debatable evidence but risk of

  • Age at first treatment (difficult to separate from ‘severity of disease’)
  • Exposure to factor replacement at time of surgery or trauma (probably real)
92
Q

What kind of bleeding do you get in primary and secondary haemostasis?

A

Primary haemostasis - vWF, platelets

  • Mucocutaneous bleeding
  • Easy bruising
  • Epistaxis
  • Gingival haemorrhage with dental intervention (include brushing teeth)
  • Heavy menstrual bleeding
  • PPH

Secondary haemostasis - coagulation factor deficiencies

  • Deep tissue bleeding
  • CNS bleeding
93
Q

What is VWF and what does it do?

A

VWF is a protein made in megakaryocytes and endothelial cells, then packaged up into endothelial cells and platelet granules. Gets released from platelets when activated, and also floats in serum.

2 main functions
1) Acts as a bridge between platelet and endothelium, and between platelets (helps platelets stick together and form a plug)

2) Chaperone of factor 8
- Increases stability and half life of factor 8 and stops it from breakdown

94
Q

What are the 3 types of vWD?

A

Type 1 = VWF deficiency

  • Most common (75% of cases)
  • Autosomal dominant

Type 2 = VWF dysfunction
- Doesn’t bind well to platelets, or too much platelet binding leading to thrombocytopenia and low VWF, or decreasing binding to platelets, or can’t bind factor 8 (looks like mild haemophilia A)

Type 3 = VWF absent

  • Very rare
  • Autosomal recessive
95
Q

How long do B12 stores last for?

A

2-4 years

96
Q

Most common fungal infection after induction chemotherapy for AML

A

Candida due to prolonged neutropenia

Everyone gets posaconazole prophylaxis so its pretty rare now

97
Q

What kind of disease do you get with the following deficiencies?

1) No B cells or plasma cells
2) No T cells
3) No neutrophils
4) No spleen

A

1) No B cells or plasma cells –> no immunoglobulins –> recurrent sinopulmonary disease
2) No T cells –> AIDS-defining illnesses e.g. MAC
3) No neutrophils –> fungal infection, bacterial sepsis (neutropenic sepsis)
4) No spleen –> encapsulated bacteria (streptococcus pneumoniae, klebsiella, haemophilus influenzae, neisseria meningitidis, pseudomonas aeruginosa)

98
Q

What’s the usual time interval at which neutrophils reach their nadir after chemotherapy following a 28 day cycle?

A

Typically 7-12 days

Almost all myelosuppressive chemo acts like this

99
Q

What abnormalities do you expect to see on coags with the following?

1) Apixaban
2) Rivaroxaban
3) Dabigatran

A

1) Anti Xa
Apixaban doesn’t do anything to coags. Hence if you get abnormal coags, its not the apixaban!

2) Anti Xa, PT
3) TT, APTT

100
Q

How to reverse warfarin?

A

Vit K + Prothrombinex +/- FFP

Remember reversing warfarin always carries the risk of thrombosis

If stable, always consider doing nothing especially if recent clot

101
Q

How to manage someone on warfarin with high INR?

1) INR higher than the therapeutic range but <4.5 and no bleeding
2) INR 4.5-10 and no bleeding
3) INR >10 and no bleeding

A

1) INR higher than the therapeutic range but <4.5 and no bleeding
- Resume warfarin at a lower dose when the INR approaches therapeutic range. If the INR is <10% above therapeutic range, dose reduction is generally not necessary.

2) INR 4.5-10 and no bleeding
- Cease warfarin
- Consider reasons for elevated INR
- Vitamin K is not usually necessary
- If bleeding risk is high: consider vitamin K 1-2mg PO or 0.5-1mg IV
- Measure INR within 24h
- Resume warfarin at a reduced dose once INR approaches therapeutic range

3) INR >10 and no bleeding
- Cease warfarin
- Give vitamin K 3-5mg PO or IV
- Measure INR in 12-24h. Close monitoring of INR daily-second daily over the next week
- Resume warfarin at a reduced dose once INR approaches therapeutic range
- If bleeding risk is high: consider prothrombinex-VF, 15-30 units/kg. Measure INR in 12-24h.

