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A Practical Guide to Laboratory Haemostasis

 

Data Interpretation: Factor Assays



Introduction

This section covers factor assays but strays into other areas and so is not specific to factor assays.

Question 1

A 72-year-old man is admitted through Accident and Emergency with a 2-week history of easy bruising. He was on no drugs at the time of his visit to hospital. Shown below are the results of his initial investigations:

Test Patient Reference Range
PT 13s 10.6-12.4s
APTT 105s 21-32s
Fibrinogen (Clauss) 3.9g/L 2-4g/L

1. What are the possible diagnoses taking into account the patient's history.
2. What additional investigations would you request?

Click HERE for Part 2


The results of factor assays are show below:

Factor Assay Patient Reference Range
FVIII 0.23 IU/mL 0.45 - 1.49 IU/mL
FIX 1.18 IU/mL 0.50 - 1.51 IU/mL
FXI 1.01 IU/mL 0.50 - 1.50 IU/mL
FXII 1.67 IU/mL 0.45 - 1.49 IU/mL

1. What additional tests might you request and why?


Click HERE for Part 3

Shown below are the results of additional investigations on this patient:

Assay Patient Reference Range
VWF:Ag 0.21 IU.mL 0.48 - 1.55 IU/mL
VWF:Act 0.19 IU/mL 0.50 - 1.50 IU/mL
FVIII:C 0.19 IU/mL 0.45 - 1.49 IU/mL
Protein electrophoresis M Band [IgM 11.3g/L]
Immunoglobulins IgG 4.2g/L
IgM 17.3g/L
IgA 2.2g/L
IgG 6 - 13g/L
IgM 0.4 - 2.2g/L
IgA 0.8 - 3.7g/L
Renal & LFTS
Calcium
Normal  

1. What is the diagnosis?
2. Are there any additional tests you might request?


Click HERE for Part 4


Shown below are two images from a bone marrow aspiriate on this patient. What do these show and what is the diagnosis?


 

How would you manage this patient if he needed a cholecystectomy?


Question 2

A 52-year-old man is admitted through Accident and Emergency with a short history of haematuria. He was on no drugs at the time of his visit to hospital. Shown below are the results of his initial investigations:

Test Patient Reference Range
PT 12s 10.6-12.4s
APTT 95s 21-32s
Fibrinogen (Clauss) 3.1g/L 2-4g/L

1. What are the possible diagnoses taking into account the patient's history.
2. What additional investigations would you request?

Click HERE for Part 2


The results of factor assays are show below:

Factor Assay Patient Reference Range
FVIII 0.12 IU/mL 0.45 - 1.49 IU/mL
FIX 0.79 IU/mL 0.50 - 1.51 IU/mL
FXI 1.23 IU/mL 0.50 - 1.50 IU/mL
FXII 1.10 IU/mL 0.45 - 1.49 IU/mL

1. What additional tests might you request and why?

 

Click HERE for Part 3


Shown below are the results of additional investigations on this patient:

Assay Patient Reference Range
VWF:Ag 0.13 IU.mL 0.48 - 1.55 IU/mL
VWF:Act 0.03 IU/mL 0.50 - 1.50 IU/mL
FVIII:C 0.11 IU/mL 0.45 - 1.49 IU/mL
Protein electrophoresis M Band 17g/L
IgG Κappa
Immunoglobulins IgG 22g/L
IgM 2.3g/L
IgA 2.1g/L
IgG 6 - 13g/L
IgM 0.4 - 2.2g/L
IgA 0.8 - 3.7g/L
Renal & LFTS
Calcium
Normal  

1. What are the possible diagnoses?
2. Are there any additional tests you might request?

 

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He is admitted 6 weeks later with a major GI haemorrhage. Endoscopy shows diffuse bleeding from the stomach but no obvious ulcer.
How would you manage this patient?


Question 3

A 6-week-old male baby is found at home unconscious. He is admitted to hospital and investigations show a large intracerebral haemorrhage. A series of haemostasis investigations are performed and these are show below:

Test Patient Reference Range
PT 14s 11-14s
APTT 35s 28-34.5s
Fibrinogen (Clauss) 3.5g/L 1.9-3.7 g/L

1. What additional tests would you request?

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The results of a Factor XIII screen are shown below:

5M Urea FXIII Screening Test Patient: Complete lysis at 24 hours

Control: No lysis at 24 hours

What tests would you request next?
What is the sensitivity of a FXIII screening assay?


