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Haematology Lab Exam > Disorders of coagulation > Flashcards

Disorders of coagulation Flashcards

1
Q

What are the risk factors associated with the development of inhibitors in haemophilia A?

A
  • Severe haemophilia A
  • Younger age (most common in childhood)
  • Within the first 25 years of exposure to factor replacement
  • During times of increased factor replacement, infection or inflammation
  • Underlying FVIII mutation: more common in large deletions or where there is an insertion of a stop codon. 25% with the common intron-22 mutation develop inhibitors.
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2
Q

How many patients with Haemophilia A develop inhibitors over the course of their lifetime?

A
  • 20-30%
  • Most= lower level, transient inhibitors that are not a long term problem
  • These usually have a BU between 5-10
  • High responding inhibitors are seen in ~10-15%
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3
Q

What is the recommended screening protocol for the development of inhibitors in those with severe haemophilia A?

A
  • Screen every three months until 20 exposures

- Then every 3-6 months until 150 exposures

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4
Q

How do you screen for inhibitors in Haemophilia A

A

1) APTT 1+1 with normal (test at 0h and 2h) → non-correcting suggests inhibitor
2) Dilutions of patient plasma + FVIII concentrate → incubate 37C for 60min. Assay FVIII level: ​<90% control sample​ suggests inhibitor
3) Bethesda assay

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5
Q

Are one stage or chromogenic factor assays preferred when monitoring extended half life factor replacement?

A
  • Many guidelines, including ISLH, recommended using chromogenic assays when monitoring factor levels on treatment
  • This is because there can be discrepancies between the one stage and chromogenic results
  • With extended half life products, the impact depends upon the product itself and what substance is used as an activator
  • Adynovate (FVIII EHL product)= similar recoveries with different APTT activators and across the one stage and chromogenic assays
  • Aliprolix (FIX EHL product)= different recoveries with different APTT activators (underestimation with Kaolin)
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6
Q

What is one way that the recovery from the one stage factor assay can be improved in factor replacement monitoring?

A
  • Using a recombinant FVIII reference standard instead of a plasma standard
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7
Q

What is emicizumab and how does it differ from endogenous FVIII?

A
  • Chimeric bispecific humanised antibody that mimics the cofactor activity of FVIII.
  • Binds to FIXa with one arm and to FX with the other placing both in spatially appropriate positions promoting FIXa catalysis of X to Xa and tenase formation.

Differences from FVIII:

1) Longer half life (30 days vs 12hrs)
2) No on/ off mechanism (i.e. does not need to be activated by thrombin/ inhibited by APC)
3) Does not distinguish between activated (i.e. IXa) and inactivated (i.e. X) forms of substrate
4) Shows only partial co-factor activity
5) Target concentration of emicizumab is much greater then the plasma concentrations of IXa and X: activity dependent upon the amount of IXa produced (whereas FVIII is usually the rate limiting step in tenase formation)
6) 11 fold lower catalytic activity than FVIII

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8
Q

How does emicizumab affect lab tests routinely used to monitor FVIII replacement?

A

APTT: oversensitive: normalises at very low levels of emicizumab

FVIII OSA: oversensitive (can modify by calibrating against emicizumab to make sensitive)

FVIII chromogenic assay with bovine components: insensitive. Emicizumab does not bind to bovine FVIII. Can be used to measure residual FVIII in someone on emicizumab

FVIII chromogenic assay with human components: sensitive within the dynamic range of the assay.

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9
Q

How does emicizumab affect lab tests routinely used to monitor FVIII inhibitors?

A

Bethesda assay using OSA FVIII: Emicizumab not deactivated my heat. Causes false negatives as drives coagulation despite the presence of an inhibitor

Chromogenic, bovine containing inhibitor assays: will detect the presence of an inhibitor as emicizumab will not bind to bovine IX and X.

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10
Q

Discuss combined FV and FVIII deficiency

A

· Where both FV and FVIII levels are 5-20%
· Does not enhance the haemorrhagic tendency seen in each defect separately.
· Caused by mutations in the LMAN1 gene which encodes a chaperone protein for FV and FVIII or in genes which act as a cofactor for LMAN1.
· Symptoms are usually mild with easy bruising, epistaxis and bleeding after dental extractions and surgery.