High bleeding risk includes recent major bleed (within 4 weeks) or major surgery (within 2 weeks), thrombocytopenia (plat <50), known liver disease or concurrent antiplatelet therapy.

102
Q

Pathophysiology of atypical HUS

A

Atypical HUS = complement activation

103
Q

Pathophysiology of TTP

A

TTP = ADAMTS 13 deficiency

104
Q

THrombocytopenia in pregnancy ddx

A

Pregnancy specific

  • Gestational thrombocytopenia - just mild with plat rarely <70, common
  • HELLP - not common, with anaemia, thrombocytopenia and fragments on blood film
  • Acute fatty liver of pregnancy

Non-pregnancy specific

  • TTP - uncommon
105
Q

List ddx of thrombocytopenia in pregnancy

- Think pregnancy specific and non-pregnancy specific

A

Pregnancy specific

  • Gestational thrombocytopenia
  • HELLP/pre-eclampsia
  • Acute fatty liver of pregnancy

Non-pregnancy specific

  • Immune causes: ITP, APLS, SLE (can occur spontaneously during pregnancy; usually in 1st trimester)
  • TTP (rare): congenital or acquired; during pregnancy or post-partum
  • Viral: HIV, HBV, HCV, EBV, CMV
  • B12/folate and iron deficiency
  • Drug-induced thrombocytopenia including HIT, VITT (vaccine induced)
  • DIC: during pregnancy or immediately post-partum in settings such as sepsis, placental abruption, foetal death in utero, amniotic fluid embolism
  • Congenital causes may be detected for the first time in pregnancy in an otherwise well person
  • KEY DIFFERENTIALS*
  • Gestational thrombocytopenia is usually mild thrombocytopenia
  • Fragments/schistocytes: points towards MAHA (HELLP most common in pregnancy)
  • Trimester: HELLP late pregnancy
106
Q

Vitamin K related factors are…

A

2, 7, 9, 10
APTT = 8, 9, 11, 12
PT = 2, 5, 7, 10

Mainly affects PT and INR

107
Q

How does coagulation happen?

A

3 steps

1) Initiation: cell is damaged and tissue factor is exposed –> activates factor 7 –> 10 –> 5 –> thrombin
2) Priming: thrombin causes a cycle of platelet up activation of more and more platelets
3) Propagation - thrombin burst

108
Q

How does coagulation happen?

A

3 steps

1) Initiation: cell is damaged and tissue factor is exposed –> activates factor 7 –> 10 –> 5 –> thrombin
2) Priming: thrombin causes a cycle of platelet up activation of more and more platelets
3) Propagation - thrombin burst

109
Q

Haemolysis from any cause =

A

Increased LDH
Decreased Haptoglobin
Increase reticulocyte
Positive DAT - specific to autoimmune haemolysis (as opposed to other forms of haemolysis)
- Note DAT is overall not that specific to haemolysis. Can be positive in sick people with high protein

Urinary haemosiderin - specific to any cause of intravascular haemolysis

110
Q

Low grade low stage localised follicular lymphoma (NHL) Rx

A

Radiotherapy

Refer to cancer centre for MDM discussion

111
Q

What’s gestational thrombocytopenia?

A

Common - physiological change in pregnancy
Usually mild with plat rarely <70
Benign and not associated with bleeding
No specific diagnostic tests. Diagnosis of exclusion

112
Q

What’s HELLP?

A

Haemolysis elevated liver enzymes and low platelets
Disorder of late pregnancy associated with microangiopathic haemolysis
Medical emergency requiring obstetric intervention i.e. close monitoring and delivery

113
Q

What’s acute fatty liver of pregnancy?

A

Rare condition characterised by multiorgan dysfunction (liver failure, acute kidney injury, hypoglycaemia, diabetes insipidus) with associated mild thrombocytopenia and haemolysis

114
Q

What “haem/blood problems” can EBV cause?

A

1) Acute EBV infection = ‘mononucleosis syndrome’
- Lymphocytosis or lymphopenia
- Neutrophilia or neutropenia
- Thrombocytopenia
- Warm immune haemolysis
- Aplastic anaemia
- Splenic rupture –> leading cause of death in acute EBV

2) Chronic EBV
- Rare, mostly in immunosuppressed people
- Can progress to clonal proliferation of lymphocytes

3) Malignancy
- Post transplant lymphoproliferative disorder
- T or NK lymphoproliferative disorder
- Burkitt lymphoma
- Hodgkin lymphoma

Other disasters
- Haemophagocytic syndrome

115
Q

What’s post transplant lymphoproliferative disorder?

