Haematology Flashcards
What is the key cell type involved in GVHD in an allogenic stem cell transplant? A. B cells B. NK cells C. Dendritic cells D. T cells E. Macrophage
GVHD is a lymphocyte mediated process.
Answer is T cells.
What is the mechanism of Haemachromatosis?
What gene is involved?
HFE C282Y gene mutation –> disrupts HFE beta 2M.
TOO MUCH IRON.
UPREGULATES DMT1 TRANSPORTER
–> Increased Fe absorption
ALSO inhibits Hepcidin therefore less blocking of Fe absorption when patient is in Fe overload.
Presentation:
- haemosiderin in liver, pancreas, heart, joints, skin
Mx is venesection.
How does Iron get absorbed into the body?
What is the role of Hepcidin?
Fe++ (ferrous) is converted from dietary Fe+++ via Vitamin C + Cyt B, then transported into the duodenal enterocyte cell via the DMT1 TRANSPORTER on apical membrane.
Once inside the enterocyte, it can be stored as Ferritin (converted back to Fe+++ form)
Fe++ is absorbed into the blood via FERRIPORTIN on the basolateral membrane, then converted to the Fe+++ form in order to be BOUND TO TRANSFERRIN (“Ferric bound to Ferrin”)
This “Ferric-Ferrin” complex is then transported to the bone marrow and liver to act on Transferrin receptors (TfR’s) on RBCs for Hb synthesis.
IN FE OVERLOAD, HEPCIDIN INHIBITS FERRIPORTIN.
(“HepcidIN = INhibits FERRIPORTIN = INhibts Fe absorption)
In Fe overload –> Hepcidin from liver –> internalises Ferriportin–> reduces Fe absorption.
In FE DEFICIENCY, Transferrin receptors TfRs get upregulated (as there is increased demand for Fe)
What are the acquired causes of Fe overload and how do you treat it?
Thalassaemia Sideroblastic anaemia Blood transfusions Myelodysplasia Aplastic anaemia Chronic liver disease (note Haemochromatosis is genetic, not acquired)
Mx = IRON CHELATORS
Desferasirox po - S/E diarrhoea, renal
Or
Ferriprox PO - S/E Agranulocytosis
Explain the 4 stages of Fibrin formation / Coagulation.
- Initiation
- Propagation
- Termination
- Resolution
- Initiation
- vessel injury and exposure of tissue factor (III)
- interaction with factor 7 (EXTRINSIC pathway) - Propagation
- propagation of the clotting process by the coagulation cascade, mainly by INTRINSIC amplification:
factors 12 –> 11 –> 9 –> 8 plus vWF
- subsequent generation of activated factor Xa
- formation of Fibrin plug and platelet aggregation - Termination
- termination of clotting by anti thrombotic control mechanisms
- downregulates clotting response and contains the thrombus - Resolution
- removal of the clot by FIBRINOLYSIS
- PLASMIN (= tPA released by endothelium) breaks down crosslinked Fibrin –> forms fibrin degradation products ie. D-DIMER.
Hence D-dimer positivity in clots and DIC.
(note D-dimer negative when there is naturally-occurring primary fibrinolysis, eg. In TTP, cancers)
What are the natural anticoagulants present in the bloodstream at all times?
tPA
Urokinase
Protein C
Protein S
- all released by endothelium
–> breaks down fibrin clot
In Haemophilia A, at what point would you expect spontaneous bleeding, based on the % activity of factor 8?
% Activity of factor 8:
> 50% no bleeding.
> 25% bleeding after severe trauma only.
> 5% - No spontaneous bleeds. Only major bleeding with surgery/trauma. Slight bleeding after minor trauma.
< 1% - Spontaneous bleeding into joints and muscles.
Knees > elbows > ankles
What parts of the coagulation cascade are reflected by PT, APTT, Thrombin time and the reptilase test?
PT = “television factors” 2, 7, 9, 10. Also liver disease, Vit K def, warfarin.
APTT = INTRINSIC = 12, 11, 9, 8, vWF. Also circulating inhibitors such as Lupus anticoagulant. Heparin (=anti thrombin III)
BOTH PT and APTT = reflects the final common pathway. ie. Activated factor Xa and downstream ie. Factor 5, prothrombin (2) –> thrombin (2a) , Fibrin (1a) and factor 13 which makes cross-linking/stable fibrin.
Thrombin time = reflects Fibrinogen conversion to FIBRIN.
If TT is normal then it means the problem lies upstream, ie factor 5 or 10, or prothrombin (factor 2)
If ALL 3 affected (APTT, PT, TT) your differentials should be:
A combined factor deficiency
Presence of inhibitors
Factor 10, 2 or 5 deficiency or dysfunction of some sort
Liver disease
DIC!!! = tissue factor dependent
Reptilase test:
- detects reduced fibrinogen ie. Fibrin clots can’t form
How do you differentiate between a time-dependent inhibitor and a lupus anticoagulant inhibitor on a mixing study?
