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Julija's Path > Hematology ✔ > Flashcards

Hematology ✔ Flashcards

1
Q

what factors in the clotting cascade are procoagulant?

A 
V
VIII 
XI 
IX
X
II
Fibrinogen
Platelets
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2
Q

what factors in the clotting cascade do proteins C &S act on?

A

FVIIIIa

FVa

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3
Q

what factors in the clotting cascade does antithrombin act on?

A

Thrombin

FXa

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4
Q

what are the anticoagulant components of the clotting cascade?

A 
TFPI
Protein C
Protein S
Thrombomodulin
EPCR
Antithrombin
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5
Q

what is the natural state of the vessel wall?

A

anti-coagulant

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6
Q

what factors in the vessel wall make it anti-coagulant?

A 
1) Expresses anticoagulant molecules
Thrombomodulin, Protein C receptor; Tissue factor pathway inhibitor; Heparans 
2) Does not express tissue factor
3) Secretes antiplatelet factors
(Prostacyclin, NO)
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7
Q

what changes on the vessel wall make it pro-thrombotic?

A

infection, malignancy, vasculitis, trauma…

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8
Q

how does stasis in the vessels promote thrombosis?

A
  • Accumulation of activated factors
  • Promotes platelet adhesion
  • Promotes leukocyte adhesion and transmigration
  • Hypoxia produces inflammatory effect on endothelium
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9
Q

what are causes of stasis in the blood vessel?

A 
immobility
compression
tumors 
viscosity (eg polycythemia)
congenital
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10
Q

what anticoagulant drugs work immediately?

A

heparin - unfractionated (IV) or LMWH (SC)

Act directly anti-Xa and anti-IIa

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11
Q

which anticoagulant drug works delayed?

A

vitamin K antagonist (Warfarin)

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12
Q

what is dabigatran method of action?

A

anti-IIa anticoagulation

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13
Q

what is rivaroxaban or apixaban method of action?

A

anti-Xa

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14
Q

what is the INR derived from?

A

prothrombin time

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15
Q

how do you reverse heparin?

A

protamine

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16
Q

how do you reverse warfarin?

A

factor concentrate vitamin K

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17
Q

what are risk factors for VTE?

A
  • infection
  • inflammation
  • immobility
  • age
  • flow obstruction
  • trauma
  • previous vte
  • family history
  • genetic traits
  • obese
  • chronic disease
  • elderly
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18
Q

what is the empirical therapeutic treatment of DVT/PE?

A
  • LMWH + Warfarin OR rivaroxaban
  • stop LMWH when INR > 2 for 2 days
  • continue for 3-6 months
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19
Q

what are the causes & findings in iron deficiency anemia?

A

Causes: blood loss, GI cancers, Urinary tract cancers, Renal cell carcinoma, Bladder cancer
Laboratory findings: Reduced ferritin, reduced transferrin saturation, raised TIBC

Fe deficiency is bleeding until proven otherwise!

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20
Q

what are two cancer/systemic disease associated anemias?

A

-leucoerythroblastic anemia
-acquired hemolytic anemia
(immune mediated or non immune - MAHA)

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21
Q

what is seen on blood film of leuco-erythroblastic anemia?

A

RCC & WCC precursor anemia

  • teardrop RBCs
  • nucleated RBCs
  • immature myeloid cells
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22
Q

what are some causes of leucoerythroblastic film?

A

the core cause is bone marrow infiltration:

  • cancer: hematopoietic or breast, bronchus, prostate
  • severe infection (miliary TB, severe fungal infections)
  • myelofibrosis (w/splenomegaly)
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23
Q

what are the common distinguishing features of any hemolysis?

A
  • anemia
  • reticulocytosis
  • raised bilirubin (unconjugated)
  • raised LDH
  • reduced haptoglobins
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24
Q

what are the 5 main types of inherited hemolytic anemias?

A

1) membrane abnormalities
- Spherocytosis
- Elliptocytosis
2) Hemoglobin abnormalities
- structural (sickle cell disease)
- quantitative (thallasemias)
3) enzymes
- G6PD

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25
Q

what are the 4 types of acquired hemolytic anemias?

A
  • auto-immune (see spherocytes and DAT+)
  • cancer of immune system (lymphomas)
  • disease of immune system (SLE)
  • infection
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26
Q

when do you get a positive DAT test?

A
  • idiopathic causes

- underlying lymphoma/chronic leukemia/SLE

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27
Q

what are causes of non-immune and DAT negative acquired hemolytic anemias?

A
  • infection (eg malaria)

- MAHA (red cell fragments, low platelets, DIC, usually an underlying adenocarcinoma)

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28
Q

what symptoms do we see in MAHA?

A

-red cell fragments
-low platelets
-DIC
-bleeding
There is often an underlying adenocarcinoma.

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29
Q

what are the type of polycythemia?

A

Polycythemia can either be ‘true’ i.e. polycythemia vera or can be secondary ie. raised EPO and inappropriate to what you expect to see.

Causes of secondary - hepatocellular cancer, bronchial cancer, renal cancer

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30
Q

what carcinomas are associated with secondary polycythemia?

A

HCC
bronchial
renal

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31
Q

what is polycythemia vera?

A

acquired mutatoins in JAK2 leading to clonal myeloproliferative disorder

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32
Q

what 3 types of cells are immature WBC?

A

myelo-/lympho-blasts
promyelocytes
myelocytes

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33
Q

what are causes of neutrophilia (raised WCC)?

A
  • steroids
  • underlying neoplasia
  • tissue inflammation
  • myeloproliferative/leukemic disorders
  • infection
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34
Q

what blood signs indicate a malignant cause of neutrophilia?

A

-neutrophilia basophilia plus immature cells (myelocytes)
-splenomegaly
Suggests CML.

-neutropenia + myeloblasts. Suggests AML.

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35
Q

what causes reactive eosinophilia?

A
  • Parasitic infestation
  • allergic diseases (e.g. asthma, rheumatoid, polyarteritis, pulmonary eosinophili)
  • Underlying Neoplasms (esp. Hodgkin’s, T-cell NHL)
  • Drugs (rxn eg erythema mutiforme)
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36
Q

when do we see monocytosis?

A
  • TB, brucella, typhoid
  • Viral; CMV, VZV, sarcoidosis
  • chronic myelomonocytic leukaemia (MDS)
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37
Q

when do we expect to see neutrophil counts elevated?

A
  • bacterial infection
  • autoimmune tissue necrosis
  • all types of neoplasia
  • CML
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38
Q

when do we expect to see eosinophil counts increased?

A
  • parasitic infections
  • allergic reactions
  • Hodgkin’s
  • Non-hodgkin’s lymphoma
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39
Q

when do we see basophil counts increased?

A
  • pox viruses

- CML

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40
Q

what is a reactive lymphocytosis?

A

when only lymphocytes are raised (not other aspects of WCC)

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41
Q

what infections can cause a reactive lymphocytosis?

A
  • EBV
  • CMV
  • Toxoplasmosis
  • infectious hepatitis
  • rubella
  • herpes
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42
Q

what diagnosis might we expect if we see small lymphocytes or smear cells?

A
  • CLL

- Non Hodgkin’s lymphoma

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43
Q

what characterizes myelodysplastic syndromes?

A

the development of a clone of marrow stem cells with abnormal maturation resulting in functionally defective blood cells and a numerical reduction in blood cells

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44
Q

what are some blood/bone marrow morphological features in myelodysplastic syndromes?

