Haematology

Question 1

What type of inheritance is factor v Leiden?

Answer 1

autosomal dominant

Question 2

By how much is the risk of post-op DVT increased if factor V Leiden heterozygote? homozygote?

Answer 2

2, 11.5

Question 3

With which coagulation factor deficiency are haemophilia A, B & C associated?

Answer 3

A=VIII
B=IX
C=XI

Question 4

How are haemophilia A & B inherited?

Answer 4

X-linked recessive- mutation on long arm of chromosome X at F8 gene (haemophilia A) & F9 gene (haemophilia B), respectively

Question 5

With X-linked recessive disorders, which gender is affected & which gender are carriers?

Answer 5

males effected, females carriers

Question 6

What proportion of pts with haemophilia have no FHx?

Answer 6

1/3

Question 7

In which pathway of clotting cascade are VIII & IX important?

Answer 7

intrinsic; required for thrombin generation & fibrin formation

Question 8

When is Dx of haemophilia suspected?

Answer 8

bleeding beginning spontaneously or persisting after trauma
Bleeding often in weight-bearing joints (knees, ankles, elbows), muscles & rarely genitourinary system
most common cause of death= intracranial bleed

Question 8

When is Dx of haemophilia suspected? what may be seen on clotting screen?

Answer 8

bleeding beginning spontaneously or persisting after trauma
Bleeding often in weight-bearing joints (knees, ankles, elbows), muscles & rarely genitourinary system
most common cause of death= intracranial bleed

routine clotting screen may be normal aside from prolonged aPTT

definitive Dx is made by a factor level assay

Question 9

What’s the prevalence of the most common inherited bleeding disorder? Is it generally clinically significant?

Answer 9

1:100

only clinically significant in 1:10000

(most are asymptomatic, 85% have type 1, mild)

Question 10

how does deficiency of vWF manifest?

Answer 10

easy bruising from trivial trauma
bleeding from mucosal surfaces (epistaxis, gums, bowel)
may have prolonged postop bleeding (depends on the type)

Question 11

pts with which blood group tend to have lower vWF levels?

Answer 11

O

Question 12

How is a Dx of VWD usually made?

Answer 12

lab Ax of quantitative vWF & Factor VIII levels, ristocein cofactor activity, collagen binding assays, multimeric analysis
qualitative assays with tests such as glycoprotein binding assay, ristocein cofactor activity (VWF:RCo), ristocein-induced plt aggregation

normal screening tests don’t usually rule out vWF; PT is normal, plt are normal or reduced, bleeding time & aPTT normal or prolonged.

Question 13

what’s the incidence of haemophilia A & B?

Answer 13

A= 1/5000 male births
B= 1/25000 male births

Question 14

what’s the incidence of dysfibrinogenaemia? it’s inheritance? and factor II, V, VII, X, XIII deficiency?

Answer 14

<1/million, AD

<1/million, AR

Question 15

How’s the severity of haemophilia graded?

Answer 15

based on the % activity of factors- mild is 5-40%, mod 1-5%, severe <1% (<0.01 IU/mL)

Question 16

Pre-op Ax/planning, intra-op Mx for VWD or haemophilia?

Answer 16

History:
detailed- bleeding symptoms
any diagnoses, type, severity, Rx & response to Rx (eg, DDAVP response? have factors been given previously, previous blood transfusions)?
FHx

Exam: airway
joint deformities/contractures

Ix:
CBC, coags, fibrinogen, specific factor assays incl VIII, VWF
transfusion-related infections (eg, HIV, hep B/C)
Clotting screen & specific factor assays depending on the type of bleeding disorder
screen for inhibitors

Preop liaison/R/V with haematology, blood bank, surgeon & anaesthetist for risk mitigation (eg. consider preop transfusion of recombinant factors 30-60mins preop) & multi-D plan, pre-emptive recommendations in the event of bleeding

eg. goals pre-op may include haemophilia pts requiring 80-100% correction of FVIII confirmed before major surgery, VWD need vWF:RCo>100% & FVIII>50%

schedule surgery early in week, preferably am, centre with haematology, availability for factor assays & product (eg. factor concentrate) provision