Failure to correct with mixing study (APTT remains prolonged)
= Lupus Anticoagulant
Normal mixing study PLUS prolonged APTT / failure to correct after 2 hours incubation = Time-dependent inhibitor is present (that now had time to work)
= Factor 8 inhibitor
What is in Prothrombinex?
When do you use this?
PROTHROMBIN-X contains:
- Prothombin (plasma derived) (note Prothrombin/”factor2” –> Thrombin/2a)
- X (factor 10)
- factor 9
- low levels factor 7
= the TELEVISION FACTORS!!
= Localised to PLATELET MEMBRANE surface
Used in WARFARIN REVERSAL ONLY.
Then give Vit K to maintain effect.
(Contraindicated in DIC, AMI, thrombosis, stroke)
What is in Cryoprecipitate?
When do you use this?
Cryo contains: - Fibrinogen - factor 8 plus VWF (intrinsic pathway) - factor 13 (important for cross linking of fibrin to form a stable clot) - Fibronectin (binds fibrin) = HELPS TO STOP BLEEDS
Useful in DIC emergencies or Fibrinogen deficiency/dysfunction
When do you use Recombinant factor VIIa?
Contains activated Tissue Factor (III) plus 7a.
(Recombinant 7 – think of extrinsic pathway, vessel injury etc)
Use Recomb”INH”ant Factor 7 in patients with INHIBITORS to factors:
eg. In factor 9 def, or in time-dependent inhibitor factor 8.
What is DDAVP and when do you use it?
DDAVP is a synthetic analogue of ADH/ Antidiuretic Hormone
- -> increases vWF and factor 8
- -> activates platelet aggregation!!!
USED IN:
- URAEMIA + BLEEDS
- vWF deficiency (Von Willebrand disease)
(DDAVP - think of APTT –> vWF and 8)
What is the mode of action of Tranexamic acid?
What are the indications for using Tranexamic Acid?
(“TRANNIES don’t like PLACID MEN” [plasmin] )
Tranexamic acid BLOCKS PLASMIN and therefore inhibits Fibrinolysis.
Used for:
- Mucocutaneous bleeds
- GI Bleeds
- tumours that secrete Fibrinolysis proteins
(Note - renally excreted)
Delayed Immune Mediated Transfusion Reactions.
What is the mechanism of GVHD?
How does it present clinically?
What is the prophylaxis and Mx of GVHD?
DELAYED reactions = usually days to weeks after transfusion.
There are THREE types of DELAYED Immune Mediated Transfusion Reactions.
- Delayed Haemolytic Transfusion Reactions
- Transfusion-associated GVHD
- Post-transfusion Purpura
In GVHD:
- The donor’s T lymphocytes reacts with the recipient’s Antigen (donor’s WBC recognises recipients’s antigen as foreign)
- Highest risk if HLA mismatch.
- -> usually 2/52 AFTER AlloSCT or transfusion
- -> may get pancytopaenia
PRESENTATION: Acute: Skin lesions - diffuse macular rash Fever Liver - Abdo pain, nausea GI - diarrhoea painful gritty eyes
chronic - any organ can be affected
PROPHYLAXIS -
In AlloSCT - CNI (Tac/CsA), may use MTX of MMF as an adjunct
Can be prevented by using IRRADIATED blood products in patients with:
- NHL or HL
- Stem cell or BM transplant
- Donation from family
- HLA compatible single donor of platelets / granulocytes
MX with STEROIDS.
(ADDIT: MECHANISM OF OTHER DELAYED REACTIONS - less examinable:
Delayed Haemolytic Transfusion Reactions - due to anamnestic Antibody response to Non-ABO red cell antigens
Post-transfusion Purpura - occurs as a result of prior sensitisation to foreign platelet antigens, usually during pregnancy)
What is TRALI?
Transfusion Related Acute Lung Injury, occurs 6 hrs after transfusion.
TRALI is one of the 4 Acute Immune-Mediated Transfusion Reactions.
= donor’s antibodies interacts with recipient’s Leukocytes
(“trA-Li” = Antibodies-to-Leukocytes)
–> granulocyte activation in pulmonary vasculature, resulting in increased vascular permeability
–> activation of COMPLEMENT and Cytokine Storm
–> APO, ARDS
Acute Immune-Mediated Transfusion Reactions.
What is the mechanism behind:
- Haemolytic transfusion reactions
- Febrile Non-haemolytic transfusion reactions (FNHTR)
Immune mediated transfusion reactions are classified into:
- ACUTE (within 24 hrs of transfusion)
Or
- DELAYED (days to weeks after transfusion)
There are FOUR types of Acute transfusion reactions:
- Haemolytic transfusion reactions
- Febrile Non-Haemolytic Transfusion Reactions (FNHTR)
- Allergic transfusion reactions
- TRALI
—Acute transfusion reactions are most often the result of clerical/identification error —
MECHANISMS:
- Haemolytic transfusion reactions:
- Usually due to ABO incompatibility
- Donor’s ANTIGEN interacts with Recipient’s pre-existing antibodies
- Results in complement activation, leading to intravascular haemolysis and its associated severe acute inflammatory cascade, which may ultimately progress to DIC, shock, and/or acute renal failure.