A
  • Pelger-Huet anomaly (bilobed neutrophils)
  • Dysganulopoieses & mature hypersegmented look of neutrophils
  • Dyserythropoiesis of red cells
  • Dysplastic megakaryocytes
  • Increased proportion of blast cells in marrow (normal < 5%)
  • ringed sideroblasts (hemosiderin deposits) that stain with prussian blue
  • Auer rods
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45
Q

what is the pathophysiology of myelodysplasia?

A

deterioration of blood counts –> consequences of marrow failure –> development of AML (in 50% within 1 year) –> die from AML, infection, or bleeding

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46
Q

are there any treatments for myelodysplastic syndromes?

A

1) allogenic SCT
2) intensive chemo

But neither of these are very effective at all

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47
Q

how do we treat myelodysplastic syndromes?

A

1) supportive - blood products; antimicrobials; growth factors
2) biological modifiers - immunosuppressants, azacytidine, lenalidomide
3) chemo therapy
4) SCT

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48
Q

what happens in bone marrow failure?

A

damage or suppression of stem/progenitor cells results in pluripotent hematopietic cells which impairs the production of all peripheral blood cells

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49
Q

how do we classify bone marrow failure?

A

primary or secondary

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50
Q

what are causes of primary bone marrow failure?

A
  • congenital: Fanconi’s anemia
  • diamond-blackfan anemia
  • kostmann’s syndrome
  • idiopathic aplastic anemia (acquired)
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51
Q

what cells are involved in Fanconi’s anemia?

A

multipotent stem cell failures

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52
Q

what cells are involved in Diamond-Blackfan anemia?

A

rbc progenitors

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53
Q

what cells are involved in Kostmann’s syndrome?

A

neutrophil progenitors

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54
Q

what cells are involved in aplastic anemia?

A

multipotent stemm cells (same as Fanconi’s)

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55
Q

what are some causes of secondary bone marrow failure?

A
  • marrow infiltration
  • hematological (leukemia, lymphoma, myelofibrosis)
  • tumors
  • radiation
  • drugs/chemicals
  • autoimmune
  • infections
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56
Q

what drugs can cause a bone marrow failure (eg aplastic anemia)?

A
  • cytotoxic drugs
  • gold salts
  • chloramphenicol
  • sulphonamide antibiotics
  • thiazides
  • carbimazole
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57
Q

what are the two age groups in which aplastic anemia peaks?

A

15-24 year olds

>60 year olds

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58
Q

how do we classify aplastic anemia?

A

1) idiopathic (70-80% of cases)
2) inherited
3) secondary

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59
Q

what are the potential causes of inherited aplastic anemia?

A

1) dyskeratosis congenita
2) fanconi anemia
3) shwachman - diamond syndrome

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60
Q

what are the potential causes of secondary aplastic anemia?

A
  • radiation
  • drugs
  • viruses (eg hepatitis)
  • SLE
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61
Q

Aplastic anemia presents with the ‘triad’ of bone marrow failure symptoms. What are those?

A

1) anemia (fatigue, breathless)
2) leucopenia (infections)
3) platelets (easy bruising/bleeding)

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62
Q

how do we diagnose aplastic anemia?

A

1) cytopenia in the blood

2) hypocellular bone marrow

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63
Q

what are some differential diagnoses for aplastic anemia?

A

Hypoplastic MDS / Acute Myeloid -Leukaemia

  • Hypocellular ALL
  • Hairy Cell Leukaemia
  • Mycobacterial infection
  • Anorexia Nervosa
  • Idiopathic Thrombocytopenic Purpura
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64
Q

how do we determine if someone has ‘severe’ aplastic anemia?

A

Camitta criteria

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65
Q

what are the Camitta criteria?

A

for diagnosis of severe aplastic anemia -
2 out of 3 of the following features….. reticulocytes low, neutrophils low, platelets low, bone marrow <20% cellularity

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66
Q

how do we manage bone marrow failure?

A
  • Seek a cause
  • Supportive (bloods, Antibiotics, Iron Chelation Therapy)
  • Drugs to promote marrow recovery (Oxymetholone, Growth factors)
  • Immunosuppressive therapy
  • Stem cell transplantation
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67
Q

what are some complications of aplastic anemia?

A
  • relapse
  • clonal haem disorders (myelodysplasia, leukemia)
  • solid tumors
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68
Q

what is Fanconi’s anemia?

A
  • most common form of inherited aplastic anemia
  • AR/X-linked
  • multiple mutated genes responsible for abnormalities in DNA repair and chromosomal fragility
  • the patient has a normal blood count at birth but marrow failure and pancytopenia develop slowly from age 5-10 years old.
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69
Q

how do we treat fanconi’s anemia?

A
  • supportive

- androgens can transiently improve counts but have hepatic toxicity

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70
Q

what congenital malformations may occur in patients born with fanconi’s anemia?

A
  • Short Stature
  • Hypopigmented spots and café-au-lait spots
  • Abnormality of thumbs
  • Microcephaly or hydrocephaly
  • Hyogonadism
  • Developmental delay
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71
Q

what is dyskeratosis congenita?

A

An inherited disorder (via 3 patterns, involving abnormal telomeres) characterized by bone marrow failure, cancer predisposition, and somatic abnormalities.

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72
Q

what classic triad do patients with dyskeratosis congenita present with?

A
  • skin pigmentation
  • nail dystrophy
  • leukoplakia
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73
Q

what type of anitbodies are Rh immune antibodies?

A

IgG (won’t cause immediate reaction)

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74
Q

what technique is used in Group & Save blood tests?

A

indirect antiglobulin technique

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75
Q

how are RBC kept?

A
  • stored at 4C for 35 days. Must be transfused within 4 hours of leaving the fridge.
  • transfuse 1 unit RBC over 2-3 hours
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76
Q

how are platelts kept?

A
  • need to be RhD compatible
  • stored at room temperature for 1 week
  • transfuse 1 unit of platelets over 20-30 min
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77
Q

what are the indications to transfuse RBC?

A
  • major blood loss
  • perioperatively
  • post chemotherapy

(Hb < 70-80)

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78
Q

when do we use irradiated blood for transfusions?

A

required for highly immunosupressed patients, who cannot destroy incoming donor lymphocytes: which can cause (fatal) transfusion associated graft versus host disease (TA-GvHD)

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79
Q

when do we give patients platelets?

A

CONTRAindicated in heparin-induced thrombocytopenia, TTP.

  • massive transfusion
  • prevent bleeding in surgery or post chemo
  • active bleeding with platelet dysfunction
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80
Q

when do we give FFP?

A
  • massive transfusion
  • DIC
  • liver disease
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81
Q

what clotting factors does FFP contain?

A

all of them

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82
Q

what is the treatment of choice for warfarin reversal?

A

FFP is not the treatment of choice to reverse warfarin: PCC (prothrombin complex concentrate)

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83
Q

how do we classify adverse reactions to transfusions?

A
  • acute (<24 hours)

- delayed (>24 hours)

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84
Q

what are the potential causes of acute blood transfusion reactions? (6)

A
  • ABC incompatible
  • allergy/anaphylaxis
  • infection (bacterial)
  • TACO (transfusion associated circulatory overload)
  • TRALI (acute lung injury)
  • febrile non-hemolytic rxn
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85
Q

what are the potential causes of delayed blood transfusion reactions?

