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Year 3 > Week 3 Haematology > Flashcards

Week 3 Haematology Flashcards

1
Q

Site of Haemopoiesis

A

Site: red marrow inside bone marrow of long bones

First few weeks of gestation: yolk sac

From 6 weeks to 6 months of feotal life: liver and spleen are main sites

After 6 months: bone marrow

In child and adult, bone marrow is only site:

  • During childhood, marrow is replaced by fat.
  • In adults, haemopoiesis only occurs in central skeleton and proximal ends of femur
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2
Q

Haemopoietic stem cell characteristics

A

Self renew

Unspecialised

Can differentiate

Rare (not many in bone marrow)

Quiescent (sometimes undergoes cell division)

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3
Q

Where are Haemopoietic stem cells found?

A

Bone marrow

Peripheral blood after G-CSF (granulocyte colony stimulating factor)

Umbilical cord

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4
Q

Haemopoietic stem cell fate

A

Self renew

Differentiate

Apoptosis

Stem cell fate influenced by micro-environmental signals (niche) and internal cues

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5
Q

Appreciate importance of bone marrow microenvironment

A

Bone marrow is composed of stromal cells and a microvascular network.

Stroma (bone marrow microenvironment) supports growth and development of stem cells

Stromal cells: macrophages, fibroblasts, fat cells, reticulum cells

  • Display adhesion molecules to keep developing cells in bone marrow
  • Supported by an extracellular matrix
  • They secrete extracellular molecules e.g. collagen, fibronectin, proteoglycans
  • Secrete adhesion molecules and growth factors

Bone marrow architecture: the stromal layer, the glycoproteins and extracellular matrix

Two types of bone marrow:

Red (erthrocytes) and yellow (fat cells)

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6
Q

Conditions that impair bone marrow function

A

Hereditary: Fanconi syndrome,. Sickle cell anaemia

Acquired: Leukaemia, Myelodysplasia Myeloproliferative disorders

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7
Q

Stages of leukaemogenesis (development of leukaemia)

A

Neoplastic cell is a haemopoietic stem cell, or early myeloid or lymphoid cell

The healthy haemopoietic stem cell is hit by event e.g. virus leading to mutations

This cell self renews and generate leukaemic cells

Leads to dysregulation of cell growth and differentiation

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8
Q

Develop basic understanding of clonal disorders of haemopoietic stem cells

A

Haematological malignancies and pre-malignant conditions are termed “clonal” if they arise from a single ancestral cell

Overproduction: Myeloproliferative disorders e.g. Polycythaemia rubra vera, Essential thrombocytosis

Abnormal stem cells: Leukaemia, Myelodysplasia e.g. refractory anaemia with excess blasts

Underproduction: Aplastic anaemia e.g. Fanconi’s anaemia

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9
Q

Myeloproliferative disorders

A

Clonal disorders of haemopoiesis leading to increased numbers of one or more mature blood progeny

  • Can transform into acute myeloid leukaemia (cancer, which bone marrow makes abnormal myeloblasts)
  • Associated with JAK2 and calreticulin mutation

Essential thromocytosis, polycythaemia ruba vera (too many red cells, myelofibrosis (BM filled with fibrous tissue)

Essential thrombocytosis: Overproduction of platelets (thrombocytes)

50% cases due to mutation of JAK2

50% cases due mutation of calreticulin mutation

Clinical features:

  • Thrombotic or haemorrhagic complications (as platelets don’t clot, or clot too well)
  • Splenomegaly
  • Can become polycythaemia rubra vera (too many RBCs produced)
  • leukaemic transformation in around 3%

Treatments:

Low risk group (under 40, no high risk features e.g. cardiac conditions, diabetes, previous thrombosis): aspirin or anti-platelet agent

Medium risk group (40-60, no high risk features): aspirin, hydroxycarbamide (low dose chemotherapy)

High risk group (over 60, or high risk feature): 1st line: Aspirin + hydroxycarbamide (ribonucleotide reductase inhibitor causing reduced deoxyribonucleotides)

2nd line: aspirin + anagrelide (inhibits megakaryocyte differentiation)

IFN-a: useful in managing ET in pregnancy

Bulsulphan, 32P (associated with increased risk of leukaemogenesis (development of leukaemia)

Jax2 inhibitor e.g. ruxolitinib (inhibits Jak1 and 2, 70% pts have reduced splenomegaly, functional improvement). However can cause thrombocytopenia (low platelets)

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10
Q

Abnormal cells produced: Myelodysplasia, leukaemia (example – Refractory anaemia with excess blasts)

A

Myelodysplastic syndromes:

Group of cancers characterised by dysplasia, ineffective haemopoiesis leading to cytopenias (impaired blood cell production)

  • May have increased myeloblasts (normally lead to production of granulocytes)
  • Associated with cytogenetic abnormalities e.g. trisomy 8
  • Most characterised by bone marrow failure

Includes refractory anaemia with excess blasts and refractory anaemia with ring sideroblasts

High and low risk characterised by proportion of blast cells

Refractory anaemia with excess blasts:

  • constitute 40% of MDS cases
  • Multilineage dysplasia and increased myeloblasts
  • Chance of progressing to acute myeloid leukaemia

Clinical features:

  • fatigue, infections, bleeding (due to anaemia, neutropenia, thromobocytopenia)
  • mostly elderly
  • IPSS (international prognostic scoring system) based on:
  • BM blasts
  • Karyotype
  • Cytopenias

Treatment: Blood and platelet transfusion

Iron chelation in younger pts

Growth factors - erythropoietin, G-CSF (granulocyte colony stimulating factor)

Low dose chemo e.g. Hydroxycarbamide

Demethylating agents e.g. azacytidine

Intensive chemo

Allogenic stem cell transplantation

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11
Q

Fanconi anaemia

A

Autosomal recessive inheritance

Bone marrow failure

20% of anaplastic anaemia cases (anaplastc anaemia - decreased haemopoietic stem cells in BM - leading to pancytopenia and low reticulocytes)