Question 4

A 4-year-old boy with multiple developmental problems, is referred by the paediatricians for investigation of a potential bleeding disorder. He had a long history of easy bruising and had bled after minor ENT surgery. There was no family history of note. He was followed up by the paediatricians because of various congenital abnormalities and developmental delay.

Investigations showed:

Test Patient Reference Range
PT 48s 11-14s
APTT 39 28-34.5s
Fibrinogen (Clauss) 3.9g/L 1.9-3.7 g/L
Thrombin Time 14s 12-14s

On the basis of these tests what you do next?

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The results of factor assays are shown below:

Factor Assay Patient [IU/dL] Reference Range [IU/dL]
Factor II 103 70-130
Factor V 98 75-155
Factor VII 34 70-130
Factor VIII 167 75-155
Factor IX 99 75-135
Factor X 32 70-130
Factor XI 86 75-155

What do you think might explain these findings?
What would you request next?

 

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Karyotype analysis shows a partial deletion of the long arm of chromosome 13 [13q34].
Does this fit in with your explanation for the low factor assays and if so why?


Question 5

Plot the following factor X assay data [from a PT-based assay] and calculate the factor X levels for the four plasma samples. The concentration of FX:C in the reference plasma is 94 IU/dL.

 
Dilutions
1/10 1/20 1/30 1/40 1/80 1/100 1/1000
Reference plasma 25s   32s     38s 59s
Patient 1
35s
   
  54s
82s
Patient 2
22s  
28s
   
34s
 
Patient 3
180s
   
182s
   
182s
Patient 4
30s
34s   39s
45s
   

A. If the concentration of FX in the reference plasma was 112 IU/dL - what would your answers be?
B. If the concentration of FX in the reference plasma was 0.90 IU/ml - what would your answers be?


Question 6

The following are the clotting times [in seconds] for a 1-stage APTT Factor VIII assay.

Plot the following factor VIII data and calculate the factor VIII:C levels.
The concentration of FVIII in the reference plasma is 94 IU/dl.

 
Dilutions
1/5 1/10 1/20 1/40 1/80 1/100
Reference plasma  
41
53
66
 
82
Patient 1  
55
 
79
 
96
Patient 2 108
120
       
Patient 3  
70
82
 
107
 
Patient 4  
30
42
55
 
71

If the concentration of FVIII in the standard was 0.89 IU/ml what would your answers be?


Question 7

A 23-year-old woman of Iranian descent presents to her GP with menorrhagia. The GP requests a coagulation screen and the results of this are shown below:

Test Patient Reference Range
PT 34s 11-14s
APTT 82s 23-35s
Fibrinogen (Clauss) 2.9g/L 1.5-4.0g/L
Thrombin Time 13s 10-13s

How would you proceed with the investigation of this patient?

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You request factor V and VIII assays. The raw data for these assays is shown below.
Plot the data and derive the concentrations of these two factors.

Factor V Assay

Dilutions Patient PT [s] Reference PT [s]
1/10 60 23
1/20 92 38
1/40 160 59

Reference Factor V:C concentration 85 IU/dL.

Factor VIII Assay

Dilutions Patient APTT [s] Reference APTT [s]
1/10 50 35
1/20 57 43
1/40 64 50
1/100 74 59

Reference Factor VIII:C concentration 90 IU/dL.

 

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The diagnosis of combined FV and FVIII deficiency is confirmed.

1. What is the molecular basis for this disorder?
2. How would you manage her menorrhagia?


Question 8

A 7-year-old boy is investigated with prolonged bleeding following dental surgery. A coagulation screen is requested:

Test Patient Reference Range
PT 23s 11-14s
APTT 56s 28-34.5s
Fibrinogen (Clauss) 2.1g/L 1.9-3.7 g/L
Thrombin Time 13s 12-14.2s

i. What factor assays would you request and why?

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Shown below are the data for a PT-based factor X assay. From this data derive the patient’s factor X level.