A
  • delayed hemolytic transfusion antibodies
  • infection (viral, vCJD)
  • TA-GvHD (graft vs host)
  • post transfusion purpura
  • iron overload
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86
Q

what is the causes of Febrile Non-Haemolytic Transfusion Reaction (FNHTR)?

A

white cells releasing cytokines during storage - cause chills, fever, rigors in patient when transfusion happens. Just stop/slow transfusion and treat with paracetamol

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87
Q

what is the cause of an allergic transfusion reaction?

A

allergy to a plasma protein in the donor which is common in recipients esp. if they have other allergies. It can cause a wheeze or itchy rash - stop/slow transfusion and give IV antihistamines

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88
Q

what are the symptoms or signs of an acute intravascular hemolysis from ABO incompatibility?

A
  • IgM mediated
  • restlessness
  • chest/loin pain
  • fever
  • vomiting
  • flushing
  • collapse
  • dec. BP/ inc. HR, inc. temperature
  • hemoglobinuria
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89
Q

how does bacterial contamination of transfusion blood present?

A
  • restless, fever, vomiting, flushing, collapse
  • dec. BP/inc. HR/ inc temperature

The bacterial growth can cause endotoxin productoin which causes immediate collapse.

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90
Q

what is TACO (with relation to transfusions) and how does it present?

A
  • Transfusion associated circulatory overload
  • pulmonary edema/fluid overload
  • SOB, dec. O2, inc. HR, inc BP
  • CXR shows fluid overload and/or HF
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91
Q

what is TRALI (in relation to transfusions) and how does it present?

A

-transfusion related acute lung injury (ARDS) from anti-WBC antibodies in the donor interacting with antigen on patient’s WBCs
These aggregates get stuck in the pulmonary capillaries and release neutrophil proteolytic enzymes/toxic O2 metabolites causing lung damage.

  • SOB, dec. O2 sats, inc. HR/BP (similar to TACO)
  • CXR will show bilateral pulmonary infiltrates within 6 hours of transfusion
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92
Q

what is the pathophysiology of transfusion associated GvHD?

A

graft vs host disease happens when the donor’s blood contains some lymphocytes that are not destroyed and recognize the patient’s tissue HLA antigens as foreign. They then attack the patient’s gut, liver, skin and bone marrow. This causes severe diarrhea, liver failure, skin desquamation, bone marrow failure, and death some weeks after transfusion. It is very rare but ALWAYS fatal, so in those known to be immunosuppressed we always irradiate blood components

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93
Q

what happens in post-transfusion purpura?

A

Purpura appear 7-10 days after the transfusion of blood/platelets and usually this resolves in 1-4 weeks but it can cause some life threatening bleeding. The purpura appear due to very low platelet count - i.e. platelet destruction has occurred. The treatment is infusing IV Ig.

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94
Q

what can happen in thalassemic patients related to their monthly transfusions?

A 
iron overload (can cause organ damage)
Tx - desferrioxamine (iron chelation)
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95
Q

what happens in hemolytic disease of fetus/newborn?

A
  • IgG antibodies from mom can cross placenta and destroy fetal RBCs
  • cause fetal hemolytic anemia, potentially hemolytic disease of newborn (leading to hydrops fetalis or kernicterus)
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96
Q

what is the mechanism of action of prophylactic anti-D Ig injections?

A

RhD positive (fetal) red cells get coated with anti-D Ig and then they get removed by the mother’s reticuloendothelial system (spleen) before they can sensitise the mother to produce anti-D antibodies. To be effective, this must be given within 72 hours of the ‘sensitizing event’

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97
Q

what are potential ‘sensitizing events’ for pregnant mom?

A
  • delivery of child that is RhD +
  • spotaneous miscarriages if ERPC needed
  • amniocentesis
  • CVS
  • abdominal trauma
  • ECV
  • stillbirth/IUD
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98
Q

what changes to FBC occur in pregnancy?

A 
-mild anemia 
(rise of plasma volume by more than red cell mass)
-macrocytosis 
-neutrophilia
-thrombocytopenia (inc. platelet size)
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99
Q

what can iron deficiency in pregnancy cause?

A
  • IUGR
  • prematurity
  • PPH
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100
Q

how much iron & folic acid is recommended in pregnancy?

A

-60mg Fe
-400 mcg Folic acid
in healthy mom

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101
Q

what can cause thrombocytopenia (low platelet counts) in pregnancy?

A
  • physiological*
  • pre-eclampsia*
  • ITP (immune thrombocytopenia)*
  • microangiopathic syndromes
  • bone marrow failure
  • leukemia
  • hypersplenism
  • DIC
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102
Q

what is the pathophysiology of MAHA?

A

MAHA = microangiopathic hemolytic anemia. It is due to a deposition of platelets in small blood vessels leading to a thrombocytopenia and fragmentation/destruction of RBC within the vasculature. Ultimately, this leads to organ damage.

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103
Q

what do you see on the blood film of a pregnant woman with MAHA?

A
  • RBC fragments
  • low platelets
  • polychromasia
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104
Q

what tests are safe to perform in pregnancy for VTE exclusion?

A

-doppler safe
-V/Q safe
If indicated and necessary, CXR OK.
-d-dimer is NOT useful for the exclusion of thrombosis because it is often elevated in pregnancy

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105
Q

what factors increase the hypercoagulable state of the woman inducing an increased risk of thrombosis in pregnancy?

A
  • reduced venous return
  • changes in vessel wall
  • hyperemesis (dehydration)
  • obesity
  • pre-eclampsia
  • operative deliveries
  • inc. maternal age
  • previous VTEs
  • parity
  • multiple pregnancy
  • any pre-existing sickle cell diseae or nephrotic syndrome
  • IVF (risk of ovarian hyperstimulation)
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106
Q

what is treatment of VTE in pregnancy?

A
  • TED stockings
  • early mobilisation
  • maintain hydration
  • LMWH as for non-pregnant (because it does not cross placenta)
  • Do NOT convert to warfarin (crosses placenta)*
  • Stop for labour or planned delivery, esp. for epidural
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107
Q

what are the leading causes of mortality in pregnancy?

A
  • VTE
  • pre-eclampsia/eclampsia
  • ectopic pregnancies
  • hemorrhage
  • amniotic fluid embolism
  • genital tract sepsis
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108
Q

what is an amniotic fluid embolism and how does it present?

A

Sudden onset shivers, vomiting, shock –> DIC –> death

Usually in third trimester and presumed to be due to tissue factor in amniotic fluid

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109
Q

if mom is a carrier of hemoglobinopathy what are her further options?

A
  • test partner first.
  • Proceed
  • Prenatal diagnosis@ CVS sampling (10-12 weeks) or Amniocentesis (15-17 weeks)
  • cffDNA (fetal blood sampling)
  • Ultrasound screening for hydrops
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110
Q

what happens to a sickle cell mom in pregnancy?

A
  • HbSS (HbS clinically abnormal)
  • vaso-occlusive crises will become more frequent and anemia/chronic disease exaggerated
  • potential fetal complications: IUGR, miscarriage, pre term labor, VTE
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111
Q

how do we treat sickle cell moms in pregnancy?

A
  • RBC transfusions (top up/exchange/prophylactic)
  • alloimmunisation
  • extended phenotype for Group & Saves (RhD, RhC, RhE, Kell….)
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112
Q

what is a lymphoma?