Characteristics:

  • Bone marrow failure (so defective haemopoiesis)
  • Short telomeres
  • Malignancy (increased risk of AML)

Clinical features: Microphtalmia (small eyes), GI/GU malformations, Mental retardation

Fanconia anaemia mutations leads to alteration in DNA damage response (FA-BRCA pathway) leads to:

  • abnormalities in MAPK, TNFa
  • abnormal oxidative stress response

Leads to genomic instability, altered cell checkpoints and survival

Leads to formation of FA cancer cell

Main cause mortality is premature bone marrow failure

Gold standard therapy: allogenic stem cell transplant

Other treatments: Corticosteroids, androgens

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12
Q

Understand basic concepts of stem cell mobilisation and stem cell transplant

A

Autologous transplant: Patient’s own blood stem cells

Allogenic transplant: Donor’s blood stem cells

Types of donor:

Syngeneic Transplant - transplant between identical twins

Allogeneic sibling - HLA identical

Haplotype identical - half matched family member e.g. parent, half matched sibling

Volunteer unrelated (VUD)

Umbilical cord blood

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13
Q

Autologous transplant

A
  1. Collection - Pts receive Granulocyte colony stimulating factor +/- chemotherapy to make stem cells leave bone marrow so they can be collected
  2. Processing - Blood/bone marrow is processed to purify and concentrate stem cells
  3. Cryoperservation - Blood/bone marrow is frozen
  4. Chemotherapy - High dose chemo given to pt
  5. Reinfusion - Stem cells reinfused into patient

Can be used in pts with Hodgkin’s disease, non Hodgkins lymphoma, myeloma Almost all autografts use mobilised peripheral blood stem cells harvested by apheresis

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14
Q

Allogenic transplant

A

Peripheral blood stem cells, bone marrow, umbilical cord

Indications: acute and chronic leukaemias, relapsed lymphoma, aplastic anaemia

In malignant disease, has benefit of graft versus leukaemia effect as well as high dose chemo. However also has graft versus host disease.

Myeloablative regime: Pt has very high dose of chemo and high dose radiotherapy then transplant is given

Non myeloablative regime: Low-dose, less toxic regime. Provides immunosupressants to allow cells to engraft, but allows graft versus leukaemia to eradicate tumor

Donor lymphocyte infusion: T-cells from original bone marrow induces a graft versus leukaemia effect.

Prevents or treats relapse after SCT

High rate of graft versus host disease

Umbilical cord transplant:

Collected from umbilical cord and placenta

Advantages: more rapidly available than VUD (volunteer unrelated donor), less rigorous matching as immune system is naive

Disadvantages: small amount (adults need double transplant), slower engraftment, cannot use DLI if relapse occurs

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15
Q

Graft versus host disease

A
  • Occurs in pts with allogenic transplant
  • Donor’s immune system recognises host cells as foreign and attacks them -

Manifests as skin rash, jaundice or diarrhoea

2 forms: acute (occurs within 100 days of transplant) and chronic (occurs after 100 days of transplant)

GvHD treated with immunosuppressants e.g. cyclosporin

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16
Q

Graft versus leukaemia

A

Same cells which cause GvHD also attack leukaemia cells

GvL effective, especially in pts have been difficult to maintain remission

Minimising GvHD also minimises GvL thus causing increased risk of relapse

No GvHD in autologous transplant, so no GvL which causes increased risk in relapse

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17
Q

Problems in stem cell transplant

A

Limited donors available (upper age limit <65)

Mortality 10%-50%

GvHD

Immunosuppression required (1-2 years)

Infertility

Risk of cataract formation, hypothyroidism, osteoporosis

Relapse

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18
Q

To describe the requirements for normal red cell production

A

Erythropoietin Iron, B12, folate, minerals

Functioning bone marrow

Iron Transported by transferrin (glycoprotein made in liver) which transports iron to all tissues, erythroblasts, hepatocytes, muscle

  1. binding domains 30% saturated with Fe
    - Iron ingested Fe3+ converted to Fe2+ by duodenal cytochrome B
    - Iron enters enterocyte by divalent metal transporter type I
    - Stored as ferritin
    - Exits enterocyte through ferroportin (and hepcidin) Fe2+ converted to Fe3+
    - Transported round body by binding to transferrin
    - Old RBCs are removed by macrophages of RES
    - Stored as ferritin in macrophages
    - Hepcidin reduces levels of iron plasma.

Degrades ferroportin, reducing iron absorption and decreases release from RES.

Hereditary haemochromotosis - loss of hepcidin

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19
Q

Iron deficiency anaemia

A

Commonest anaemia in world

Gradual onset

Hypochromic and microcytic RBCs

Less iron ( and more transferrin produced to compensate)

  1. Low serum ferritin indicates low RES stores

Development of IDA

Latent iron deficiency: Serum ferritin: low, RES iron stores: low, Hb: normal

Serum ferritin: low, RES iron stores: low, Hb: low (IDA)

  1. Ferritin (acute phase protein) In presence of tissue inflammation (e.g. RA, IBD), IDA can occur with normal serum ferritin

Clinical features:

Koilonychia

Angular stomatitis

Atrophic Glossitis (pale, smooth, painless tongue)

Oesophageal web (Plummer vinson syndrome)

Causes:

Dietary

Blood loss

Malabsorption e.g. coeliac IDA in men and post menopausal women due to GI blood loss until proven otherwise

Treatment

Iron replacement: Ferrous sulphate

Ferrous gluconate IV iron (for oral intolerance, compliance, renal anaemia)

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20
Q

Anaemia of chronic disease

A

Failure of iron utilisation

Iron trapped in RES

Causes: Infection, Inflammation (kidney disease, rheumatologic, autoimmunity), Neoplasia