A
  • Type of lymphoma that occurs after any type of transplant
  • Caused by EBV infected B cells. An immunosuppressed patient cannot stop the B cells infected with EBV from growing out of control
  • Monitor EBV viral load in post-allo patient.
  • Usually treated with withdrawal of immunosuppression +/- rituximab
116
Q

What does it mean by clonal?

A

Originating from one cell line

Vs polyclonal - originating from several cell lines; more likely associated with inflammatory conditions

117
Q

What’s the difference between autograft and allograft?

A

Autograft: high dose chemotherapy with rescue by patient’s OWN stem cells

Allograft: high dose chemotherapy with rescue by SOMEONE ELSE’S stem cells

118
Q

What is MGUS?

A
  • Presence of monoclonal protein WITHOUT signs of end organ damage
  • Cell line can produce IgG, IgA, IgM or free light chain
  • Generally, IgG is less concerning than IgA
  • Rate of change more concerning than absolute number
  • Levels >15g/L more concerning
119
Q

What’s free light chains disease?

A

Plasma cells are so dysfunctional they’re just spitting out junk (part of an ab). Can’t even make a proper ab.

120
Q

Definition of MM

A

Clonal plasma cells >10% OR extramedullary plasmacytoma (ball of plasma cells outside the BM)

WITH

Evidence of organ damage
C - calcium
R - renal insufficiency 
A- anaemia
B- bone lesions 
OR
Biomarkers of malignancy
>60% of plasma cells on BMAT
Serum involved/unvionovled F light chain ratio of >100
>1 focal lesion on MRi that is at last 5mm or greater in size

Almost always IgG, IgA or FLC
(IgM paraproteins tend to be something else)

121
Q

What’s smouldering myeloma?

A

Clonal plasma cells >10%
Serum monoclonal protein >30g/L
Absence of myeloma defining events

122
Q

Bone marrow trephine - CD138 positive cells indicates …

A

Multiple myeloma

123
Q

Multiple myeloma Rx

A

VRd treatment
- Bortezomib, Lenalidomide, dexamethasone induction

Followed by autograft (melphalan) if they’re fit

Lenalidomide maintenance until progression

1st relapse: daratumumab

  • Anti CD38
  • Causes pan agglutination - CD38 is found on alot of red cells hence you can’t crossX these people in the future. Important to phenotype blood before commencing treatment.

Bone protection - monthly zoledronic acid if bone lesions

124
Q

Is MM curable?

A

It’s not curable. Aim is to give sequential treatments until you run out of treatments. The older you are, the better it is, because you don’t have much long to live.

125
Q

IgM is associated with which disease?

A

Associated with lymphoplasmacytic lymphoma (Waldenstroms macroglobulinaemia)

Associated with syndrome of hyperviscosity (IgM is a pentamer of IgG = Big structure and makes the blood thick)

Very rarely associated with myeloma (1% of cases)
Also associated with marginal cell lymphoma

126
Q

Staging of lymphoma

A

Lugano staging system
Based on PET CT imaging

1: single lymphatic site
2: 2 or more lymph node regions on the same side of the diaphragm (spleen doesn’t count)
3: lymph node regions on both sides of the diaphragm; nodes above the diaphragm with spleen involvement
4: disseminated disease involvement of extralymphatic sites

A or B
- B: presence of B symptoms

127
Q

Typical markers of Hodgkin lymphoma

A

Classic HL (majority): reed sternberg cells (typically CD30, CD15+ve, lack CD45)

128
Q

Which type of Hodgkin lymphoma has best prognosis?

A

Lymphocyte rich

129
Q

Hodgkin lymphoma rx

A

ABVD chemotherapy
- Doxorubicin, bleomycin, vinblastine, dacarbizine

After 2 cycles, get an interim PET scan
If not responded, need escalation of therapy (BEACOPP)
De-escalation of therapy (get rid of bleomycin) if complete response and for those with risk factors for lung toxicity

130
Q

What kind of toxicity does bleomycin cause?