A

a neoplastic malignant tumor of lymphoid cells usually found in LNs, lymphoid organs, skin, or ‘anywhere’ systemic

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113
Q

what are the known risk factors for lymphoma development?

A
  • constant antigenic stimulation
  • infection (direct viral of lymphocytes)
  • loss of T cell function (eg HIV)
114
Q

Chronic antigen stimulation may cause lymphoma. Which lymphoma is then associated with

a) H Pylori
b) Sjogren’s syndrome
c) Coeliac’s disease

A

a) Gastric MALT lymphoma
b) parotid lymphoma
c) small bowel T cell lymphoma EATL (enteropathy associated T cell lymphoma)

115
Q

what lymphoma is HTLV1 virus associated with?

A

Adult T-cell leukemia/lymphoma in the carribean & japan. Infects T cells by vertical transmission.

116
Q

what lymphoma is EBV infection associated with?

A

EBV infects B lymphocytes… carrier state… regulated by healthy T cells. Any form of future immunosuppression then causes B cell lymphomas.

117
Q

what are reed-sternberg cells diagnostic of?

A

classical hodgkin’s lymphoma

118
Q

what are the potential cells involved in non-hodgkin’s lymphoma development?

A

T cells or B cells from precursors or mature

119
Q

how do we classify hodgkin’s lymphoma?

A
  • nodular sclerosing (80%) with good prognosis
  • mixed cellularity (17%) with good prognosis
  • lymphocyte rich (good)
  • lymphocyte depleted (rare) with poor prognosis
120
Q

how do we stage Hodgkin’s lymphoma?

A
  • FDG/PET scan

- consider biopsy of other site if possibly infiltrated

121
Q

what are the stages of Hodgkin’s lymphoma?

A

I: one group of nodes
II: >1 group of nodes on same side of diaphragm
III: nodes above/below diaphragm
IV: extra nodal spread

Each stage then classified into A & B dependent on presence of ‘B symptoms’ - fever, weight loss, night sweats

122
Q

what is the chemotherapy treatment of Hodgkin’s lymphoma?

A

ABVD

A- adriamycin
B- bleomycin
C- vinblastine
D- DTIC

This is an effective treatment which still preserves fertility

123
Q

what is the treatment of Hodgkin’s lymphoma?

A

-chemotherapy (ABVD) 2-6 cycles

and/or RT

124
Q

what is non-hodgkin’s lymphoma?

A

a neoplastic proliferation of lymphoid cells originating in lymphoid tissue (LNs, bone marrow, spleen) that presents with B symptoms, compression symptoms, and painless lymphadenopathy

125
Q

what are the prognostic markers of non-hodgkin’s lymphoma?

A

LDH

performance status

126
Q

what are the aggressive subtypes of non-hodgkin’s lymphoma?

A
  • Burkitt’s
  • T or B cell lymphoblastic leukemia/lymphoma
  • diffuse large B cell lymphomas
  • mantle cell lymphomas
127
Q

what are the indolent/low grade potential non-hodgkin’s lymphomas?

A
  • follicular lymphoma
  • CLL
  • MALT
128
Q

what are the risk factors in diffuse large B cell lymphoma (DLBCL)?

A

age > 60 years
serum LDH > normal
stage III/IV
more than one extranodal site

129
Q

how do you treat diffuse large B cell lymphoma (DLBCL)?

A

-6-8 cycles of R-CHOP (Rituximab-CHOP)

A combination chemotherapy using a mixture of drugs: cyclophosphamide, adriamycin, vincristine, prednisolone

130
Q

what chromosomal translocation is follicular non-hodgkin’s lymphoma associated with?

A

t (14;18)

over expression of bcl2, an anti-apoptosis protein

131
Q

what score is used to stage/grade follicular non-hodgkin’s lymphoma?

A

FLIPI score

132
Q

how do you treat follicular non-hodgkin’s lymphoma?

A

It’s an indolent & slow progressing B-cell NHL so it is incurable. We ‘watch & wait’ and only treat if indicated (i.e. nodes compress bowel, ureter, vena cava, or massive and painful). The treatment is combination immuno-chemotherapy, maintenance rituximab. Not curative.

133
Q

what is a MALT lymphoma?

A

a marginal zone lymphoma (MZL) involving extranodal lymphoid tissue (similar to parotid lymphoma or thyroid lymphoma). It usually presents without B-symptoms, but with dyspepsia and epigastric pains.

134
Q

how is a gastric MALT lymphoma treated?

A

stage I : antibiotic sensitive; H Pylori eradicated –> omeprazole, clarithromycin, amoxicillin

  • repeat breath test after 2 months
  • repeat endoscopy every 6 months
135
Q

what are the lab findings in CLL?

A
  • lymphocytosis (5-300 x 10^9/L)
  • smear cells
  • normocytic normochromic anemia
  • thrombocytopenia
  • bone marrow lymphocytic replacement of normal marrow elements
136
Q

what are the prognostic factors we can use with CLL?

A
  • staging (Rai or Binet)
  • CD38 expression (bad)
  • FISH panel
  • IgH gene mutation status
137
Q

what are the clinical effects of having Malignant (non functional) mature B cells+ and dec. levels of IgG?

A

increased risk of infectoin

138
Q

what is the clinical effect of having proliferation of cells within the bone marrow (that maybe aren’t meant to be there)?

A

bone marrow failure

139
Q

what is the clinical effect of these malignant lymphoid cells circulating to nodes, spleen, through the blood?

A

Lymphadenopathy+/splenomegaly, lymphocytosis

140
Q

What is Richter’s syndrome?

A

the transformation of CLL to a high grade lymphoma. Treat it with CHOP-R as a high grade lymphoma

141
Q

what are the indications for treatment in leukemia?

A

‘Watch & wait unless….’

  • progressive lymphocytosis
  • progressive bone marrow failure
  • massive/progressive lymphadenopathy and splenomegaly
  • systemic B symptoms
  • autoimmune cytopenias
142
Q

what are the modern treatment options for CLL?

A 
chemo-immunotherapy
immunotherapy
BCR kinase inhibitors (eg Ibrutinib)
BCL2 inhibitors
allogenic SCT
143
Q

what is the difference between true (primary) polycythemia and secondary polycythemia?

A
  • primary polycythemia is a true and malignant one. Blood tests show a reduced EPO.
  • secondary polycythemia is a non-malignant effect from other causes. There is an elevated EPO, appropriately or inappropriately
144
Q

what is pseudopolycythemia?

A

this is a relative effect from other causes. While the plasma volume has decreased, no changes have occurred in red blood cell mass. This can be due to alcohol, obesity, or diuretics

145
Q

what are some causes of TRUE secondary polycythemia?

A

appropriately raised EPO: high altitude, hypoxic lung disease, cyanotic heart disease, high affinity Hb

inappropriately raised EPO: renal disease (cysts, tumors…), uterine myoma, or tumors in liver/lung

146
Q

what type of disorder is polycythemia?

A

myeloproliferative - along with primary myelofibrosis

147
Q

Hematological malignancies can come from lymph tissue, bone marrow, or blood. What are some types of myeloid malignancies?

A

Acute myeloid leukaemia (blasts >20%)
Myelodysplasia (blasts 5-19%)
Myeloproliferative disorders (thrombocythemia, polycythemia)
Chronic myeloid leukaemia (CML)

148
Q

what are the malignancies of mature hematological cells?