Anaemia of CRF (chronic renal failure) = ACD + low EPO

Lab values: Normochromic/normocytic or hypochromic/hypocytic

ESR (non specific marker for inflammation): increased

Ferritin: N or increased

Iron: low

TIBC (total iron binding capacity): low

When ESR raised, can show RBC roleaux (aggregrations)

Causes: - RES iron blockade, iron trapped in macrophages and not getting to erythrocytes, raised levels hepcidin

  • Reduced EPO response
  • Depressed marrow activity e.g. cytokine marrow depression

Treatment: Treat underlying disorder

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21
Q

B12/Folate

A

Essential for DNA synthesis and nuclear maturation

Required for all dividing cells, deficiency noted first in RBCs

Deficiency causes megaloblastic anaemia

B12

Dietary sources: Meat, dairy products

Absorption: B12 ingested

Gatsric parietal cells produce intrinsic factor

Intrinsic factor binds to B12

Intrinsic factor-B12 complex binds to cubulin (specific receptor in ileum)

B12 absorbed in blood and binds to transcobalamin

Stores: 3-4 years

Folate

Dietary sources: green veg

Absorption in SI

Stores: few days only

  • Lack of B12 can lead to folate deficiency due to “methyl trap”

Lack of B12 leads to lack of methionine production.

  • Leads to disparity in rate of synthesis of DNA precursors
  • Leads to fragile DNA, abnormal cell division
  • Ineffective erythropoiesis
  • death of mature cells still in marrow
  • Raised billirubin, raised LDH
  • Affects all rapidly growing, DNA synthesising cells esp. bone marrow, epithelial surfaces - mouth, stomach, small intestine

Clinical features: - Megaloblastic anaemia (abnormal, immature precursors of RBCs), jaundice (raised bilirubin), CNS symptoms, demyelination SC tracts

  • Neural tube defects in fetus

Symptoms and signs:

  • Tired (macrocytic/megaloblastic anaemia)
  • Easy bruising
  • Mild jaundice “lemon yellow tint” (raised bilirubin)
  • Neurological problems e.g. subacute combined degeneration of SC (due to B12 deficiency)

Causes of B12 deficiency:

  • Dietary - no B12 intake
  • Pernicious anaemia (auto immune condition - antibodies target gastric parietal cells so intrinsic factor not produced)
  • Problem in terminal ileum e.g. Chron’s, resection

Causes of folate deficiency:

  • Dietary
  • Extensive small bowel disease e.g. Chron’s
  • Increased cell turnover e.g. pregnancy
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22
Q

Causes of macrocytosis

A

B12/folate deficiency

Reticulocytosis

Cell wall abnormality e.g. alcohol, liver disease, hypothyroidism

With anaemia: bone marrow failure syndromes

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23
Q

Haemolytic anaemia

A

Anaemia related to reduced RBC lifespan

No blood loss or haematinic deficiency

Haematology:

20-100d: Hb normal, increased reticulocytes, increased UB (compensated haemolytic state)

<20d: decreaed Hb, increased reticulocytes, increased UB, splenomegaly (haemolytic anaemia)

2 types:

Congenital haemolytic anaemia

Acquired haemolytic anaemia

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24
Q

Abnormal RBC destruction: Intravasuclar vs Extravascular haemolysis

A

Intravasuclar haemolysis: destruction in general circulation

  • mechanical trauma to red cell (red cell fragmentation syndromes
  • ABO incompatible transfusion
  • malaria
  • cold IgM autoantibodies (cold autoantibodies cause RBCs to aggluitnate to blood film)

Lab findings:

Anaemia, reticulocytosis, raised UB

Haemoglobinuria (due to excess Hb in plasma filtered at glomerulus)

Haemosiderinuria (Hb broken down in haemosiderin which appears in urine)

Extravascular: destruction in RES system of spleen, liver, BM

  • Warm (incomplete) antibodies (IgG). IgG attaches to red cell antigen and damages RBC membrane. Becomes spherocytic and phagocytosed by RES, esp. spleen, causing it to enlarge.
  • Positive direct antiglobulin test detects presence of antibodies on RBC surface
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25
Q

Acquired haemolytic anaemia

A
  1. Autoimmnune
    - Warm type (IgG)
    - Cold type (IgM)
  2. Isoimmune (antibodies from something else .e.g mother) - haemolytic disease of newborn
  3. Non-immune - fragmentation haemolysis
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26
Q

Cold AIHA (autoimmune haemolytic anaemia)

A

IgM autoantibodies bind to RBC membrane, leading to its destruction

Causes:

Primary (idiopathic)

Secondary: Mycoplasma pneumoniae, infectious mononucleosis (glandular fever), lymphoproliferative disorders

Clinical features:

painful fingers/toes assoc with cold exposure

Treatment:

Mycoplasma - self limiting

Keep warm

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27
Q

Warm AIHA (autoimmune haemolytic anaemia)

A

Autoantibody IgG attaches to RBC membrane, causing destruction.

Damaged RBCs become spherocytic (RBCs round, rather than biconcave, no central pallor, smaller) and polychromatic. Phagocytosed by RES, esp. spleen, causing enlargement

Causes:

Idiopathic

Lymphoproliferative disorders - CLL, Non Hodgkin’s lymphoma

Drugs e.g. cephalosporins

SLE

Management:

Corticosteroids - Prednisolone

Folic acid

Blood transfusion

Splenectomy

Risks of splenectomy: increase risk of Strep. pneumoniae, Haemophilus Influenzae, Neisseria Meningitidis causing overwhelming post splenectomy infections

  • Penicillin prophylaxis required
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28
Q

Direct Coombs Test

A

Detects antibody on RBC surface

Anti-IgG added to patient’s RBCs

Agglutination occurs, if there are RBCs are coated with IgG antibodies, present

Postive - AIHA, HDN (haemolytic disease of newborn. IgG antibodies produced by mother, target antigens on RBCs of fetus)