Intra-op:
ensure products available, haematology aware, plan ready to be executed
avoid mucosal trauma (eg. minimal airway attempts- videolaryngoscope 1st line, ideally avoid nasal route (cophenylcaine if must), ideally avoid NG if able, avoid IM injections, pressure area care)
maintain normothermia, avoid acidosis, use US for IV access to limit bleeding risk
avoid HTN & tachycardia

risk/benefit consideration for neuraxial/regional (generally avoided) vs GA

avoid medications increasing bleeding risk (eg. NSAIDs)

implement thromboprophylaxis; promote early mobilisation, consider mechanical, discuss risk:benefit of pharmacological with surgeon & haematologist

multimodal analgesia, avoiding NSAIDs

consider TxA in discussion with surgeons

Question 17

To what level do pts with haemophilia need factor VIII corrected before major surgery? for how long should levels be maintained?

Answer 17

80-100%, this must be confirmed before surgery

levels should be maintained for up to 6/52 after orthopaedic procedures & 1-2/52 for other procedures

Question 18

are recombinant factors VIII& IX a risk for disease transmission? what is their limiting factor?

Answer 18

no. lyophilised so free from disease transmission risk

limiting factor= cost

Question 19

By how much will each unit factor VIII per kg raise plasma FVIII level? it’s t1/2? how to calculate units required?

Answer 19

2%
8-12hrs
wt of pt x % factor level desired x 0.5

Question 20

By how much will each unit factor IX per kg raise plasma FVIII level? it’s t1/2? how to calculate units required?

Answer 20

1%
18-24hrs
wt of pt x % factor level desired

Question 21

What’s another element to consider when deciding the amount of deficient factor to give?

Answer 21

screen pts for inhibitors to factor VIII or IX

low risk is inhibitor level <5 Bethesda units/mL

high risk is >5 Bethesda units/mL

low-risk group requires higher level of deficient factor, high-risk group requires approval for alternative regimens eg. rVIIa (which is a thrombosis risk

Question 22

How may methylene blue treatment be of benefit added to cryo?

Answer 22

reduces risk of transmission of pathogens

Question 23

What’s the role of cryoprecipitate & prothrombin complex concentrate & recombinant factor VIIa for patients with inherited disorders of coagulation?

Answer 23

cryo contains VIII, XIII, vWF, fibrinogen, has risk transmission blood-borne infections, only use iii recombinant factors aren’t available.
PCC has II, VII, IX, X, protein C & S. main indication= emergency reversal warfarin. licensed for use in pts with inhibitors to factors VIII & IX.
rFVIIa is effective in achieving haemostasis in haemophilia pts with inhibitors in about 80% of cases but is thrombogenic- thrombogenic activity is optimised when fibrinogen & pH are normal. it’s licensed for platelet dysfunctional disorders & FVII deficiency.

Question 24

For which haematology pts is DDAVP mainly used?

Answer 24

pts with mild haemophilia A & type 1 VWD.

It produces a 2-5x increase in FVIII levels which may be sufficient in mild haemophilia for minor surgery but it’s ineffective in severe haemophilia A or haemophilia B.

It promotes release of VWF which forms a complex with FVIII, preventing it’s breakdown.

Question 25

What are the ways/doses for DDAVP delivery?

Answer 25

intranasal, sublingual, oral, IV

IV peak effect 60mins, s/c or intranasal 90-120mins.

IV or S/C dose is 0.3mg/kg, adult nasal spray dose of 300microk is equivalent to 0.2microg/kg IV.

Question 26

How does TxA work? For which haematology pts is it useful & for which should it be avoided?

Answer 26

Synthetic derivative of lysine. Competitive inhibition of conversion of plasminogen to plasmin which degrades fibrin hence TxA= antifibrinolytic.
Plasma half-life 2hrs.

Useful for VWD & haemophilia, avoid in pts with haematuria due to obstructive uropathy.

Question 27

For high-risk subtypes of VWD, what are the recommended VWF:RCo levels pre & postop? and FVIII?

Answer 27

> 100IU/dL & >50IU/dl

FVIII >100IU/dL preop & 50IU/dL postop

should maintain Rx to keep these levels 7-14 days after major surgery, 1-5 days after minor surgery

Question 28

Why must the use of DDAVP in type 2 VWB be discussed with a haematologist?

Answer 28

variable effect according to subtypes

may cause thrombocytopenia for some

Question 29

What proportion of pts with type III VWD may bet aloo-antibody formation?