A

Bleomycin lung toxicity

131
Q

20 years later presents with lower limb oedema. Previously on doxorubicin and anthracycline

A

Doxorubicin (and anthracycline) cardiac toxicity

132
Q

Aggressive or indolent?

1) Lymphoblastic lymphoma (acute leukaemia)
2) Follicular lymphoma
3) Peripheral T cell lymphomas
4) Burkitt lymphoma
5) Small lymphocytic lymphoma
6) DLBCL
7) Marginal zone lymphoma
8) High grade B cell lymphoma with MYC and BCL2 rearranagement

A

1) Aggressive
2) indolent
3) Aggressive
4) Aggressive
5) Indolent
6) Aggressive
7) Indolent
8) Aggressive

133
Q

Follicular lymphoma

Stage 1 disease and not grade 3B

A

Radiotherapy

curable

134
Q

Follicular lymphoma (non-grade 3B) Rx

A

Bendamustine/rituximab (or obinutuzumab)

135
Q

Follicular lymphoma grade 3B Rx

A

Treat as aggressive lymphoma

136
Q

Obinutuzumab MOA

A

Anti CD20 humanised monoclonal ab

Rituximab is a type 1
Obintuzumab is a type 2 (slightly different binding due to ab configuration)

137
Q

DLBCL

1) which markers does it express?

A

1) Typically express pan B cell markers (CD19, CD20, CD22, CD79a) and CD45

138
Q

DLBCL which markers impact on prognosis?

A

Expression of BCL2, BCL6, MYC expression = poor prognosis

139
Q

Rx DLBCL

A

R-CHOP x6 standard treatment

Refractory disease treated with salvage chemotherapy (R-ICE), then autograft

140
Q

Rx DLBCL

A

R-CHOP x6 standard treatment

Refractory disease treated with salvage chemotherapy (R-ICE), then autograft

141
Q

What is CAR-T cell therapy?

A

Chimeric antigen receptor T-cell therapy

“reprogramming the immune system”

Similar to the idea of getting stem cells for a patient. You take off the T cells –> lab –> using a viral vector, introduce a new gene –> new cells start to express new genes –> produce ab that target tumour cells –> infuse back to patient

142
Q

What are bispecific antibodies?

A

Build ab from scratch in a lab
Make one arm express a specific marker that binds the cancer cell, make the other arm express another marker that engages with T cells

Hence brings T cells to tumour cells

143
Q

What’s CLL?

A

Chronic accumulation of mature (but functionally incompetent) B cells

144
Q

How is CLL diagnosed?

A

Peripheral blood flow cytometry

Aberrant CD5, CD19, CD20, CD23, and kappa and labda immunoglobulin light chains

145
Q

What’s Richter’s transformation in CLL?

A

Turns into aggressive lymphoma

146
Q

Rx CLL

A

Generally watch and wait approach

Stratify based on risk
IGHV unmutated - high risk
Del (17p), TP53 mutations - high risk

Lower risk and fit = FCR chemoimmunotherapy

17pdel or TP53 mutation - ibrutinib (bruton TKI) or venetoclax (bcl2 inhibitor)

Frail elderly - obinutuzumab + chlorambucil

147
Q

Venetoclax

A

BCL2 inhibitor
BCL2 is anti-apoptotic - stops cells dying. By inhibiting BCL2, let cells die

High risk of tumour lysis - people can die from this

148
Q

CML mechanism

A

Driven by the Philadelphia chromosome
Reciprocal translocation t(9;22)
Produces BCR-ABL protein

149
Q

Rx CML

A

TKIs - imatinib (1st gen), dasatinib (2nd gen), nilotinib (2nd gen), ponatinib (3rd gen)

Dasatinib and nilotinib achieve faster and deeper molecular response compared to imatinib

150
Q

Common TKIs and side effects

A

Imatinib

  • Well tolerated in elderly
  • Dose dependent AEs
  • Preferred in vasculopaths

Dasatinib (2nd gen)
- AE: Pleural effusions (Rx steroids, diuretics), pulm HTN

Nilotinib (2nd gen)
- AE: cardiovascular toxicity, strokes, MI, PVD

Ponatinib (3rd gen)