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29
Q

Indirect Coombs Test

A

Detect antibodies in serum

Anti-IgG and test RBCs mixed with pt’s serum. Agglutination occurs if serum antibodies present

Blood transfusion - antibody screening, cross-matching

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30
Q

Myelofibrosis

A

Myeloproliferative disorder

BM filled with fibrous tissue

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31
Q

Congenital haemolytic anaemia

A

1. Abnormalities of RBC membrane

Hereditary spherocytosis

  • AD, RBCs are spherocytic and polychromatic (increased reticulocytes)

Jaundice

Splenomegaly

2. Haemoglobinopathies

3. Abnormalities in RBC enzymes

Pyruvate kianse deficiency anaemia

  • AR, extravasuclar haemolysis, ATP depletion

Glucose 6 phosphate dehydrogenase deficiency:

  • X-linked recessive, acute episodic intravascular haemolysis
  • acute haemolysis from oxidative stress e.g. drugs - anti-malarials
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32
Q

Causes of Microcytic and Hypchromic RBCs

A

IDA

Thalassaemia

ACD

Siderblastic anaemia

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33
Q

Haemoglobinopathies

A

Inherited conditions where there is a lack of globin chains due to absent genes (thalassaemias) or abnormal globin chain (sickle cell)

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34
Q

Normal Hb production

A

Globin chains produced on ribosomes

Adult Hb (HbA) made up of 2 alpha and 2 beta chains

  • 4 alpha globin genes (chromosome 16) and 2 beta globin genes (chromosome 11)

Feotal Hb (Hb F) made up of 2 alphas and 2 gammas

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35
Q

Beta thalassaemia

A

Beta thalassaemia major (missing 2 genes)

  • unable to make adult Hb
  • significant dyserythropoiesis

Clinical features:

Maxillary prominence

Skulls thicker

Enlarged spleen

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36
Q

Thalassaemias

A

Relative lack of globin genes

Normally 4 alpha and 2 beta globin genes

Alpha thalassaemias:

A+thal trait (missing one gene): mild microcytosis

Homozygous a+ thal trait (missing two): mild microcytosis, mild anaemia

HbH disease (missing 3): significant anaemia, abnormal shaped RBCs

Alpha thal major (missing 4): incompatible with life

Treatment:

Transfusion

Iron chelators - as iron overload major cause of mortality

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37
Q

HbH disease

A

Missing 3 alpha genes

As there is not enough alpha globin chains, causes excess beta globin chains

Beta chains join up together becoming a tetramer (HbH)

Blood transfusion required during stress

38
Q

Haemaglobinopathies: Hb variants

A

Includes Sickle cell disease, Hb C, D, E

Sickle cell pathogenesis:

Point mutation on beta globin chain (glutamine to valine) at position 6 leads to:

  • RBCs becoming rigid, and occluding blood vessels leading to tissue infarction
  • RBCs have reduced life span (10d)

Clinical features:

Brain - stroke, moya moya

Lungs - pulmonary hypertesnsion

Urogenital - priapism (maintain erection)

Management:

Hydration, analgesia, prophylactic vaccinations, O2, fluids, blood transfusion

39
Q
A
40
Q

What happens when you cut yourself?

A

Blood vessel damage, disrupts endothelium

Exposure of tissue factor and collagen

Primary haemostasis (platelets recriuted)

Secondary haemostasis (coagulation factors activated)

41
Q

Haemostasis

A

Primary haemostasis:

When endothelium damaged, exposes collagen and tissue factor

Platelets have receptors (GPIb) which bind to von Willebrand factor allowing platelets to adhere to vessel wall

Platelets release granular contents (ADP, thromboxane A2)

ADP allows expression of GPIIb/IIIa on platelets, which allows them to aggregrate with each other, and with fibrinogen, forms a weak platelet plug

Phospholipid is exposed on surface of platelets

Secondary haemostasis

Coagulation cascade is activated

Events:

Intiation - extrinsic pathway (due to TF)

Propagation - instrinsic pathway (due to subenothlelial collagen)

Thrombin generated, converts fibrinogen to fibrin, which is cross-linked to form stable platelet plug.

42
Q

Coagulation cascade

A

Intrinsic pathway (PTT)

Subendothelial collagen

Factor 12, 11, 9, 8

Extrinsic pathway (PT)

Tissue factor

Factor 7

Common:

10, 5, 2 (thrombin), 1 (fibrin)

Factor 10, 5, 2 (prothrombin complex)

Factor XIIIa (13a) allows crosslinking of fibrin

Every step requires phospholipid and Ca2+

43
Q

Coagulation cascade: regulation

A
  • Tissue factor pathway inhibitor: inhibits TF and Xa
  • Thrombomodulin activates protein C to APC (activated protein C)

Protein C and Protein S inactivate factor V + VIII (5, 8)

Antithrombin inactivates factor 7, 5, 2,

44
Q

Coagulation cascade: fibrinolysos

A

As fibrin made, stimulates uPA and tPA which activates plasminogen to plasmin

Plasmin breaks down fibrin to fibrin degradation products e.g. D-dimer

a2-antiplasmin: regulates plasmin production

Plasminogen activator inhibitors: inhibits uPA and tPA

TAFI (thrombin activateable fibrinolysis inhibitor): inhibits uPA and tPA, reduces breakdown of fibrin

45
Q

Lab analysis of coagulation

A

Assess primary haemostasis

in vivo: bleeding time

ex vivo: FBC (platelet count), platelet function (assessed by light transmission aggregometry)

Assess secondary haemostasis:

Prothrombin time (PT)

Activated partial thromboplastin time (APTT)

Thrombin clotting time (TCT)

46
Q

Coagulation test

A

Take sample of blood, place in citrate tube (chelates Ca2+, stopping blood from clotting)

Cetrifuged creating platelet poor plasma

Ca2+ added to PPP

Clot forms

How long clot formed measured)