Dilutions Patient PT [s] Reference PT [s]
1/10 35 20
1/20 42 24
1/40   28
1/80 59 34
1/100 62 35


Is there any value in performing an APTT-based FX assay?

 

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There are 5 methods for assaying Factor X - what are they?


Question 9

A developmentally normal 2-year-old girl is referred with a history of easy bruising, haematoma formation after vaccination and more recently of a probable left knee haemarthrosis. A coagulation screen shows:

Test Patient Reference Range
PT 12s 11-14s
APTT 90s 23-35s
Fibrinogen (Clauss) 2.9g/L 1.5-4.0g/L
Thrombin Time 13s 10-13s
Full Blood Count Normal  

1. What tests would you request and why?

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1. You request Factor VIII, IX and XI assays.
2. Shown below are the data for a 1-stage factor VIII assay. From this data derive a factor VIII result for the patient.

Dilutions Patient APTT [s] Reference APTT [s]
1/10 42 29
1/20 47 34
1/40 52 39
1/100 58 45

Factor VIII:C Reference 104 IU/dL.

3. What additional tests would you request and why?
4. What additional questions might you ask the parents?

 

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1. You request Von Willebrand Factor Assays - they are normal.
2. You request a FV assay - although the PT is not prolonged. The FV is 110 IU/dL.
3. A karyotype shows: 46,XX - with no obvious chromosomal abnormalities.
4. The parents are unrelated. The father is well with a normal PT and APTT. The mother tells you that her father had severe haemophilia A and was shown to be hemizygous for the F8 intron 22 inversion.

How would you explain these findings and how would you investigate further?


Question 10

An 18-year-old male patient with factor VII deficiency has a factor VII assay performed.
Calculate the FVII levels in the patient.
The results of his parents are also shown. Calculate their FVII levels.

Dilutions Index Case PT [s] Mother PT [s] Father PT [s] Reference PT [s]
1/10 55 36 36 29
1/100 68 50 50 41
1/1000 82 64 64 56

All clotting times are in seconds. FVII standard: 115 IU/dl.
What can you infer from these family studies? What might you ask the parents?


Question 11

A 56-year-old male with moderate Haemophilia A diagnosed 16 years ago requires surgery to repair an inguinal hernia. In advance of this he has a pre-operative screen performed:

Test Patient Reference Range
PT 12s 11-14s
APTT 33s 23-35s
Fibrinogen (Clauss) 2.9g/L 1.5-4.0g/L
Thrombin Time 13s 10-13s
Full Blood Count Normal  

1. Are you surprised by these results?
2. What might explain this?

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Below is data from a 1-stage APTT FVIII assay.
Derive the FVIII:C from this assay.

Dilutions Patient APTT [s] Reference APTT [s]
1/10 37 35
1/40 44 42
1/160 49 47

Factor VIII:C Reference 100 IU/dL.

Are you surprised by this result?
What would you request next?

 

Click HERE for Part 3

Below is data from a chromogenic FVIII assay. Derive the FVIII:C from this assay.

 
FVIII:C Concentration [IU/dL]
  150 100 50 0
Absorbance [405nm]
Reference Plasma
0.47 0.32 0.19 0.04

Absorbance Patient: 0.06

1. What is the basis for a chromogenic FVIII Assays?
2, How do you explain these findings.
3. What is the molecular basis for this?


Question 12

Shown in the table below are the data for an APTT-based factor XI assay performed on 2 separate plasma samples [Plasma 1 and Plasma 2.]
Plot the data for the FXI reference plasma and draw a best fit line. For the two plasma samples plot the data but do not attempt to draw a best fit line.

1. Calculate the FXI levels for each of the five dilutions in the two plasma samples.
2, Explain your findings.
3. What would you do next ?

Dilutions Plasma Sample 1 APTT [s] Plasma Sample 2 APTT [s] Reference APTT [s]
1/10 40 37 30
1/20 43 38 33
1/40 47 40 37
1/100 52 42 42
1/160   43  

Reference Factor XI:C concentration 100 IU/dL.


Question 13
Calculate the Bethesda titres for each of the following plasma samples.