  • CVS toxicity
  • Not used much unless in breakthrough or resistance to first two
151
Q

Polycythaemia vera mechanism

A

Clonal proliferation of myeloid cells leading to an increase in red cell mass (but also in other cell lines like platelets)

Almost all Driven by JAK2 mutation

152
Q

Symptoms of polycythaemia vera

A

Pruiritis
Skin colour changes after hot shower
Thrombosis

153
Q

Rx polycythaemia vera

A

Goal is to prevent thrombosis

Aspirin (to prevent thrombosis)

Venesections (aiming HCT <0.45)

Hydroxyurea if history of thrombosis

154
Q

Essential thrombocythemia mechanism

A

Excessive clonal platelet production

Typical mutations: JAK2 (majority), CALR, MPL

155
Q

Symptoms of thrombocythaemia

A

Thrombosis and bleeding (high levels of platelets particularly >1000, can get secondary vWD)

Splenomegaly might be present

156
Q

Rx thrombocythaemia

A

1st line: Aspirin +/- hydroxyurea (age >60, thrombosis risk)
To reduce arterial thrombosis/ACS/stroke risk
Goal is to keep platelet <600

2nd line: anagrelide if intolerant to hydroxyurea

Young/pregnant: interferon

157
Q

Myelofibrosis mechanism

A

Clonal proliferation of one type of myeloid cells with variable maturity. Fibrosis is a secondary process.

It’s a myeloproliferative process but the fibrosis is a result.

Myeloid cells in the BM produce lots of cytokines and growth factors –> fibrosis of BM –> typically anaemia + push out immature red cells and white cells (leukocytosis and thrombocytosis early in the disease = the “leucoerythroblastic picture)

Splenomegaly = extramedullary erythropoiesis

158
Q

Rx myelofibrosis

A

Difficult to treat. Disease of the elderly
Use international prognostic score to determine prognosis. If high risk score, treat.

Allograft is the only cure

Transplant ineligible: Ruxolitinib (JAK inhibitor) can improve spleen size, constitutional symptoms and reduce transfusion requirement; also survival benefit

159
Q

What is the risk of myelofibrosis?

A

Transformation into acute leukemia

160
Q

MOA of TKIs e.g. imatinib

A

Sit at ATP site of the BCR-ABL protein and block activity

161
Q

Treatment goal/target in CML

How do we monitor?

A

Monitor quantitative BCR-ABL in blood

Goal is to achieve deep molecular response. If achieved after 1-2 years, can trial coming off TKI. May achieve long-term cure.

162
Q

Myeloproliferative neoplasms (essential thrombocytopenia, polycythaemia vera) is commonly driven by … mutation

A

Mutated JAK2 –> overactive kinase activity –> erythropoiesis and thrombopoiesis that is constantly turned on

163
Q

Diagnosis of essential thrombocythaemia requires

A

BM biopsy

Look for JAK2, CALR, MPL mutation

164
Q

Secondary polycythaemia
How to differentiate from polycythaemia vera?

Causes?

A

Raised Hb/Hct with normal/high EPO
JAK 2 mutation neg

Causes

  • High altitude
  • COPD
  • Smoking
  • OSA
  • Drugs (EPO, testosterone)
  • Less common: renal, hepatic tumours, hereditary
165
Q

Diagnosis of polycythaemia vera

A

Elevated Hb + Hct

BM biopsy hypercellular marrow

Presence of JAK2 mutation

166
Q

Clinical features of myelofibrosis

A

Splenomegaly (abdo pain)
Weight loss
Fatigue, anorexia, night sweats, fever, bone pain, pruritis

167
Q

Diagnosis of primary myelofibrosis

A

Blood film: giant platelets, tear drop, tear drop RBCs

BM: dry tap

Presence of JAK2, CALR or MPL mutation

168
Q

Regarding Myeloproliferative neoplasm
Which one is incorrect?
1) Nearly all patients with PV have JAK2 mutation
2) All patients with JAK2 ET should be on aspirin
3) Interferon is the treatment of choice in the young high risk ET patient
4) Ruxolitinib improves symptoms and survival in high risk myelofibrosis

A

3) is incorrect

Hydroxyurea is the treatment of choice

169
Q

Hepcidin and ferroportin regulate systemic absorption of iron by the inhibition of …

A

Enterocyte basolateral iron release

170
Q

Howell jolly body and acanthocytes in coeliac disease

What’s the cause?