Answer 29

10-15%- if inhibitors, may consider VIIa (discuss with haematology)

Question 29

What proportion of pts with type III VWD may bet aloo-antibody formation?

Answer 29

10-15%- if inhibitors, may consider VIIa (discuss with haematology)

Question 30

what’s the consensus re: use of regional techniques in VWD or haemophilia?

Answer 30

lack of RCTs or consensus advice re: minimum “safe” level of factors or platelets in haemophilia or VWD

Question 31

What’s the annual incidence of venous thrombosis? What proportion of venous thrombosis is due to deficiencies in antithrombin, protein C & protein S?

Answer 31

1:1000

<5%

Question 32

by how much does factor V Leiden, prothrombin or dysfifrinogenaemia increase the lifetime probability of thrombosis?

Answer 32

2.2

Question 33

How are the deficiencies of anticoagulants inherited (protein C, protein S, antithrombin)?

Answer 33

autosomal dominant

they increase the lifetime probability of thrombosis around 8%

Question 34

What’s the issue with factor V Leiden mutation?

Answer 34

protein C usually degrades factor V

the factor V Leiden mutation makes it resistant to activated protein C–> thrombosis

Question 35

What are some uses for FFP?

Answer 35

in discussion with haematology:
factor V replacement
plasma exchange in pts with TTP & haemolytic uraemic syndrome

Question 35

What are some uses for FFP?

Answer 35

in discussion with haematology:
factor V replacement
plasma exchange in pts with TTP & haemolytic uraemic syndrome

Question 36

What’s sickle cell disease? what are it’s hallmarks?

Answer 36

congenital haemoglobinopathy, mutation on chromosome 11–> production of unstable & relatively insoluble HbS (from an amino acid substitution on the B-globin subunit of normal adult HbA) which can precipitate out of solution when deoxygenated, forming “sickle cells”

may be either:

-sickle cell trait (heterozygous, both HbA & 30-40% HbS, generally benign & cells only sickle under extraordinary physiological conditions, provides some protection against malaria)

or

-homozygous (near 100% HbS, debilitating disease characterised by chronic haemolytic anaemia (since sickle cells have half life of only 12 vs 120 days) & recurrent vaso-occlusion with severe pain. The hallmarks of SCD–> vaso-occlusion & haemolysis, resulting in recurrent painful episodes & organ dysfunction. Survival beyond 5th decade is rare with sickle cell disease. HbS gene primarily in Africa & south-west Asia.

Question 37

What are the anaesthetic management principles for pts with sickle cell disease?

Answer 37

Pre-op:
establish type (sickle cell trait minimal health impacts, SCD usually multi-organ damage due to repeated vascular occlusion & a background of poor development & FTT. Many pts have frequent hospital admissions, seek Hx re: this & triggers/number/timing of crises).

pt may have chronic pain, opioids pre-op

screen for signs/symptoms of sickle cell disease with Hx/exam/Ix:

-head/neck/airway:
may have frontal bossing & prominent maxilla due to marrow hyperplasia
may have microvascular retinopathy, vitreous haemorrhage & retinal detachment (similar to DM)
may develop functional asplenism associated with hypertrophy of other lymphoid tissue, including Ts & As
may have Hx OSA

-CNS: incr risk TIA/CVA & haemorrhagic events

-Cardiovascular:
may have cardiomegaly due to anaemia or CCF
may have pulm HTN secondary to recurrent pulmonary infarction
-ECCG, echo

-resp:
recurrent pulmonary infarctions–> dyspnoea, cough, haemoptysis, pleuritic chest pain, may compromise lung function
CXR
PFTs before major surgery

-genitourinary:
renal impairment common
painful priapism may be seen

-GIT:
eventually there’s complete auto infarction of the spleen & immune incompetence, prior to this there may be sudden enlargement of spleen with splenic sequestration of rbcs & platelets
pigment gallstones & need for cholecystectomy are common
painful hepatic enlargement may occur

-skin: deformities, aseptic necrosis & leg ulcers common

-Haematological:
There may be acute Hb decreases due to splenic sequestration, bone marrow failure