Prothrombin time - extrinsic pathway and common (1.0-1.2)

depends on:

  • Factors VII

Factors X, V, II and fibrinogen

INR (international normalised ratio) - standardised form of PT

Activated partial thromboplastin time - intrinsic pathway

depends on:

  • Factors XII, XI, IX, VIII
  • Factors X, V, II and fibrinogen

Thrombin clotting time (TCT): measures conversion of fibrinogen to fibrin

Depends on:

  • How much fibrinogen present
  • How well fibrinogen functions

Prolonged by:

Thrombin inhibitors (heparin)

Inhibitors of fibrin polymerisation (paraproteins)

47
Q

Anti-thrombotic agents

A

Anti-coagulants - inhibit coagulation factor

Anti-platelets - inhibits platelet aggregration

Fibrinolytic agents - Enhances lysis of fibrin clot

48
Q

Anti-coagulation agents

A

Inhbits formtion of fibrin clot

Heparin - inhibits Xa, thrombin (IIa)

Warfain - Vit K antagonist, inhibits II, VII, VIII, X

DOACs:

Dabigatran - inhibits thrombin (IIa)

Apixaban, edoxaban - inhibits Xa

49
Q

Heparin

A

Enhances activity of antithrombin

Anti-IIa and anti-Xa activity

Doesn’t cross placenta

Given parenterally

LMWH has superior pharmacokinetic profile, side effect profile, can be used in out-patients (as doesn’t need monitoring)

But more expensive

Not readily reverisble (UF can be reversed by protamine)

Indications:

Immediate, short acting effect

Acute DVT, PE (LMWH)

Cardiac bypass (UFH)

50
Q

Warfarin

A

Inhibits Vit K oxide reductase, inhbitiing Vit K

Inhibits II, VII, VIII, X

Delayed onset/offset (takes 5-7 days for steady state - full anticoagulable effet)

Narrow therapeutic window

Requires INR monitoring

Indications:

AF, Acute DVT, PE, prosthetic heart valve

NOT for immediate anti-coagulation

51
Q

DOACs

A

Dabigatran: inhibits IIa (thrombin, preventing conversion of fibrinogen to fibrin)

Apixababn, edoxaban: inhibits Xa (prevents conversion of prothrombin to thrombin)

Indications: prophylaxis venous thromboembolism

Don’t require monitoring

Contra-indications: pregnancy, breast feeding, liver disease, drugs (CYP3A4 inhibitors)

Warfarin vs DOACs

Warfarin: slow onset/offset

dosing are individualised

INR monitoring

Many food, drug interactions

Renal impairment may increase bleeding risk

Rapid reversal with Vit K

DOACs: rapid onset offset

dosing based on CrCl

annual monitoring

Few food, drug interactions

Renal impairment contra-indicated

No rapid reversing

52
Q

Fibrinolytic drugs

A

Enhances lysis of fibrin clot

2 classes:

Kinases e.g. Urokinase

Tissue plasminogen activators: Tenecteplase

53
Q

Kinases

A

Streptokinase, Urokinase

Binds to plasminogen - increases plasmin and directly increases breakdown on fibrin clot

  • Causes fibrinolysis and fibringenolysis

Streptokinase:

  • Made from streptococci bacteria
  • Antigenic: can cross react with anti-streptococcal antibodies

Urokinase:

  • Made from renal cells in culture so not antigenic

Indications: MI

Problems: significant bleeding risk, streptokinase antigenic

54
Q

Tissue plasminogen activators

A

Tenecteplase, Alteplase

Activates plasminogen

Selective for clot bound plasminogen, so minimal unwanted fibrinolysis effects

Tenecteplase: short half life

Indications

  • MI
  • Ischaemic stroke (alteplase)

PE with haemodynamic instability (alteplase)

Side effects:

Risk of haemorrhage

Contra-indications

Haemorrhagic stroke

Major trauma

55
Q

Catheter directed thrombolysis

A

Catheter passes through to site and fibrinolytic drugs infused

Pros:

Smaller doses

Less systemic effects

Uses:

Acute limb ischaemia

DVT

56
Q

Anti-platelet drugs

A

Inhibits platelet activation, platelet aggregration

Clopidogrel - irreversibly blocks ADP mediated platelet aggregration

  • decreases expression of GPIIb/IIIa receptors leading to reduced binding of fibrinogen

Abciximab - monoclonal antibodies which antagonise GPIIb/IIIa. Causes reduced platelet aggregration, and binding of fibrinogen

Aspirin - irreversibly binds to cyclooxygenase (blocks conversion of arachidonic acid to thromboxane A2) leading to decrease platelet activation

Phosphodiesterase inhibitor III e.g. Dipyridamole - Increased platelet conc of cAMP, decreased responsiveness to ADP leading to decrease platelet aggregration

Thromboxane synthetase inhibitors (Picotamide)

Thromboxane receptor blockers (Ifetroban)

Indications:

Cardiovascular disease

Acute MI - aspirin, clopidogrel (up to 12 months)

Cerebrovascular disease (no AF)

Acute stroke (clopidogrel)

57
Q

Disseminated intravascular coagulation

A

Pathological activation coagulation cascade

Formation of micro-thrombi leading to ischaemia, infarction, and organ failure

Depletion of coagulation factors leading to bleeding

Causes:

  • sepsis e.g. meningococcal septicaemia due to nisseria meningitidis)
  • malignancy e.g. acute promyelocytic leukaemia
  • severe trauma
  • pre eclampsia

Symptoms: Multiple bleeding sites, petechiae, bruising of skin

Investigations

FBC+film, platelets (reduced), RBC fragmentation

Coagulation: PT (prolonged), APTT(prolonged)

D-dimer (increased)

Management:

Treat underlying case

Fresh frozen plasma+/- platelets

Heparin

Anti-thrombin concentrate

58
Q

What to do if INR too high?