Sample Plasma Dilutions Residual FVIII Titre [BU/ml]
1 Undiluted 70%  
2 Undiluted 40%  
3 Undiluted 0.5 IU/ml  
4 Undiluted 0.6 IU/ml  
5 Undiluted 45 IU/dl  
6 1/5
1/10
1/20
33%
55%
68%
 
7 1/20
1/40
1/80
35%
55%
68%
 
8 1/320
1/640
1/1280
0.30 IU/ml
0.52 IU/ml
0.65 IU/ml
 


Question 14

A 56-year-old woman of Jewish ancestry is referred for an aortic valve replacement (AVR). Her pre-operative screening tests show:

Test Patient Reference Range
PT 13s 11-14s
APTT 61s 23-35s
Fibrinogen 2.9g/L 1.5-4.0g/L
Thrombin Time 13s 10-13s
Full Blood Count Normal  

What tests would you perform next?

Click HERE for Part 2

The results of a FXI assay are shown below:

Dilutions Patient APTT [s] Reference APTT [s]
1/10 36 26
1/20 39 29
1/100 48 38

Reference FXI:C 100 IU/dL
1. Calculate the FXI levels in the plasma sample.
2. How will you manage her surgery?

 

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This lady has an uneventful AVR. She is supported through the surgery and the post-operative period with FXI concentrate. 12 days later she begins to ooze from her wound from her chest drain sites. A repeat clotting screen shows:

Test Patient Reference Range
PT 11.8s 11-14s
APTT 85s 23-35s
Fibrinogen 2.9g/L 1.5-4.0g/L
Thrombin Time 12s 10-13s
Full Blood Count Normal  


Y0u request a further FXI:C assay - the raw data is shown below:

Dilutions Patient APTT [s] Reference APTT [s]
1/10 50 26
1/20 54 29
1/100 62 38

Reference FXI:C 100 IU/dL.
1. What is the FXI level.
2. How would you explain the differences in FXI:C assays.

 

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An inhibitor assay is undertaken - the results of which are shown below:
1. Calculate the residual FXI:C. This was based upon a 1:20 dilution of plasma.
2. What is the inhibitor level.

Dilutions Patient APTT [s] Reference APTT [s]
1/10 29 26
1/20 32 29
1/100 41 38

Reference FXI:C 100 IU/dL.
1. What is the FXI level.
2. How would you explain the differences in FXI:C assays.


Question 15

A 23-year-old male is diagnosed with mild haemophilia A (VIII:C 12 IU/dL) following prolonged bleeding after dental surgery. He requires further dental surgery and you elect to treat him with DDAVP and tranexamic acid.

1. How do DDAVP and tranexamic acid work – illustrate with a diagram if you find this easier.
2. What are the side effects of DDAVP and how do we minimise these?

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He is treated with DDAVP and his 1 hour post-DDAVP FVIII:C is 89 IU/dL. He proceeds to surgery which is carried out uneventfully. However, 4 hours following dental surgery he has profuse bleeding from the extraction sites and a repeat FVIII:C is 14 IU/dL.
Comment upon these results?
What do you think is the problem?


Question 16

A 45-year-old male is referred for further investigation following the finding of an abnormal coagulation profile. He had contacted his GP having developed bruising and epistaxes.
His health had previously been excellent apart from a recent chest infection for which he had been prescribed amoxicillin.

Test Patient Reference Range
PT 45s 11-14s
APTT 79s 23-35s
Fibrinogen 3.2g/L 1.5-4.0g/L
Thrombin Time 13s 10-13s
Full Blood Count Normal  

Outline how you would investigate this patient. Give the reasons behind these investigations.

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The results of relevant factor assays are shown below:

Factor Patient Reference Range
FII 132 IU/dL 50-150 IU/dL
FV 2IU/dL 50-150 IU/dL
FX 89 IU/dL 50-150 IU/dL

1. What do you think has happened and why.
2. Are there any other tests you might request?
3. Why does this problem arise?
4. How would you manage this patient?


Question 17

What are the differences between a 1-stage and a 2-stage factor VIII assay?
Why might you request a 2-stage factor VIII assay?


Question 18

A 3-year-old boy with severe haemophilia B (IX:C<1 IU/dl) has a poor response to factor IX concentrate. An inhibitor screen is performed which is positive.