Planning: consider hydroxyurea prior to elective surgery if time permits
educate & informed consent: perioperative mortality approx 1%
Limit fasting time & ensure preop hydration (often admit day before surgery)
chest PT pre&postop
discuss transfusion triggers with haematologist
Generally intraop cell salvage is a relative contraindication- exchange transfusion (which reduces the proportion of sickle cells & the incidence of periop sickle cell crisis) may be performed & then ICS considered on weighing risks:benefits in discussion w haematologist
get vitals, FBC, urea, electrolytes, LFTs
ABG useful as higher proportion of metHb & the pulse oximeter may underestimate SpO2

intra-op:
oxygenation (pts who are homozygous develop sickling at approx SpO2 85% while homozygous not until 40%)
tissue perfusion
normothermia & active warming
hydration
analgesia: pt may be opioid tolerant. Multimodal & opioid-sparing techniques. avoid NSAIDs if evidence renal dysfunction.
positioning: limit venous stasis
caution ++ with tourniquets

no particular approach to anaesthesia proven to be advantageous but AVOID LA with epinephrine

may consider epidural analgesia for painful vaso-occlusive crises

Postop:
extended period of monitoring appropriate as complications such as painful vaso-occlusive crises, acute chest syndrome & stroke may occur in postop period.
attention to O2, hydration, analgesia.

Question 38

What are thalassaemias & anaesthetic considerations?

Answer 38

hereditary anaemias, caused by defective synthesis of the alpha chain (alpha thalassaemias) or beta chain (beta thalassaemias) of Hb.

Normal adult HbA (95% of adult Hb) consists of 2 alpha subunits (coded on chromosome 16) & 2 beta subunits (coded on chromosome 11). HbA2 (alpha2 & delta2) <3% & HbF (alpha2 gamma2- abcs have 70-90% of this until 2-4/12).

Unbalanced alpha & beta chain synthesis in thalassemias leads to unstable Hb & early red cell death, usually in the marrow.

heterozygotes have mild anaemia, homozygotes severe anaemia.

heterozygous beta thalassaemia= thalassaemia minor, mild hypochromic, microcytic anaemia.
homozygous= thalassaemia major, profound anaemia & repeated transfusions.

alpha thalassaemias are prevalent in SE Asia. increased splenic uptake of red cells (hence reduced lifespan).

Considerations:
need to evaluate haematocrit before operations.
splenomegaly may–> thrombocytopenia.
thorough preop cardiac Ax as haemosiderosis (secondary to chronic haemodialysis or repeated transfusions) may impair cardiac function.
marrow hyperplasia may cause frontal bossing or prominent maxilla.
incr risk postop infection if have had a splenectomy.
oxidant drugs (eg, prilocaine, nitroprusside, vit K, aspirin & penicillin) may precipitate haemolysis.

Question 39

What are some adults prescribed for sickle cell disease? what’s Rx in the symptom-free period? and for acute crisis?

Answer 39

hydroxyurea to elevate HbF levels (which protect against sickling)- reduces the frequency & severity of symptoms of vast-occlusive crises & reduces transfusion needs

• education to prevent dehydration including advice re: hydration during exercise or hot weather, avoiding excess ETOH
• vaccinate against pneumococcus, HiB & neisseria meningitides if evidence splenic involvement
• folic acid prescription prevents deficiency as a result of chronically elevated erythropoiesis within the bone marrow

acute crisis: symptom control with analgesia & rehydration (either @ home or hospitalised)
may require blood transfusion
treat triggers (eg. Rx suspected infection with broad-spectrum antibiotics after culture blood/sputum/urine)

Question 40

aside from hypoxia, what may exacerbate sickling?

Answer 40

cold
stasis
dehydration
infection

Question 41

what’s the definitive test for haemoglobinopathies? can a screening test be done?

Answer 41

Hb electrophoresis

sicledex test= a rapid screening test which can detect levels of HbS >10% but can’t distinguish SCD from trait

Question 42

What may be seen on peripheral blood film with sickle cell disease?

Answer 42

sickle cells & elevated reticulocyte count relative to Hb (may not be present in sickle cell trait where red cell morphology may be normal)

Question 43

What’s the curative therapy for sickle cell disease? limitations/restrictions of this?

Answer 43

bone marrow transplantation

pre-existing organ damage & limited availability of compatible donors + the 10% mortality limit the use of bone marrow transplant to children <16yo

Question 44

How does sickle HbC disease vary?

Answer 44

These pts have both HbS & HbC (lysine substituted for glutamate on B globin chain)
less frequent & less severe vaso-occlusive crises, usually only mildly anaemic, use similar perioperative precautions as with SS disease given variability in clinical picture.