A

Stop warfarin, reduce dose

Give Vit K

Give coagulation factors (II, XII, XIII X)

59
Q

How does liver disease cause coagulopathy (impaired ability to form clots)?

A

Poor coagulation factor synthesis (as liver produces coagulation factors)

Vit K deficient (which leads to deficient factors (2, 7, 9, 10)

Poor clearence of activated coagulation factors

DIC

60
Q

Haemophilia

A

Haemophilia A: Factor VIII deficiency

Haemophilia B: Factor VIIII deficiency

X-linked

Prolonged APTT (as factor 8 and 9 due to intrinsic pathway)

PT normal (extrinsic pathway)

Treatments:

Education

Desmopressin

Replacement therapy - FFP

61
Q

Von Willebrand disease

A

AD

Most common anti-coagulation disorder

Reduced vWF

+/- reduced platelet aggregration

reduced VIII (as vWF binds to VIII and prolongs its half life)

Mucosal type bleeding pattern

Clinical features: epistaxis (nose bleed), mennorhagia, GI bleeding, haemoptyis

62
Q

Severe inherited platelet disorder

A

AR

Mucosal type bleeding pattern

Bernard Soulier Syndrome (defective GPIb/V/IX)

  • platelet adhesion impaired, macrothrombocytopenia (englarged platelets) on blood smear (as produces immature platelets)

Glansmanns thrombasthenia (defective GPIIIa/IIb) - platelet aggregation impaired

Management:

Pressure

Desmopressin

Platelet transfusion

63
Q

Thrombophilia: Inherited

A

Deficiencies of natural anticoagluants:

  • Anti-thrombin
  • Protein C
  • Protein S

Specific genetic mutations:

Factor V leiden: mutation in V, stopping activated protein C to cleave factor 5, leading to increase in blood clotting

Prothrombin gene mutation - increase prothrombin and thrombus formation

64
Q

Lupus anticoagulant

A

Antibody that binds to phospholipids, leading higher chance of blood clotting

Anti-phospholipid syndrome: persisting Lupus anticoagulant + thrombosis

Investigations

APTT prolonged

APTT 50:50 mixing partially corrects

DRVVT ratio prolonged

65
Q

Prolonged APTT

A

Perform 50:50 mix - combine 1 part normal plasma and 1 part patient’s sample

If APTT fully corrects: prolongation due to factor deficiency (as normal plasma replaced the factors)

If APTT partially corrects: inhibitor(e.g. lupus anticoagulant)

66
Q

Thrombophilia - acquired

A

Hyercoagulable state due to another condition

E.g. Antiphospholipid syndrome - presence of antiphospholipid antibodies e.g. Lupus anticoagulant, anti cardiolipin antibodies

Disrupts Annexin 5 shield, exposes excess phospholipid

Clinical scenario:

  • Venous/arterial thrombosis
  • Recurrent miscarriage
67
Q

Idiopathic thrombocytopenic purpura

A

Self limiting postviral illness where immune system destroys platelets

Most common in children

Presents with purpuric , epistaxis, mennorhagia, (spleen not enlarged)

Treatment

Steroids, IVIG

68
Q

Infectious mononucleosis

A

EBV infection resulting in lymphocytic leukocytosis (increase lymphocytes as fighting infection) - comprising of CD8 T cells

Clinical features: fever, tonsilitis, cervical lymphadenopathy. splenomegaly

Tests: monospot test - detects heterophile antibodies (produced during EBV reaction which reacts with animal (sheep, horse) antibodies causing blood to agglutinate)

EBV titres

Treatment

Self limiting

Amoxicillin should not be given as due to virus not bacteria, and can cause amoxicillin rash

Complications:

Can become dormant in B cells

69
Q

A 21 year old medical student presents with a facial rash (butterfly distribution) and polyarthritis.

  1. What is likely diagnosis?

Her coagulation screen shows

PTT: Prolonged (did not correct with 20% normal plasma)

PT: Normal

Fibrinogen: Normal

Platelets: Normal

Likely cause?

A

SLE

Prolonged anti-coagulant due to lupus anticoagulant

Pt has increased thrombotic tendency (different to what laboratory tests shows)

70
Q

Haemolytic uraemic syndrome

A

Due to E.coli 0517

Symptoms: bloody diarrohea

Clinical features: anaemic, thromocytopenic, uraemia

RBCs look fragmented

Coagulation not affected

71
Q

Hodgkin’s lymphoma

A

Malignancy from mature B cells. Characterised by presence Reed Sternberg cell (large, lots of cytoplasm, bilobed nucleus. Owl’s eye appearence)

Staging:

History for B symptoms (systmeic symptoms - weight loss, night sweats, pyrexia), lymphadenopathy

  • physical examination
  • CT
  • BM to determine stages 1-4 (1=localised, 2= 2 or more sites on same side of diaphragm, 3=both sides of diaphragm, 4=widespread)
72
Q

A 71 year old female patient is found to have painless cervical lymphadenopathy. She is otherwise well. She has rubbery nodes (1-2cm) in all areas and splenomegaly of 2 fingerbreadths.

Full blood Count

White count 100 x 109/l (NR 4-10)

Haemoglobin 13 g/l (NR 12-17)

Platelets 200 x 109/l (NR 150-400)

The WBC differential shows 90 x 109/l lymphocytes. These are later shown to be B cells.