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11
Q

Discuss factor XI deficiency

A
  • Functional deficiency in FXI, usually accompanied by a low FXI level.
  • FXI has the least correlation between factor levels and bleeding manifestations.
  • Bleeding is more likely to occur if FXI is <20% although some individuals with severely reduced FXI levels show no increased propensity to bleeding.
  • Women with FXI deficiency are more likely to suffer from menorrhagia but the majority of pregnancies are uneventful.
  • The site of bleeding appears to be more important that the level of FIX. Bleeding is more severe when a site of injury with high local fibrinolytic activity is involved (i.e. the urogenital tract and oral cavity).
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12
Q

How is FXIII deficiency diagnosed?

A

Diagnosis suspected when a patient presents with significant, delayed bleeding and normal screening coagulation tests

Clot solubility: only detects severe deficiency <5%

  • Plasma + thrombin + Ca → clot: suspend in 5M urea at 37C: normal is stable >24h
  • Absent FXIII: clot dissolves

Chromogenic amide release assay: automated, sensitive, precise, quantitative

  • Thrombin activates FXIII → crosslinks peptide substrate and releases ammonia, which reduces NADH → NAD+
  • The reduced NADH is measurable at 340nm and is proportional to FXIIIa

ELISA: antigenic assay: distinguishes A/B subunits (not clinically relevant)

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13
Q

How do vitamin K dependent factors become activated?

A

Require γ-carboxylation of glutamic acid residues at their Gla domains to enable binding of calcium and attachment to phospholipid membranes.

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14
Q

What are the two principle functions of vWF?

A
  1. Binding to matrix molecules, particularly collagen, at sites of vascular injury and capture of platelets
    - vWF binds to exposed collagen, and uncoils exposing the GPIba site for platelet binding.
    - Platelets roll in the direction of the blood flow until they bind to exposed collagen. Binding to collagen activates the GPIIb/IIIa receptor enabling fibrinogen to bind and further platelet aggregation
  2. The stabilisation of FVIII in the circulation.
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15
Q

What is type 1 vWD?

A
  • Partial quantitative defect in vWF
  • Activity/antigen ratio >0.7
  • Reduction in monomers of all sizes if multimer analysis performed.
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16
Q

What is type 2A vWD?

A
  • Decreased vWF-dependent platelet adhesion with selective deficiency of HMW multimers.
  • Can occur if there is excessive cleavage of HMW vWF by ADAMTS13.
  • Disproportionately low vWF:CB and vWF:RCo (activity/antigen ratio <0.7)
  • Low numbers of intermediate to high MW multimers if multimer analysis performed.
17
Q

What is type 2B vWD?

A
  • Increased affinity for platelet GP1B
  • Often associated with thrombocytopenia
  • Disproportionately lower vWF:CB and vWF:RCo (activity/ antigen ratio <0.7).
  • Abnormal response to low dose ristocetin on platelet aggregation assays
  • Low numbers of intermediate to high MW multimers if multimer analysis performed.
18
Q

What is type 2N vWD?

A
  • Markedly decreased binding affinity for FVIII
  • Leads to reduced half-life and rapid clearance of FVIII.
  • Low FVIII levels, FVIIIB/vWF:Ag <0.7
  • Normal multimer analysis.
19
Q

What is type 2M vWD?

A
  • Decreased vWF-dependent platelet adhesion without selective deficiency of HMW multimers
  • Activity/ antigen ratio <0.7
  • Normal multimer analysis
20
Q

What is type 3 vWD?

A
  • Complete deficiency of vWF
  • Undetectable vWF
  • No multimers on multimer analysis
21
Q

How is vWF:RCo performed?

A

Three different methods:
1) Traditional vWF:RCo= An assay that measures VWF activity and employs platelets and Ristocetin in the assay

2) VWF:GPIbR= A recombinant form of GPIb is coated on a latex bead (which mimics a platelet) by a specific monoclonal antibody that orientates the GPIba in a way where it can interact with vWF in the presence of ristocetin.
3) vWF:GPIbM assay= Mutant GPIb with two gain of function mutations. Will bind vWF without the need for adding ristocetin (more correctly- GP1b binding assay)

22
Q

What is “low vWF” and what are the difficulties with this diagnosis?

A

vWF levels between 30-50 IU/dL. Associated with an increased risk of bleeding.

Difficulties include:
1) Slightly low levels of vWF are common. Many of those with low levels do not have excessive bleeding

2) A history of minor bleeding is very common and is not a good predictor of bleeding in other circumstances. A patient with a bleeding disorder may have a negative bleeding history if they have not been exposed to significant haemostatic challenges.
3) A history of minor bleeding such as easy bruising and low vWF will often be found together. This does not necessarily mean that the patient has vWD .
4) The family history is often unhelpful particularly in mild cases or where penetrance is weak. This is because low vWF can be due to a combination of modifying genes rather than a defect in the vWF gene itself.