- -> Acute Tubular Necrosis
- -> Fevers, haemolysis, back pain, DAT positive - FNHTR
- Donor’s LYMPHOCYTES interact with recipient’s antibody
- immune mediated but multifactorial mechanism
- self limiting but still need to investigate fevers
ADDIT:
3. Allergic transfusion reactions - (mechanism is self explanatory) Hypersensitivity reactions to allergens in the transfused blood
- TRALI - see next flashcard
What is the purpose of measuring Factor Xa levels?
To measure the adequacy of a LMWH.
LOW ANTI-Xa level = Adequate anticoagulation
HIGH ANTI-Xa level = Insufficient anticoagulation.
Antithrombin III agonists such as Clexane & Dalteparin (inhibit activation of factor X –> Xa)
Fondaparinux (a new “pentasaccharide” selective Xa inhibitor but also indirect action via Antithrombin III)
–> all inhibit coagulation via blocking activation of Xa.
If these drugs are present –> inhibits factor Xa.
What is the method for warfarin reversal? (eTG)
(From eTG)
OVERDOSE OR POISONING:
- single-dose activated CHARCOAL if patient presents within 1 HOUR of the time of gestation
- if patients not usually taking warfarin, give Vit K (PHYTOMENADIONE) 10-20mg po or IV stat, and if actively bleeding give ProthrombineX PLUS Fresh Frozen Plasma. Monitor INR 6-12 hourly.
FOR OVER-ANTICOAGULATION in someone already on warfarin:
- INR < 5: omit next dose
- INR 5-9: Vit K (Phytomenadione) 1-2mg orally, or 0.5-1mg (half dose) IV.
- INR >9: Vit K 2.5-5mg PO, or 1mg IV if low risk of bleeding.
If high risk of bleeding, give Vit K 1mg and consider Prothrombinex PLUS FFP.
ANY SIGNIFICANT BLEEDING:
Vit K 5-10mg IV
Prothrombinex PLUS FFP
BLOOD FILMS. Extended matching question.
Match the abnormality with the haematological condition:
- tear drop RBCs
- smear cells
- Auer rods
- association with Budd chiari syndrome
- CD5 and CD19
- pelger cells
- howell jolly bodies
- Pencil cells
- Rouleaux
- Hypersegmented neutrophils
- oval macrocytes
- Blister cells (RBC blisters)
- Bite cells
- Elliptocytes/Ovalocytes
- Cold agglutination (Rouleaux in cold, spherocytes, polychromasia)
- Heinz bodies
- target cells
- Nucleated red blood cells
- Acanthrocytes
- fragmented cells
- tear drop RBCs = myelofibrosis
- smear cells = CLL
- Auer rods = AML
- association with Budd chiari syndrome = PRV
- CD5 and CD19 expression = CLL
- Pelger cells = “pale girl” cells :) mainly MyeloDYSPLASIA (but also AML/CML)
- howell jolly bodies = asplenia (functional or splenectomy)
- Pencil cells = Fe deficiency (“pencil thin” skinny girls are Fe deficient!)
- Rouleaux = Multiple Myeloma or Waldenstroms (“Mathew McConaughey (MM) wears a ROLEX”)
- Hypersegmented neutrophils = B12 deficiency
(note MMA / Methylmalonic acid is SENSITIVE but not specific for B12 def) - oval macrocytes = B12 def
- Blister cells (RBC blisters) = G6PD def
- Bite cells = (looks like Pacman cells– “Pacman eats 6 Ghosts”) G6PD def ** with Haemolysis! **
- Elliptocytes/Ovalocytes = SE Asian Ovalocytosis
- Cold agglutination (Rouleaux in cold, spherocytes, polychromasia) = Paroxysmal Cold Haemoglobinuria (IgG) OR
Cold Agglutinin Disease (IgM, associated with Lymphoma and Mycoplasma) - Heinz bodies = “BEans means Heinz” = BEta Thalassaemia (excess alpha globins)
- target cells = (any defective globin chain synthesis eg haemoglobinopathies) Thalassaemia or Sickle cell
- Nucleated RBCS = immature BABY RBCs!! = normal in infants HbF, In adults indicates Thalassaemia
- Acanthrocytes (spur, thorn or spiculated cells) = splenectomy, cirrhosis, haemolytic anaemia or Thalassaemia
- fragmented cells = DIC
Match the mutations with their haematological conditions, and indicate whether they are good/bad prognostic factors:
- t (9:22)
- JAK2
- t (15:17)
- t (8:21)
- t (9:22) = Bcr Abl (Philadelphia) = classically CML, but also present in Acute leukaemias AML and ALL.
- JAK2 = Polycythemia Rubra Vera
- t (15:17) = good prognosis! = APML
- t (8:21) = good! = AML
(How to remember: 9:22 “minus one” is 8:21
= CML “minus one” maturation step in the myeloid cell line is AML)