1. Outline the basis of the inhibitor screen.
2. From the data provided establish the factor IX inhibitor titre in this patient.

Dilutions Residual FIX [%]
1/5 33
1/10 55
1/20 68


Question 19

Shown below are the results of DDVAP studies in five patients with Von Willebrand Disease.
Comment upon the results of the these studies and identify the possible VWD subtype(s).

Patient Pre-DDAVP

FVIII:C
VWF:Ag
VWF:RCo
[IU/dL]
1 hour post-DDAVP

FVIII:C
VWF:Ag
VWF:RCo
[IU/dL]
2 hour post-DDAVP

FVIII:C
VWF:Ag
VWF:RCo
[IU/dL]
4 hour post-DDAVP

FVIII:C
VWF:Ag
VWF:RCo
[IU/dL]
8 hour post-DDAVP


FVIII:C
VWF:Ag
VWF:RCo
[IU/dL]
1
30
10
22
110
85
80
50
42
40
30
28
27
28
22
20
2 20
15
14
162
143
144
100
96
92
88
75
73
67
60
60
3 20
15
14
160
140
140
100
95
96
86
78
74
67
62
61
4 1
1
1
1.5
1.2
1.2
1
1
1
<1
1
<1
1
1
1
5 18
62
64
150
140
140
40
95
96
20
78
74
17
62
61
Control 110
95
90
400
220
218
320
300
310
280
260
248
200
190
100

Assume all references ranges are 50-150 IU/dL.
Nb Patient 2 showed a fall in platelet count during the study.

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1. In patient 1 - what additional investigations may be of benefit?

2. In patient 2 - what additional investigations may be of benefit?

3. In patient 3 - what additional investigations may be of benefit?

 

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1. In patient 1 - you request VWF propeptide [VWFpp] studies: Why?

2. In patient 2 - you request platelet aggregation tests with low dose ristocetin [0.5mg/mL]: Why?

3. In patient 3 - you request multimers: Why?


Question 20
A 2-year-old boy develops a haemarthrosis of his left knee following a minor injury. Investigations show:

Test Patient Reference Range
PT 13s 11-14s
APTT 91s 28-34.5s
Fibrinogen (Clauss) 3.6g/L 1.9-3.7 g/L
FVIII:C 1.32 IU/mL 0.50-1.45 IU/mL

1. What is the most likely diagnosis?
2. How would you confirm this?

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You request a Factor IX assay - the raw data for a 1-stage FIX assay are shown below. From the data provided what is the FIX:C level in the patient?

Dilution Patient Control
1/10 78s 41s
1/50 80s 50s
1/100 109s 82s

The FIX:C of the reference preparation is 110 IU/dL.




Question 21

A 4-year-old boy is diagnosed with haemophilia B with a level of 1.2 IU/dL. He is treated on demand with factor IX concentrate to which he responds well.
15 years later at the age of 19 yrs of age he comes for review and you note that he has had no bleeds over the preceding 3 years and required no replacement FIX therapy.

1. What might explain these findings?
2. What further tests might you request?

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1. A possible explanation for these findings is that he has Haemophilia B Leyden.
2. You request F9 gene sequencing. What is this likely to show?


Question 22

A 22-year-old woman from North African decent is investigated for recurrent miscarriages. She gave a long history suggestive of an inherited bleeding diathesis and this included prolonged bleeding from the umbilical stump and poor wound healing.

1. What questions might you ask this patient?
2. What tests would you request next?

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You request a panel of screening tests - the results of which are shown below:

Test Patient Reference Range
PT 13s 11-14s
APTT 28s 28-34.5s
Fibrinogen (Clauss) 2.9 g/dL 1.9-3.7 g/L
Thrombin Time 12s 12-14s
Platelet count 367 x 109/L 150 - 400 x 109/L
PFA-100 Closure times within the reference ranges

What additional tests would you request and why?