23
Q

What are the causes of acquired vWD?

A
  • Hypothyroidism (reduced synthesis)
  • Aortic stenosis (shear stress and increased cleavage)
  • MPNs (adherence to platelets and increased cleavage)
  • Paraproteins (immune)
  • Wilms tumour (adsorption)
24
Q

What is the differential diagnosis for DIC and how can these be differentiated from DIC?

A
  • Liver disease (D-dimer often normal, FVIII normal)
  • Massive transfusion
  • MAHA (coags normal)
  • Hyperfibrinolysis (plts normal)
  • Catastrophic APLS (fibrinogen normal)
25
Q

How does APML lead to DIC?

A

Cell surface of APML blasts contain:

  • TF
  • ‘Cancer procoagulant’
  • Fibrinolytic molecules

Granules of APML blasts contain:

  • Fibrinolytic molecules (plasminogen, tPA)
  • Elastase proteinase 3 (cleave HMW vWF)

APML blasts stimulate cytokine production

26
Q

What are the definitions of and differences between early, classical and late vitamin K dependent bleeding in paediatric patients?

A

1) Early
- Onset within first 24hrs of life
- Occurs in infants whose mothers are on VKAs
- Severe bleeding manifestations: ICH, intrathoracic bleeding

2) Classical
- From day 2-7 of life
- Occurs in infants with poor feeding and who did not get vitamin K administered at birth
- Intracranial, gastrointestinal and umbilical stump bleeding most common

3) Late
- From day 8 to 6 months of age
- Occurs in infants with cholestatic or malabsorptive disorders
- Very high incidence of intercranial haemorrhage

27
Q

What coagulation changes occur during pregnancy?

A

Prothrombotic state

  • Fibrinogen and factors II, VII, VIII, X and XIII increase by 20 to 200% (factor V and IX remain normal)
  • vWF increases 2-4x during pregnancy, peaking within 24hrs post-partum.
  • Concentrations of protein S and anti-thrombin are reduced. Protein C unaffected.
  • Activity of fibrinolytic inhibitors increase including TAFI and PAI-1
28
Q

What factors contribute to the development of coagulopathy in trauma and/or massive blood loss/ transfusion?

A

o Tissue injury with increased exposure/ expression of tissue factor
- Brain injury results in the release of brain-specific thromboplastins into the circulation

o Loss of procoagulant factors and platelets directly through blood loss

o Physiological and therapeutic haemodilution

  • Filling of the vascular space with fluid from extracellular and interstitial spaces
  • Administration of intravenous fluid and plasma poor red cells.

o Hyperthermia

o Hypoxia

o Acidosis

o Disseminated intravascular coagulation

29
Q

What are the mechanisms by which paraproteins can cause coagulation abnormalities?

A

o Hyperviscosity: arterial and venous bleeds secondary to abnormal wall shear stress

o Increased clearance of FVIII and vWF leading to an acquired haemophilia A or von Willebrand disease

o Impaired platelet aggregation

o Inhibited fibrin polymerisation

o Have a heparin like anticoagulant effect that can be reversed by protamine

30
Q

How does amyloidoisis lead to an increased risk of bleeding?

A

o FX deficiency: adsorption of FX onto the amyloid fibrils
o Abnormal fibrin polymerisation
o Hyperfibrinolysis
o Platelet dysfunction
o Vessel fragility
- Caused by amyloid deposition in the vessel walls

31
Q

Describe the haemostatic changes seen with asparaginase

A
  • Endothelial and/ or white cell activation
  • Increased tissue factor expression
  • Thrombin generation, consumption of procoagulants and natural anticoagulants
  • Hypofibrinogenaemia, prolonged APTT/ PT and reduced antithrombin and other physiological anticoagulants
  • Thrombosis
  • Also directly reduces the synthesis of coagulation factors
  • Other contributing factors: liver dysfunction, infection, age etc…
32
Q

What are some of the acquired causes of antithrombin deficiency?

A 
Active thrombosis
Heparin therapy
Asparaginase therapy
Liver disease
Nephrotic syndrome
DIC
33
Q

What are some of the acquired causes of protein C deficiency?

A 
Vitamin K deficiency
Vitamin K antagonists
Sepsis (meningococcal)
Liver disease
DIC

Haematology Lab Exam (27 decks)

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