A

lymphoma - Hodgkin’s and NHL
multiple myeloma
CLL

149
Q

what type of malignancy is…

a) CML
b) ALL
c) CLL

A

a) myeloid
b) lymphoid - precursor cells
c) lymphoid - mature cells

150
Q

Tyrosine kinase mutation is important for the presence of hematological malignancies. What is tyrosine kinase normally and what happens when malignant?

A

Tyrosine kinases transmit cell growth signals from surface receptors to nucleus, and are activated by transferring phosphate groups to self and downstream proteins. They are normally held tightly in inactive state, to promote cell growth without blocking maturation.

A mutation leads to an expansion increase in mature/end cells: polycythaemia (RBCs), essential thrombocythaemia (platelets) or CML (granulocytes)

151
Q

what gene mutation is polycythemia vera associated with?

A

JAK2

152
Q

how does polycythemia vera present?

A

Usually incidentally on FBC findings. But symptoms include…

  • Headaches, light-headedness, stroke
  • Visual disturbances
  • Fatigue, dyspnoea
  • Aquagenic pruritus
  • Peptic ulceration
  • splenomegaly
  • thrombosis
  • retinal vein engorgement
  • gout (from increased RBC turnover & uric acid production)
  • red, painful extremities
153
Q

how do we treat polycythemia vera?

A
  • aim to reduce the viscosity as blood viscosity rises exponentially with rising Hematocrit
  • -> venesection and/or hydroxycarbamide (as maintenance cytoreductive therapy)

-consider also aspirin to reduce thrombosis risks

154
Q

what is essential thrombocythemia?

A

overproduction of platelets from a primary hematological source. Chronic nyeloproliferative neoplasia mainly involving megakaryocytic lineage

155
Q

how do we usually clinically find essential thrombocythemia?

A

often an incidental finding in patients with a lot of thromboses, bleeding (mucous/cutaneous), headaches, dizziness. Usually the splenomegaly is not too significant.

156
Q

how do we treat essential thrombocythemia?

A

1) Aspirin: to prevent thrombosis
2) Anagrelide: specific inhibition of platelet formation
3) Hydroxycarbamide: maintenance cytoreductive

157
Q

what is primary myelofibrosis?

A

A myeloproliferative disease with proliferation of cells, associated with a reactive bone marrow fibrosis and haematopoieisis outside medullas (too many cells in bone marrow and then fibrosis of it). It usually is actually a following effect developed from polycythemia vera (RBCs) or essential thrombocythemia (platelets)

158
Q

how do patients with primary myelofibrosis usually present?

A
  • Cytopenias: anaemia or thrombocytopenia
  • Thrombocytosis
  • Hepatosplenomegaly
  • Budd-Chiari syndrome
  • ‘B symptoms’
  • Hyperuricaemia
159
Q

how do we classify the stages of myelofibrosis?

A
  • prefibrotic stage –> hypercellular marrow

- fibrotic stage –> dry BM tap; prominent collagen fibrosis and then osteosclerosis

160
Q

what are the blood film results in primary myelofibrosis?

A
  • Tear drop poikilocytes
  • Giant platelets
  • Circulating megakaryocytes
161
Q

how do we treat primary myelofibrosis?

A

Symptomatic….

Treat the anemia with transfusions (though platelet often ineffective). As splenomegaly continues, a splenectomy can be considered but this often worsens the condition.
hydroxycarbamide can be used for cytoreductive purposes.
if there is a JAK2 mutation (good prognostic indicator) we can consider Ruxolotinib - a JAK2 inhibitor.

162
Q

how does CML (chronic myeloid luekemia) present in clinical findings?

A
  • often aged 40-60 years
  • B symptoms +lethargic
  • massive splenomegaly
  • anemic
  • bruising/bleeding
  • gout
  • may have had a preceding thrombotic event (i.e. monocular blindness CVA)

CML arises from an abnormal pluripotent bone marrow stem cell.

163
Q

what are the FBC and blood film findings in CML?

A
  • Hb normal/increased
  • platelets normal/increased
  • leucocytosis (dec. in leukocytes)

The blood film will show: Neutrophils and some myelocytes (not blasts if chronic phase), Basophilia, mature myeloid cells. Leucocytosis.

164
Q

without treatment, if somebody has CML - what is the natural progression of the disease?

A

There will be a progression from chronic phase to advanced phase. Advanced phase is further split into accelerated and then a blast crisis at the end of lifespan…

165
Q

what is the presenting feature of blood films in the chronic (first) phase of CML?

A

-can last from a few months to about 5-6 years
-5% or fewer of the cells in the blood and bone marrow
are blast cells

166
Q

what is the presenting feature of blood films in the accelerated phase of CML?

A

• Accelerated phase (usually lasts 6-12 months)
10-19% of the cells in the blood and bone
marrow are blast cells

167
Q

what is the presenting feature of blood films in the blast crisis (final) phase of CML?

A

• Blast crisis (usually lasts 3-6 months)
≥20% of the cells in the blood and bone
marrow are blast cells

168
Q

Often, CML is associated with a chromosomal translocation causing the mutation in tyrosine kinase which leads to CML development. Which translocation is this?

A

The t(9;22) translocation produces the Philadelphia (Ph) chromosome - BCR-ABL gene

169
Q

what is the best biological therapy for CML?

A

Since the pathogenesis often starts with the t(9;22) translocation leading to upregulated tyrosine kinase, we can battle it with tyrosine kinase inhibitors:
1st Generation Imatinib (Glivec)
2nd generation Dasatanib, and Nilotinib

170
Q

what is the process of a cell developing into an erythrocyte?

A

proerythroblast –> basophilic erythroblast –> erythroblast –> normoblast –> reticulocyte –> erythrocyte

171
Q

what is the process of a cell developing into a monocyte?

A

monoblast –> monocyte

172
Q

what is the process of a cell developing into a neutrophil?

A

myeloblast –> promyelocyte–> can become neutrophil, basophil, or eosinophil

173
Q

what is the process of a cell developing into a basophil?

A

myeloblast –> promyelocyte–> can become neutrophil, basophil, or eosinophil

174
Q

what is the process of a cell developing into an eosinophil?

A

myeloblast –> promyelocyte–> can become neutrophil, basophil, or eosinophil

175
Q

what is the process of a cell developing into a lymphocyte?

A

lymphoblast –> lymphocyte

176
Q

what is the process of a cell developing into a platelet?

A

megakaryoblast –> megakaryocyte –> platelet

177
Q

what is an autologous transplant?

A

transplant from self –> self

GF –> collect cells/freeze –> thaw, reinfuse, chemo

178
Q

when is an autologous transplant appropriate?

A 
solid tumors
acute luekemia
Myeloma
Lymphoma
Chronic lymphocytic leukaemia
179
Q

what is an allogenic transplant?

A

from another person who has been the ‘donor’ of their stem cells to the ‘patient’ who is also receiving high dose chemo/RT in order to accept the transplant

180
Q

when is an allogenic transplant appropriate treatment?

A 
Acute leukaemia
Chronic leukaemia
Myeloma
BM failure
Congenital immune
deficiencies
Lymphomas
181
Q

what is the pathophysiology of GvHD?

A

the donor cells recognize the patient’s/recipient’s cells as foreign and attack them. First, recipient APC cells are activated, then donor T cells, between the two this leads to cellular and inflammatory markers to go rampant and affect all major organs.

182
Q

what are risk factors for developing GvHD?

