Haematology Flashcards
What is Kostmann syndrome?
Severe congenital neutropenia
- Rare AR disorder
- Mutations: many, incl ELA2 and HAX1
- ANC <2 +/- monocytosis +/- eosinophilia
- Children are at risk of severe bacterial infection and early death
- Management
* G-CSF
BMT is curative!
Congenital neutropenia syndrome similar to CF?
Scwachman-Diamond Syndrome!
- Presentation
* FTT
* Steatorrhoea due to pancreatic insufficiency
* Recurrent infections
* Neutropenia, then anaemia and thrombocytopenia later
* Metaphyseal dysostoses
What is Wiskott-Aldrich syndrome?
- Rare X-linked disorder characterised by severe thrombocytopenia and uniformly SMALL platelets
- Presentation
- Male, often presenting in neonatal period with thrombocytopenia
- Eczema
- Immunodeficiency
Risk of lymphoma in later life
Causes of prolonged APTT?
Causes that correct on mixing studies:
1. Factor deficiency (8, 9, 11, 12)
2. VWD with low factor 8
Causes not corrected on mixing studies
3. Heparin contamination
4. Lupus anticoagulant (note this doesn’t cause bleeding)
5. Acquired factor 8 inhibitor
Causes of prolonged PT (with normal APTT)?
PT assess the extrinsic and common pathways
- Congenital or acquired factor 7 deficiency
- Mild liver disease
- Mild vit K deficiency
- Therapeutic warfarin
Causes of prolonged PT and aPTT?
- DIC
- Liver disease
- Vitamin K deficiency
- Congenital factor 1, 2, 5 or 10 deficiency
- Supratherapeutic warfarin
What is Bernard Soulier syndrome?
An AR condition with mild thrombocytopenia and giant, abnormal platelets that do not aggregate. Absent GP1b -> defective platelet: vWF adhesion
Presents with mucocutaneous bleeding in infancy
What is Glanzmann Thrombasthenia?
An AR platelet surface receptor disorder of GPIIb/IIIa -> defective platelet: platelet aggregation
Presents with mucocutaneous bleeding in infancy
Often normal platelet count + size
MOA of Emucizumab?
New drug for Haemophilia A
MOA: Binds to factor IXa and factor X, mediating the activation of factor X
This is normally the role of factor VIII which is deficient in haemophilia A.
What does FFP contain?
Contains ALL coagulation factors at the same concentration as present in plasma. Also contains fibrinogen
Indications for FFP?
Deficiency of clotting factors with bleeding or risk of bleeding e.g
- Replacement of a single coagulation factor or protein deficiency if no factor specific concentrate is availabe (eg factor V, severe protein S deficiency)
- Prevention of dilution coagulopathy in setting of massive transfusion
- DIC
What does cryoprecipitate contain?
Contains most of the original factor 8, VWF, fibrinogen, factor 9 and fibronectin from FFP
Features of dyskeratosis congenital
Inherited BM failure syndrome with mucocutaneous features and cancer predisposition. Caused by impaired telomere maintenance -> short telomeres
Triad of reticular skin hypopigmentation, nail dystrophy, and oral leukoplakia
At risk of lung and liver fibrosis and
Cancer predisposition, most commonly head and neck cancer
Features of Fanconi anaemia
Inherited bone marrow failure syndrome
Skin hypo/hyperpigmentation/ CALMs (most common)
Short stature
UL abnormalities- hypo plastic or absent thumbs + radii
Hypogonadal + genital changes
Kidney abnormalities (ectopic, pelvis or horseshoe kidney)
Conductive hearing loss
CHD
Many meet criteria for VACTERL
Mechanism of clot breakdown?
initiated by tissue plasminogen activator (tPA) which is activated by protein C
tPA catalyses the conversion of plasminogen to plasmin which breaks down fibrin and fibrinogen and desolves the clot
What does aPTT measure?
assesses function on common and intrinsic pathway (factors 12, 11, 9, 8)
What does prothrombin time (PT) measure?
Assesses function of common + extrinsic pathway (factor 7)
“7 Pets”
What does thrombin time measure?
Measures the time it takes to convert fibrinogen -> fibrin
Will be prolonged with:
- decreased or defective fibrinogen
- presence of heparin or heparin-like anticoagulants
- elevated fibrin degradation products
Causes of small platelets (microthrombocytes)?
Wiskott Aldrich Syndrome (X-linked condition associated with severe thrombocytopenia, eczema, immunodeficiency)
Impaired platelet production in the BM (Eg due to aplastic anaemia, bone marrow infiltration, chemo, ionising radiation)
Causes of large platelets (mega thrombocytes)?
Bernard Soulier syndrome
ITP
DIC
Thrombocytic microangiopathies
MYH19 related disorders (mutations in the gene for non muscle myosin heavy chain 2a)
Normally have <5% large platelets. Increased large platelets seen with high platelet turnover
Features of Thrombocytopenia-Absent Radius (TAR) syndrome?