A

Chronic lymphoid leukaemia (CLL)

Monoclonal B cells

Different from chronic myeloid leukaemia (CML), as doesn’t change to acute leukaemia (whereas CML can become AML or ALL)

73
Q

Major haemorrhage

A

Definition: Loss of more than one blood volume (>5L in 70kg adult) within 24 hours

Loss of 50% total blood volume in 3 hours

Bleeding excess of 150mL/min

Management:

A, B, C

O2

IV access

Bloods - FBC, coagulation factors, fibrinogen

Tranexamic acid

Bloods - O neg, use group specific where possible

Complications

Hypothermia, acidosis, coagulopathy

74
Q

AML

A

Proliferation of myeloid blast cells in BM (which can’t differentiate into RBCs, neutrophils, platelets leading to BM failure)

Most common leukaemia in adults

Death within days/weeks if untreated

Aetiology

Unknown, chemo, genetic e.g. Faconi’s syndrome, blood disoders e.g. MPS, MDS

Clinical features:

Rapid onset symptoms, fatigue, infection, bleeding, bone pain, hepatosplenomegaly

Diagnosis:

FBC: Anaemia, thrombocytopenia, neutropenia, increased WBCs

Blood smear: blast cells, granualated with Auer Rods

Bonr marrow biopsy (definitive diagnosis): >20% blast cells (large, little cytoplasm with punched out nucleus)

t(15:17) - acute promyelocytic leukaemia (can also cause DIC)

Management

High dose chemo +/- SCT (<60)

Low dose chemo (>60)

Supportive treatment (elderly)

Chemo - Anthracycline, cytarabine

75
Q

ALL

A

Malignant clonal disorder characterised by increase in lymphoid blast cells (mostly B cells)

80% childhood leukaemias

Clinical features:

lymphadenopathy (enlarged lymph nodes), pupuric rash, bone pain, CNS symptoms (can cause meningeal leukaemia), testicular infiltration

Investigations

FBC: Anaemia, neutropenia, thrombocytopenia, leukocytosis (increased WBCs)

Bone marrow trephine biopsy: >20% lymphoblasts in BM

High nuclear:cytoplasm ratio

Cytogenetics:

hyperploidy (excess chromosomes) good prognosis

t(4:11), t(9:22) poor prognosis

CSF: cell count high, glucose low, blast cells - meningeal leukaemia

Managment:

Chemo

Supportive treatment: blood transfusion, FFP, antibiotics (increase risk of infections) - for older pts

Those with poor prognosis, relapsed considered for BMT
Silbings have 1/4 chance of being HLA matched

76
Q

Chronic myeloid leukaemia

A

Increase in mature myeloid cells (neutrophils, basophils, eosinophils)

More in middle-aged

Causes: radiation

Clinical features:

asymptomatic, lethargy, night sweats, weight loss, splenomegaly

Investigations

FBC: Increased WBCs, anaemia, increased/decreased platelets

Blood smear: mature myeloid cells

basophil count >20% would diagnose them in blast phase

BM biopsy: Granulocytic hyperplasia

Cytogenetics, PCR: BCR-ABL (required for diagnosis)

Stages:

Chronic - accelerated - blast crisis (AML/ALL)

Pathogenesis

Philidelphia chromosome - translocation between ch. 9 and 22 t(9:22) leading to fusion of BCR-ABL gene, creating abnormal tyrosine kinase

Treatments:

Imatinib (Tyrosine kinase inhibitor)

77
Q

Chronic Lymphoid Leukaemia (CLL)

A

Commonest leukaemia

Incidence rises with age

Proliferation of neoplastic mature, lymphoid cells ( naive B cells)

Cells co-express CD5 (normally expressed on T cells) and CD20

Clinical features: aymptomatic, lethargy, night sweats, weight loss, lymphadenoapthy, anaemia, SOB

Insiduous

Complications

Autoimmune haemolytic anaemia - (as when try to make immunoglobulins, do a crap job)

Neutropenia

Pulmonary infections (strep. pneumoniae, pneuomocystis jirovecii) - as B cells don’t mature into plasma cells so increased infection

Diagnosis:

Most are incidental

FBC - increased WBC with lymphocytosis (increased no. lymphocytes), anaemia

Blood smear: smudge cells (looks like cell has been smash)

Clinical Staging: BINET

Stage A: < 3 involved lymphoid tissue (nodes, spleen, liver)

Stage B: > 3 involved lymphoid tissue

Stage C: Anaemia, thrombocytopenia

17p deletions

Aggressive disease

del 17p causes loss of p53

78
Q

Lymphoma

A

Neoplastic disorders which causes clonal expansion of lymhoid cells involving lymoh nodes, and lymhoid tissue e.g. MALT, spleen

Divided into Hodgkin’s lymphoma (25%) and Non-Hodgkin’s lymphoma (75%)

Clinical features:

Lymphadenopathy (painless, rubbery), B symptoms, splenomegaly, anaemia

Investigations

History: B symptoms

Clinical examination: lymph nodes

Blood tests - FBC, U&Es, ESR

Imaging - CT

BM - aspirate (sucking out marrow), trephine (BM core)

Staging (Ann Arbor classification)

Stage 1: 1 lymph node group

Stage 2: more than 1 LN group but same side diaphragm

Stage 3: more than 1 LN group different side diaphragm

Stage 4: extranodal involvement e.g. liver, spleen

A and B - indicates absence (A), presence (B) of B symptoms

79
Q

Non-Hodgkin’s lymphoma

A

Group of malignant disorders involving lymphoid cells

More common than HL

Split into B and T cell

Each split into Indolent and Agressive

Low grade (indolent) lymphoma - low rate prolfieration/apoptosis. Uncurable

High grade (aggressive) lymphoma - neoplastic cells large, prominent nucleoli, high rate cell divison/death. Often curable.