A 
Degree of HLA disparity
Recipient age
Conditioning regimen
R/D gender combination
Stem cell source
Disease phase
Viral infections
183
Q

It is much better to prevent prophylactically the development of GvHD than the treat it, though the therapies are basically the same. what is used in prevention?

A

Methotrexate
Corticosteroids
Cyclosporin A
T-cell depletion

184
Q

what is seen on a blood film when a patient has iron deficiency anemia?

A
  1. Pencil cells
    1. Anisocytosis
    2. Poilkilocytosis
    3. Hypochromic
185
Q

List some potential causes of pancytopenia (i.e. all cells low - Hb, WBC, platelets…)

A 
Aplastic anaemia
Leukemia
Infiltration e.g.Lymphoma, carcinoma 
Drugs e.g. chemotherapy
 B12/folate deficiency
186
Q

what are causes of a low platelet count?

A

NOT MAKING PLATELETS
- drugs e.g. chemotherapy, thiazides,
- bone marrow disorders e.g. leukemia, aplastic, myelodysplasia, myeloma, infiltration with carcinoma
PREMATURE DESTRUCTION OF PLTS
- ITP (auto-immune)
- Disseminated intravascular coagulation
- heparin

187
Q

what can cause low platelets and abnormal clotting?

A

DIC
Alcohol
Drugs
Leukemia

188
Q

what can cause polycythemia in the fetus or neonate?

A

Twin-to-twin transfusion
Intrauterine hypoxia
Placental insufficiency

189
Q

what can cause anemia in the fetus or neonate?

A

Twin-to-twin transfusion
Fetal-to-maternal transfusion
Parvovirus infection
Haemorrhage (from the cord or placenta)

190
Q

what type of hemoglobin is present in the fetus/neonate that is not present in adults and children?

A

HbF

191
Q

what is sickle cell disease?

A

a disorder of hemoglobin (HbS/HbC or HbSS homogenous) that causes sickling of RBCs when in a hypoxic state environment

192
Q

how does vascular obstruction happen in sickle cell anemia?

A

Red cells elongate to pass through capillary bed to post-capillary venule –> become adherent to epithelium –> obstruction –> sickle cells obstruct venule & retrograde capillary obstruction occurs

193
Q

why doesn’t sickle cell anemia present in neonates?

A

the presence of HbF still in the blood

194
Q

how do we pick up sickle cell anemia now in practice?

A

Guthrie spot test

195
Q

Sites of the vaso-occlusion in sickle cell patients varies with age. Where is most common in …

a) young children
b) older children

A

a) hand-foot syndrome

b) acute chest syndrome

196
Q

what is splenic sequestration in a sickle cell patient and when do we worry about it?

A

the acute pooling of a large percentage of circulating red cells in the spleen –> acute swelling of spleen & Hb drop –> shock/possibly death. This only happens in infants because they still have a functioning spleen.

197
Q

why doesn’t splenic sequestration occur in older children and adults who are sickle cell anemic?

A

mulitple vaso-occlusive crises have left their spleen small and fibrotic

198
Q

with the growth of a sickle cell anemia child - what do we begin to worry about? (think spleen)

A

as spleen becomes smaller & fibrotic - we would worry about the state of potential hyposplenism and future bacteremia (deprived immune system)

199
Q

why does folic acid matter more in sickle cell children?

A

1) Hyperplastic erythropoiesis requires folic acid
2) Growth spurts require folic acid
3) Red cell life span is shorter so anaemia can rapidly worsen

200
Q

how do we manage sickle cell anemia in the infant & child?

A
  • educate parents
  • vaccinate
  • folic acid
  • penicillin
201
Q

Beta thalassaemia is a condition resulting from reduced synthesis of beta globin chain and therefore haemoglobin A. When do you suspect it might present?

A

first 3-6 months of life

202
Q

How do we detect beta thalassemia in practice now?

A

Guthrie spot cards in neonates

203
Q

how is beta-thalassemia major (i.e. not trait) treated?

A 
blood transfusions 
iron chelation (desferroxamine) therapy to avoid iron overload
204
Q

what are the clinical manifestations of beta-thal major?

A
  • Anaemia (heart failure, growth retardation)
  • Erythropoietic drive but wrong Hb (bone expansion, hepatomegaly, splenomegaly)
  • Iron overload from transfusion (heart failure, gonadal failure)
205
Q

what are potential hemolytic anemias in children?

A
  • Hereditary spherocytosis
  • Hereditary elliptocytosis
  • Sickle cell anaemia
  • Pyruvate kinase deficiency
  • Pentose shunt defects
  • G6PD deficiency
206
Q

what characterizes the acquired autoimmune hemolytic anemia in children?

A
  • spherocytosis

- positive Coomb’s test (DAT)

207
Q

what is the characteristic presentation of hemolytic uremic syndrome in children?

A

-hemolysis
-uremia
Same as microangiopathic hemolytic anemia.

208
Q

what is microangiopathic hemolytic anemia (HUS)?

A

This is the same as HUS. microangiopathic haemolytic anaemia happens when the red cells are damaged in capillaries and are fragmented by the process. Small angular fragments and microspherocytes are formed

209
Q

what sort of differential diagnoses can you think of for hemophilia A & B?

A
  • Inherited thrombocytopenia or platelet functional defect
  • Acquired defects of coagulation, (e.g. autoimmune thrombocytopenic purpura, acute leukaemia)
  • Non-accidental injury
  • Henoch‒Schönlein purpura
210
Q

how is hemophilia A or B treated?

A
  • Counselling of family
  • Treatment of bleeding episodes
  • Use of prophylactic coagulation factors
  • Consideration of the child
211
Q

what is the difference in presentation between Hemophilia and Von Willebrand’s disease?

A

Hemophilia A and B are x-linked recessive inheritance so females rarely, if ever, present. Will see - Bleeding following circumcision, Haemarthroses/bruises, post-traumatic bleeding.

VWD is autosomal dominant inherited so men or woman might have it - presents also with bruises and post-traumatic bleeding but is usually more superficial bleeding (i.e. mucosal bleeding instead of hemarthroses)

212
Q

how do we treat Von Willebrand’s disease?

A

lower purity factor 8 concentrates

213
Q

what is autoimmune thrombocytopenic purpura and how does it present?

A
  • superficial bleeding
  • joint bleeding
  • Hb, WBC, Platelets all NORMAL, PT NORMAL, but aPTT is PROLONGED
  • petechiae & blood blisters in mouth
214
Q

how is autimmune TTP treated?

A
  • Observation
  • Corticosteroids
  • High dose intravenous immunoglobulin
  • Intravenous anti Rh D (if Rh-positive)
215
Q

what is acute leukemia?

A

a neoplastic condition characterized by rapid onset, bone marrow failure (anemia, neutropenia, thrombocytopenia) and immature blast cells

216
Q

what cells are involved in AML?

A

pluripotent & multipotent hematopoietic/myeloid stem cells
could also be granulocyte precursors

217
Q

what cells are involved in CML?

A

pluripotent hematopoietic stem cells

218
Q

what cells are involved in CLL?

A

B-cells

219
Q

what cells are involved in ALL?

A

B or T cell precurrs

220
Q

what prognostic indication is given by AML cells with t(8;21) translocation?

A

there is some cell differentiation & maturation - not all totally blast cells

221
Q

what is the difference between AML and APML?

A

two morphological variants of the same disease. In APML, there is an excess of abnormal promyelocytes, where as in AML there is an excess of pluripotent myeloid cells (APML a bit further on)

222
Q

what is the main translocation abnormality seen in APML?