AR condition, presents with bleeding in neonate
- Thrombocytopenia (often <30), risk of IC bleeding. Can be exacerbated by infection and CMPA
- No radii but normal thumbs (unlike Fanconi anaemia)
Can also have hypo plastic carpals, syndactyly, hip dysplasia, femoral and/or tibial torsion
Dysmorphism: hypertelorism, broad forehead, low set ears
- CHD (30-35%): ASD, VSD or TOF
Management of ITP
- Steroids
- IVIG - rapid onset (24hrs)
- Anti-D (only used if Rh + due to risk of haemolytic)
- Rituximab (anti-CD20) or elthrombopag (thrombopoeitin receptor agonist - stimulates thrombopoiesis)
Pathophys of Thrombotic Thrombocytopenic Purpura?
ADAMTS-13 protease deficiency (AR) or destruction (autoimmune) -> lack of cleavage of vWF multimers. VWF circulate, stimulating microvascular platelet thrombi
Management of TTP?
Plasma exchange
Steroids
Rituximab
How does NAIT occur?
Mother develops anti-platelets antibodies against paternally-derived fetal platelet antigens (most commonly human platelet antigen/ HPA-1A) -> destruction of platelets and severe neonatal thrombocytopenia (self resolves after ~2/52)
How does neonatal AUTOimmune thrombocytopenia differ from NAIT? (ALLOimmune)
Caused by maternal autoantibodies that react with both maternal and fetal platelets, these autoantibodies develop in setting of maternal thrombocytopenia or splenectomy
Only 10-25% of infants develop severe thrombocytopenia (it is more commonly mild)
Management of neonatal autoimmune and alloimmune thrombocytopenia?
If severe thrombocytopenia or bleeding, give platelet transfusion and IVIg, otherwise monitor
Difference between type 1, 2 and 3 von Willebrands disease?
Type 1 = reduced vWF antigen (quantitative defect)
Type 2= functional defect (qualitative defect)
vWF activity: vWF antigen <0.7
Type 3= undetectable vWF and consequently low factor 8 levels (it is a carrier of factor 8)
Management of vWD
- Desmopressin (causes release of stored vWF and factor 8 from endothelial cells)
- Biostate (vWF and factor 8 concentrate)
- TXA (antifibrinolytic)
What does von Willebrand factor do?
- Promotes platelet aggregation to exposed subendothelial surface and to other platelets
- Carrier protein for factor 8 in the blood
Mechanism of action of aspirin?
Irreversibly inhibits COX -> prevents conversion of arachidonic acid to thromboxane A2 and therefore altering function of the platelet for its whole lifespan
What % of factor activity do you have in mild, mod and severe haemophilia?
Mild: 6-40%
Moderate: 1-5%
Severe: <1%
What is cryoprecipitate used for?
Cryoprecipitate contains fibrinogen, factor 8 and vWF.
Used for replacement of fibrinogen eg in DIC, trauma, congenital fibrinogen disorder
May also be used for vWF or haemophilia A
Risk factors for vitamin K deficiency bleeding
- No Vit K given
- Antibiotics
- GI malabsorption
- Maternal warfarin or phenobarbital use
- severe liver disease (as the vit-K dependent factors are synthesised in the liver)
What is factor V Leiden
Factor 5 resistance to protein C, (a naturally occurring anti-coagulant which normally cleaves factor 5a making it inactive) so factor 5 remains in its active (procoagulant) form
What is a chromosomal breakage analysis used for?
Diagnosis of Fanconi anaemia
What would you expect on bloods in transient erythroblastopenia of childhood (TEC)?
Usually occurs in a child aged 1-3yrs
- Normocytic anaemia
- Low reticulocytes
- Normal HbF and erythrocyte adenosine deaminase (ADA), unlike DBA
- 20% have a mild neutropenia
What would you expect on bloods in Diamond Blackfan Anaemia
Congenital red cell aplasia
- Macrocytic anaemia with low retics
- Elevated erythrocyte adenosine deaminase (ADA) activity - helps distinguish from TEC
- Elevated HbF
What age is the usual physiological Hb nadir?
8-12 weeks (per Nelsons)
Management of iron overload
Dexferoxamine (iron chelator)
AEs include ototoxicity, retinal changes, bone dysplasia
What would you expect on blood film with G6PD Deficiency?
Heinz bodies (precipitated Hb)
Bite cells and blister cells
Inheritence pattern of vWD?
Autosomal dominant (except type 3 which is autosomal recessive)
How does cyclical neutropenia present?
Neutropenia at REGULAR intervals (usually every 21 +/-3 days) and lasts 3-7 days
- associated fever
- apthous ulcers
- stomatitis
- pharyngitis + cervical lymphadenopathy
What is the underlying pathophysiology of Diamond Blackfan anaemia?
It is a ribosompathy - caused by a gene mutation for a protein of the 40S or 60S ribosomal subunit
What condition are giant platelets and Dohle bodies associated with?
MYH9 -related disorders
(autosomal dominant cause of thrombocytopenia, SNHL and cataracts)