B cell indolent: follicular lymphoma

B cell aggressive: diffuse large B-cell lymphoma, Burkitt’s lymphoma

Clinical features: Painless lymphadenopathy, B symptoms, cytopenias (due to marrow failure), abdominal disease

80
Q

Follicular lymphoma

A

Indolent (low grade) B cell lympoma

Neoplasm of B cells that makes follicle like nodiles

Characterised by translocation t(14:18) leading to upregulation of BCL2 (anti-apoptotic protein)

Slow growth but reduced apoptosis

Incidence increases with age

Clinical presentation: Late adulthood, painless lymphadenopathy

Complications: Can progress to diffuse large B-cell lymphoma

Treatment:

Aimed at symptom control

Early stage - radiotherapy

Advanced stages:

Rituximab

81
Q

Diffuse large B-cell lymphoma

A

Hetergenous group of B cell lymphomas

High grade B cell lymphoma

Resembles activated B-cells

Commonest subtype of Non-Hodgkin’s lymphoma

Clinical features:

Aggressive

Lymphadenopathy - rapidly enlarging LN mass

Extra-nodal presentation: Waldeyer’s ring, GI, skin

B symptoms

Treatment:

R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, prednisolone)

82
Q

Burkitt’s lymphoma

A

High grade B cell lymphoma (highly aggressive)

Neoplasm of B cells in germinal centre

  • Mostly in children

Characterised by translocations involving MYC gene t(8:14) leading to high rate of proliferation, apoptosis

  • can cause tumor lysis sydrome (cancer cells release intracellular contents when destroyed leading to arrthymias, sudden death)

Clinical features:

short history, marked B symptoms, rapidly growing tumor

Extranodal disease:

  • Jaws (African form), facial bone
  • Ileocoecal region of GI tract (sporadic form)
  • CNS involvement

Histology:

  • starry sky appearence

Treatment: CODOX-M / IVAC

CODOX-M: (cyclophosphamide, (O) vincistine, doxorubicin, methotrexate)

83
Q

Hodgkin’s lymphoma

A

Haematological malignancy from mature B cells. Characterised by Reed-Sternberg cells (bi-lobed, prominent nucleolus, gives owl’s eye appearence)

Strong expression of CD30

Assoc. with EBV infections

Incidence peaks at 20-30, then 50

Clincal features: painless lymphadenopathy (cervical common), cough, SOB, itch can precede diagnosis, alcohol related pain

Subtypes:

Classical Hodgkin’s lymphoma (90%) and nodular lymphocyte predominant

Classical Hodgkin’s lymphoma split into:

Nodular sclerosing (most common) - collagen bands divide LN into nodules. Uusally young, female, has cervical lymphadonapthy

Lymphocyte rich - large no. of lymphocytes

Mixed cellularity - fewever lymphocytes, more RS cells. Lots of eosinophils

Lymphocyte depleted - few lymphocytes, lots of RS cell. Worst prognosis

Spreads from one nodal group to adjacent group. Later, haemotological spread to liver, lungs

CXR: can show widening of mediastinum, pleual effusion

Complications: risk of Br. Ca in females, cardiovascular disease, infertility

Treatment

ABVD (adriamycin, bleomycin, vinblastine, dacarbazine)

1 and 15 of 28 day cycle

84
Q

Plasma cell myeloma/mutiple myeloma

A

Neoplasm of mature plasma cells

Abnormal plasma cells produce paraprotein (monoclonal protein) or only light chain of immunoglobulin produced (light chain myeloma)

IgG most common

Neoplastic cells resemble plasma cells

  • Mostly in elderly

Clinical presentation: CRAB

hyperCalaemia, renal insufficiency (as light chains deposit in renal tubules), Anaemia, Bone lytic lesions (as plasma cells leads to OC activation)

Classical triad: increased plasma cells in BM, paraprotein, lytic bone lesions

Investigations:

Blood tests: FBC (rouleaux), ESR, serum electrophoresis (spike in M band (monoclonal protein: IgG or IgA)

Urine tests - light chains (Bence Jones protein (light chains))

BM aspirate (increase no. of plasma cell)

Imaging: MRI (bone lytic lesions, pepper pot skull)

Complications: SC compression

Diagnosis:

>10% plasma cells in BM + at least one of CRAB symptoms

Treatment:

Asymptomatic (smoudlering) - observe

Symptomatic: Chemo inc. steroids + thalidomide

Radiotherapy

Supportive treatment: bisphosphonates

85
Q

Monoclonal gammaopathy of undetermined significance

(MGUS)

A

<10% plasma cells in BM

Serum M protein <30

Bence Jones protein rare

No symptoms characteristic of plasma cell myeloma (anaemia, hypercalcaemia, renal dysfunction, lytic bone lesions)

Can progress to myeloma

86
Q

Thrombocytopenia

A

Clinical features: pupura, mucosal bleeding

Causes:

BM failure

ITP (idiopathic thrombocytopenia purpura)

hypersplenism (overactive spleen)

Henoch Schonlein purpura (normal platelets)

87
Q

What is haematinic (increases RBC production)?

A.Selenium

B.Vitamin B6

C.Folic acid

D. Vitamin B12

A

Folic Acid

88
Q

Hypospenlism doesn’t cause increased risk of what infection?

A

E.coli

Increases risk of Strep. pneumoniae, haemophilus influenzae, nisseria meningitidis

89
Q

Definition leukaemia vs lymphoma

A

Leukaemia: malingnancy of leucocytes in BM or blood

Lymphoma: malignancy of leucocytes in LN or lymphoid tissue e.g. MALT. Usually presents as a tumor mass

90
Q

Plasmacytoma

A

Single localized tumor of monoclonal plasma cells

91
Q

Microcytic and hypochromic anaemia

A

SALTI

Sideroblastic anaemia

Anaemic of chronic dissease

Lead poisoning

Thalassaemia

Iron deficiency anaemia

92
Q

ITP (idiopathic thrombocytopenia purpura)

A

Autoimmune disease against platelet antigens (GPIIb/IIIa) which are consumed by splenic macrophages

Most common cause of thrombocytopenia

Acute form in children, weeks afer viral infection, self-limiting

Clinical features: peteichae, epistaxsis, menorrhagia

Complications: intra-cranial bleeding

No splenomegaly

Labs:

Decreased platelet count

PT, aPTT normal

megakaryocytes on biopsy

Treamtent:

Steroids, splenectomy

Year 3 (15 decks)

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