A

t(15;17)

PML-RARA gene

223
Q

how do you know if somene is suffering from AML or ALL?

A

Cytological features
Cytochemistry
Immunophenotyping

224
Q

what is it in the cytology that implies a myeloid rather than lymphoid source (ie AML vs ALL)

A

granules and auer rods imply myeloid

225
Q

how is AML diagnosed from blood film?

A
  • Usually diagnostic: circulating blasts
  • Auer rods (proves myeloid)

“Aleukaemic” leukaemia (if no WBC in the blood film, need bone marrow aspirate)

226
Q

what is ALL?

A

acute lymphoblastic leukemia, the most common childhood malignancy

227
Q

how does ALL begin?

A

if T-cells –> from thymus (which may become enlarged)

if B cells –> from bone marrow (watch for bone marrow failure - anemia, neutropenia, thrombocytopenia)

228
Q

what are some signs that give good prognosis to those with ALL?

A
  • tyrosine kinase mutation

- hyperdiploidy

229
Q

when should you suspect leukemia?

A

In children – bone pain, limping, pallor, bruising, organomegaly
In adults – pallor, bruising, bleeding, infection, organomegaly

230
Q

what are the key presenting and pathological features of multiple myeloma?

A
  • monoclonal PCs immungolobulin
  • paraproteins
  • osteolytic lesions
  • anemia
  • infections
  • kidney failure
231
Q

what is mulitple myeloma?

A

cancer of transformed plasma cells( terminally differentiated B cells) that secrete immunoglobulin and are effector cells of humoral immune response

232
Q

what is MGUS?

A

the premalignant changes of multiple myeloma

‘monoclonal gammopathy of undetermined significance’

233
Q

how does multiple myeloma present clinically? (CRAB)

A
  • elevated calcium (C)
  • ARF (R)
  • fatigue (A-anemia)
  • back pain (B- bone lesions)
  • monoclonal gammopathy protein (Bence Jones protein)
234
Q

what is a key finding in the plasma cells of multiple myeloma?

A

CD138+

also positive for CD56/58 and light chain restricted

235
Q

why do we get bone disease in myeloma?

A

plsama cells encourage osteoclasts growth –> oteolytic lesion detected on x-ray skeletal surveys OR MRI/CT

236
Q

how does renal damage and ARF happen in mulitple myeloma?

A 
proximal tubular necrosis
Fanconi sundrome (rental tubular acidosis) from light chain secretion --> FLC light chain deposition. the high concentration of proteins block the tubules and can cause cast injuryn nephropathy.
237
Q

how do we treat multiple myeloma?

A

treatment in 4 parts

1) steroids
2) immunomodulatory drugs/IMIDs- eg. thalidomide
3) proteasome inhibitors
4) cytostatic drugs - old fashioned chemo (eg melphalan)

238
Q

which of the following is NOT a typical multiple myeloma characteristic?

a) anemia
b) splenomegaly
c) renal impairment
d) lytic bone disease

A

b)splenomegaly

239
Q

which of the following is a key histopathological myeloma marker?

a) CD19
b) CD138
c) surface Ig
d) CD20

A

b) CD138

240
Q

myeloma cells have a very well developed & extensive…

a) nucleus
b) mictochondrial mass
c) ER
d) cell membrane

A

c) ER

241
Q

spot diagnosis: 83 year old with no abnormal findings. Incidental FBC shows lymphocytosis with smear cells

a) ALL
b) CLL
c) HIV
d) mono
e) whooping cough

A

b) CLL

242
Q

spot diagnosis: a 67 year old woman with a red face. Smoker & renal disease. Her Hb, RBC, PCV, WBC, neutrophil, basophil, platelet counts all high

A

polycythemia vera

243
Q

what mutation confirms polycythemia vera where WBC, RBC, PCV all high?

A

JAK2 mutation

244
Q

spot diagnosis: a 64 year old spanish woman with splenomegaly, RBC and WBC increased. Leucocytosis on FBC with myelocytes and basophilia. She DOES NOT feel unwell.

a) CML
b) normal for age
c) reactive neutrophilia
d) lab error
e) AML

A

e) CML

particularly because of inc. basophils and splenomegaly

245
Q

spot diagnosis: north africa woman with 18 month old baby, Hb LOW but RBC HIGH. Low HCT, low MCV, high RDW. Film shows microctyic, hypochromic blood cells, some anisocytosis, some elongated red blood cells.

a) normal for north african
b) beta-thal major
c) lead poisoning
d) beta-thal trait
e) IDA

A

e) IDA

246
Q

what is the classical pentad of thrombotic thrombocytopenic purpura?

A
  • microangiopathic hemolytic anemia
  • thrombocytopenia
  • fever
  • neuro abnormalities
  • renal impairment
247
Q

what causes TTP?

A

autoimmune - lacking enzyme ADAMTS13, a enzyme that is a plasma protein -VWF cleaving protease. The low levels of protease lead to high levels of very large multimers of VWF (causing thrombi to form)

248
Q

how do we define hemolytic anemias?

A

Acquired vs Inherited

Intravascular (within circulation) vs extravascular (reticuloendothelial system)

249
Q

how long do RBCs usually survive?

A

Normal red cell life span 120 days

250
Q

what does Perl’s stain look for?

A

hepatic siderosis

251
Q

what lab investigations can be done for hereditary spherocytosis?

A
  • in vitro red cells show increased sensitivity to lysis in hypotonic saline (osmotic fragilty test)
  • Reduced binding of dye eosin-5-maleimide
  • vertical protein disorder in RBC membrane
  • AD inheritance
  • seen well on blood film
252
Q

what enzyme is missing in G6PD deficiency and what does this cause?

A

*glucose 6 phosphate dehydrogenase enzyme
Normally this enzyme catalyses first step in pentose phosphate(hexose monophosphate) pathway - generates NADPH required to maintain intracellular glutathione(GSH). Without it, acute hemolysis can be triggered by oxidants, infections (otherwise ok), and neonates will present with prolonged jaundice
*methylviolet staining shows HEINZ bodies

253
Q

what are first line investigations for suspected hemolytic anemia? (7)

A
  • Direct antiglobulin test
  • Urinary haemosiderin/haemoglobin
  • Osmotic fragility
  • G6PD +/- PK activity
  • Haemoglobin separation A and F% (electrophoresis)
  • Heinz body stain (methylviolet)
  • Thick and thin blood film
254
Q

splenectomy:
a) in what conditions might it be helpful?
b) what are indications
c) what is the biggest risk post-surgically?

A

a) PK deficiency; Hereditary spherocytosis; Severe elliptocytosis/pyropoikilocytosis; Thalassaemia syndromes; Auto immune haemolytic anaemia
b) Hb < 8, transfusion dependent, growth delayed (kids), hypersplenism, age 3-10 years
c) overwhelming sepsis esp. by encapsulated bacteria

255
Q

what role do Janus kinases play in hematopoietic development of myeloid cancers?

A

a family of tyrosine kinases associated with haemopoeitic cell growth factor receptors. Phosphorylation results in conformational changes associated with GFs –> activation of the STAT pathway –> –> cell proliferation.

JAK 2 is mainly implicated in myeloid cells

256
Q

List some chronic myeloproliferative disorders and explain how they differ from myelodysplasia or leukemia/lymphomas?