A

Hyposplenism

10% coeliac patients develop splenic atrophy

171
Q

Intravascular haemolysis

Which is the most specific test?

A

Urinary haemosiderin

172
Q

How do you differentiate between gestational thrombocytopenia and ITP in pregnancy?

A

Gestational thrombocytopenia more common than ITP but 99% have platelets >100

173
Q

46F
Essential thrombocythaemia with platelet count 800
JAK2 positive
Asymptomatic
NO history of arterial or venous thrombosis

Treatment?

A

Aspirin 100mg daily
Reduced risk of vasomotor symptoms and thrombosis, patient is low risk

Hydroxyurea if previous thrombosis and higher risk (and aspirin if arterial, clexane if venous)

  • Age >60
  • History of thrombosis
174
Q

All pregnant woman with prior provoked VTE

Does she need prophylaxis?

A

Clexane 40mg postpartum for 6/52 provoked or unprovoked VTE

175
Q

What coagulation test excludes therapeutic apixaban?

A

Anti Xa only

PT does not

176
Q

What is the strongest risk factor for recurrent VTE?

A

Unprovoked VTE
20% risk at 2 years
35% at 5 years

177
Q

What do you do if there is residual thrombus on USS after course of therapeutic anticoagulation?

A

Monitor it

Stop anticoagulation

178
Q

What transfusions reactions is leucodepletion most effective in preventing?

A

Febrile non-haemolytic transfusion reaction

NO benefit in
Anaphylaxis - group issue
TRALI - antibody in the donor blood reacting with the patient’s neutrophils, monocytes or pulmonary endothelium
Delayed haemolytic transfusion reaction - caused by transfused red cells

179
Q

When to start treatment for MM?

A

CRAB features = active myeloma
Consider treatment if BM plasma cells >60%

Otherwise its just smouldering myeloma and can observe and monitor

180
Q

Which TK mutation is associated with systemic mastocytosis?

A

Too many mast cells build up –> Mast cell degranulation

Associated with cKIT D816V

181
Q

Why do patients receiving rituximab have normal IgG levels?

A

Rituximab is a CD20 antibody

Plasma cells do not express CD20 (they are very mature and lose CD20)

182
Q

Most important treatment in spontaneous tumour lysis syndrome

A

Aggressive IVT 3L/day is key

+ Rasburicase

183
Q

Classic Hodgkin’s lymphoma classically presents as a mass at which location?

A

Large mediastinal mass

184
Q

Ann arbor staging for lymphoma

What’s the difference between stage 2 and stage 2b?

A

b = B symptoms

185
Q

APML BM and FISH features

A 
BM: abnormal promyelocytes and blasts
FISH t(15:16) PML RARA fusion
186
Q

Treatment APML

A

If WCC <10 (low risk): ATRA + arsenic

If WCC >10 (high risk): ATRA + idarubicin (chemo)

187
Q

AML with isocitrate dehydrogenase 1 (IDH1) mutation

What is a specific inhibitor of this mutation used in the treatment?

A

Induction therapy with ivosidenib (IDH1 inhibitor)

188
Q

CLL - which genetic mutation has a better prognosis?

IGHV mutated
IGHV unmutated
TP53 mutation
17p deletion
t(18:21) RUNX1-RUNX1T1
A

Mutated immunoglobulin heavy chain variable

Means they’re quite mature

189
Q

In allogenic stem cell transplant, how does peripheral blood stem cell transplant compare to BM harvest?

A

Earlier engraftment

Increased rates of GVHD

190
Q

Other than bacterial infection, which of the following is most likely to occur in a patient after induction chemo for AML?

Candida albicans
Mycobacterium TB
CMV

A

Candida albicans - invasive fungal infections 11% in AML at 100 days vs 6.5% in ALL

Also aspergillus

191
Q

MTX induced myelosuppression Rx

A

IV Folinic acid

Folic acid is oral prophylaxis, takes too long

Haematology (7 decks)

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