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You request a FXIII screen [using 5M Urea]:

Test Patient Plasma Reference Plasma
Clot lysis at 1 hour + -
Clot lysis at 6 hours + -
Clot lysis at 12 hours + -
Clot lysis at 24 hours + -

[+ = lysis has occurred/- = lysis has not occurred]

What do these results suggest and what additional tests would you request


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You request a FXIIIB ELISA assay and the results are reported as 'Normal'. Are you surprised by these results [!] and if so what additional tests would you request?


Question 23
The following results were obtained from a 63-year-old male being investigated for prolonged bleeding after dental surgery. Comment upon the results of these tests.

Test Patient Reference Range
PT 12.2s 9.8-12.6s
APTT 43.8s 25.8-33.8s
Fibrinogen (Clauss) 2.9 g/L 1.6-3.7 g/L

1. What tests would you perform next?

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1. You confirm the results on repeat testing. He has a FVIII of 0.14 IU/ml and and VWF:Ag of 0.09 IU/mL.

 

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Comment upon these results which were obtained following the administration of 5000 units of an intermediate purity Factor VIII concentrate.
What do you think might provide an explanation for this.
Are there any other tests you would request and why?

Time APTT [s]
25.8-33.8s
VIII:C [IU/ml]
[0.57-1.41]
VWF:Ag [IU/ml]
[0.53-1.49]
VWF:Act [IU/ml]
[0.43-1.26]
Pre-sample 43.8 0.14 0.09 0.01
+ 1 hr 31.4 0.56 0.77 0.31
+ 2 hr 35.2 0.37 0.44 0.15
+ 4hr 37.2 0.26 0.24 0.05
+5 hr 38.8 0.20 0.19 0.02
+24hr 43.4 0.14 0.09 0.00




Question 24

Your lab is undertaking factor assays as part of an international trial of a new recombinant factor VIII. You receive a batch of plasma samples for analysis. The results of one of these samples shows:

Test Patient Reference Range
PT 23s 11-14s
APTT 68s 28-34.5s
FVIII:C 0.04 IU/mL 0.5-1.45 IU/mL
VWF:Ag 1.43 IU/mL 0.5-1.45 IU/mL
VWF:Act 1.31 IU/mL 0.5-1.45 IU/mL
FIX:C 1.15 IU/mL 0.5-1.45 IU/mL
APTT50:50 Mix with normal plasma No correction in a mix with normal plasma  

1. Comment upon the results of these tests?
2. What would you do next?

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1. You repeat the tests on a separate sample but from the same patient and collected at the same time. The results of the second batch of tests are shown below:

Test Patient Reference Range
PT 12s 11-14s
APTT 32s 28-34.5s
FVIII:C 1.12 IU/mL 0.5-1.45 IU/mL
VWF:Ag 1.43 IU/mL 0.5-1.45 IU/mL
VWF:Act 1.31 IU/mL 0.5-1.45 IU/mL
FIX:C 1.15 IU/mL 0.5-1.45 IU/mL
APTT50:50 Mix with normal plasma Not performed  

How do you explain these findings?


Question 25

A 67-year-old man is admitted for investigation of haematuria. His initials investigations show:

Test Patient Reference Range
PT 10.1s 9.8-12.6s
APTT 41s 25.8-33.8s
Fibrinogen (Clauss) 3.9g/L 1.6-3.7 g/L
Thrombin Time 13s 11.5-13s
FVIII:C 0.30 IU/mL 0.70-1.50 IU/mL
VWF:Ag 0.05 IU/mL 0.72-1.52 IU/mL
VWF:Act 0.05 IU/mL 0.72-1.52 IU/mL

1. What questions might you ask this patient that would be important?
2. What additional tests might you request and why?

Click HERE for Part 2


1. He has undergone a number of surgical procedures in the past including dental extractions without problems. His last surgical procedure was 8 years previously.
2. There was no family of note.
3. He has a monoclonal IgG paraprotein of 2.3g/L

What is the diagnosis and how will you manage this patient if he requires a prostatectomy?


Question 26

A 67-year-old man was diagnosed mild haemophilia A in 1973. He requires a cholecystectomy and you repeat his FVIII levels.

Investigations show:

Test Patient Reference Range
FVIII 1973 0.35 IU/mL 0.50 - 1.49 IU/mL
FVIII 2010 0.52 IU/mL 0.50 - 1.49 IU/mL

How would you explain these findings?


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