A

C-MPN disorders: polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis

Where as leukemia is (proliferative, not differentiated) myelofibrosis is (ineffective at both proliferating and differentiating). MPN - proliferating but also differentiated!

257
Q

A patient has raised hematocrit levels. How do we distinguish between types of polycythemia? (2 tests)

A
  • Jak2 mutation
  • EPO

If Jak2 positive: narrows down to PV or erythrocytosis (primary mutation)
If Jak2 negative: true or pseudopolycythemia dependent on EPO… True polycythemia either due to increased EPO or familial

258
Q

how does Chronic idiopathic myelofibrosis present?

A
  • cytopenia (anemia, thrombocytopenia)
  • splemogaly +/- Budd-Chiari syndrome
  • hepatomegaly
  • hypermetabolic state (weight loss, fatigue/dyspnea, night sweats, hyperuricemia)
259
Q

what hematological findings are there in myelofibrosis (regardless of cause)?

A
  • Leucoerythroblastic picture 
  • Tear drop poikilocytes
  • Giant platelets
  • Circulating megakaryocytes
  • Dry Tap on BM
260
Q

how do we treat myelofibrosis?

A
  • Anaemia
  • transfusions: may become increasingly difficult because of splenomegaly
  • Splenectomy for symptomatic relief
  • hydroxycarbamide for thrombocytosis
  • thalidomide +/- prednisolone may be helpful
261
Q

what are the two functions of the endothelium in vasculature?

A
  • Synthesis of PGI2, vWF, plasminogen activators, thrombomodulin
  • maintain barrier between blood and procoagulant subendothelial structures
262
Q

how does platelet adhesion work - which factors? (4)

A

G1pIB on platelet attaches to VWF or to collagen in basement membrane that has been disrupted by trauma/inflammation/etc. This releases ADP & thromboxane which in turn causes platelet aggregation with factors GIpIIB/IIIa on platelets adn fibrinogen/Ca2+ holding the aggregated platelets together.

263
Q

what is the role of thromboxane A2 and prostacyclin PGI2 in platelet aggregation on vessel walls?

A

arachidonic acid –> COX enzyme turns it into cyclic endoperoxides –> thromboxone A2 and prostacyclin PGI2.

Thromboxane A2 leads to platelet aggregation by exposing the GpIIB/IIIA factors.
Prostacyclin PGI2 leads to inhibition of platelet aggregation

264
Q

what is the role of thrombin in blood clot formation?

A
  • Cleaves Fibrinogen
  • Activates Platelets
  • Activates procofactors (FV and FVIII)
  • Activates zymogens (FVII, FXI and FXIII)
265
Q

what are the three phases of fibrin clot formation in the vessels and what happens in each of them?

A

1) initiation phase - injury of vessel walls leads to contact between blood/subendothelial cells… Tissue Factor binds clotting factors converted to F7a which activates F9a/10 and binds to cell surface
2) Amplification phase - F10a/5a convert prothrombin to thrombin which activates F8, F5, F6, platelets and the activated platelets bind further clotting factors
3) propogation phase - the existing complexes & activated platelets convert prothrombin –> thrombin in a ‘thrombin burst’ leading to formation of stable fibrin clot

266
Q

what happens in fibrinolysis?

A

plasminogen –> plasmin –> cuts fibrin into fibrin degradation products.

1) plasminogen activator tPA and factors 11a,12a all act to convert to plasmin
2) plasmin is controlled by TAFI (activated by thrombin; thrombin -activatable fibrinolysis INHIBITOR)

267
Q

what is the likely causative defect if bleeding is immediate & local vs delayed & deep?

A

Immediate, skin/membranes, petechiae – (Platelet)

Delayed, deep bruising, muscle/joint bleeding – (Coagulation)

268
Q

what is the mechanism of action for the following drugs:

a) Clopidogrel
b) Aspirin

A

a) Clopidogrel: irreversibly inhibiting the binding of ADP to its platelet membrane receptors. Inhibits the activation of the GPIIb/IIIa receptor, its binding to fibrinogen and further platelet aggregation.
b) Aspirin: inhibits the cyclo-oxygenase enzyme, reducing the production of prostaglandin and TXA2 from arachidonic acid. TXA2 activates the GPIIb/IIIa binding site on the platelet, allowing fibrinogen to bind

269
Q

List immune mediated (4) and non-immune mediated (2) cause of thrombocytopenia:

A

Immune-mediated: idiopathic (auto ITP), drugs, connective tissue disease, sarcoid

Non-immune mediated: DIC, MAHA

270
Q

what are presenting features of auto-ITP (immune thrombocytopenia) in children?

A
  • 2-6 years
  • commonly preceding infection
  • abrupt onset
  • 2-6 weeks duration
  • common spontaneous remission
271
Q

what are presenting features of auto-ITP (immune thrombocytopenia) in adults?

A
  • rarely preceding an infection
  • abrupt or indolent onset
  • long term issue
  • unlikely to go into spontaneous remission
272
Q

what is the initial treatment of autoimmune thrombocytopenia (ITP)? (bleeding or not bleeding in the presentation)

A

If not bleeding - steroids

if bleeding and <50k - IV Ig

273
Q

what are the aPTT and PT results in hemophilia (A or B)?

A

aPTT will be prolonged

PT will be normal

274
Q

what clotting factors & proteins are required for vitamin K production?

A

Factors II, VII, IX ,X Protein C, S and Z

275
Q

what events and disorders can trigger DIC (disseminated intravascular coagulation)?

A

Activation of BOTH coagulation & fibrinolysis… triggered by:

  • sepsis
  • trauma
  • malignancy
  • transplant rejection
  • toxins (eg snake venom)
  • vascular disorders
  • amniotic fluid embolism
  • abruptio placentae
276
Q

what is the mechanism of DIC (disseminated intravascular coagulation)?

A

Systemic coagulation activation leading to both intravascular fibrin deposition & depletion of platelets/clotting factors. This causes simultaneously thrombosis of small/midsize vessels and organs (from the former) and bleeding (from latter)

277
Q

Given that DIC is due to both clotting & fibrinolysis simultaneously, what are the bloods in this condition (aPTT, PT, Thrombin Time, Fibrinogen, Plasmin levels - FDP, Platelets)?

A 
aPTT - HIGH
PT - HIGH
Thrombin Time - HIGH 
Fibrinogen - LOW
FDP - HIGH
Platelets - LOW
278
Q

how do we treat DIC?

A
  • Treat cause (ALWAYS secondary)
  • Treat coagulation issue, fibrin: heparin
  • Treat lack of platelets and clotting factors: platelet transfusion +/- FFP
  • Supportive
279
Q

what chromosomal translocation is indicated in
A) CML
B) AML
C) APML

A

a) t(9;22) BCR-ABL gene (Phildelphia chromosome)
B) t(8;21) RUNX1 gene
C) t(15;17) PML-RARA gene

280
Q

what is the defining blood feature of CML?

A

Myeloproliferative disorder where large numbers of differentiated neutrophils (and eosinophils and basophils) are present in the peripheral blood plus excess of myelocytes

281
Q

what are the three layers of atheromatous plaque?

A
  • raised lesion
  • soft lipid core
  • white fibrous cap
282
Q

what does thromboxane A2 do in the clotting cascade?

A

thromboxane A2 which potentiate platelet release reactions, platelet aggregation and also has powerful vasoconstrictive ability.

Julija's Path (6 decks)

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