Practical-Haemostasis.com

A Practical Guide to Laboratory Haemostasis

 

Data Interpretation: Thrombophilia Assays



Introduction

This section covers thrombophilia assays and thrombophilia testing but strays into other areas and so is not specific to these tests. The reference section will provide information that you may find of help.

Question 1

A 34-year-old woman [II:1 in the pedigree below] is 12 weeks pregnant. She had a brother [II:3] who died from purpura fulminans shortly after birth and subsequent investigations showed that he had homozygous Protein C deficiency with a Protein C activity of <1 IU/dL.

1. What is the risk that her baby [III:1] will be born with homozygous Protein C deficiency. The mother and her partner are unrelated and the prevalence of heterozygous protein C deficiency in the population is 1/500 [for this example].
2. What is the risk that her baby will be born with homozygous Protein C deficiency if the partner is found to have low Protein C activity levels consistent with Protein C deficiency.

The pedigree is shown below to help you:
[Squares - males; circles - females; solid square - affected male;

                   

Click HERE for the Answers
1. I:1 and I:2 must be heterozygous for a mutation in the PC gene as they had a son who had homozygous PC deficiency. II:1 is unlikely to be homozygous for the PC gene mutation as she would have presented early in the neonatal period with neonatal purpura fulminans. The risk, therefore, that II:1 is a carrier of a PC gene mutation is 2/3.

If the carrier frequency of heterozygous PC deficiency in the general population is 1:500 then the risk that III:1 will have homozygous PC deficiency is: 2/3 x 1/500 x 1/4 = 2/6000 = 1/3000.

If there was no family history of PC deficiency and this couple wished to know if they could have a child with homozygous PC deficiency [unlikely scenario] then the risk is the product of the probability that each is a carrier multiplied by 1/4 i.e. 1/500 x 1/500 x 1/4 = 1/1,000,000.i.e. very rare.


2. If the partner [II:2] has heterozygous PC deficiency then then the risk that III:1 will have homozygous PC deficiency is 2/3 x 1/2 x 1/4 = 2/24 = 1/12.


Question 2

A 65-year-old man is admitted for a bioprosthetic aortic valve replacement [AVR]. He comes off cardio-pulmonary bypass without problems but 3 days later develops an iliofemoral DVT. He is treated with unfractionated heparin but his platelet count begins to fall and 5 days into treatment he has a platelet count of 28 x 109/L.

What tests are you going to request and how will you manage this patient?

Test Patient Reference Range
INR 1.2 1.0
APTT 65s 28-34s
Fibrinogen (Clauss) 3.4 g/L 2-4 g/L
Thrombin Time >60s 11.5-13s
Platelet Count 28 x 109/L 150-400 x 109/L


Click here for Part 2


1. You make a diagnosis of HIT and treat him with fondaparinux.

There are a number of tests currently available to confirm a suspected diagnosis of HIT:

Test
Serotonin Release Assay [SRA] Specificity High
Sensitivity High
Technically Demanding
Requires 14C serotonin
Not widely available
Platelet Aggregation Testing Specificity High
Sensitivity Low
Relatively easy to perform
Not recommended due to low sensitivity
ELISA Specificity High
Sensitivity Low
Easy to perform and rapid turnaround times.
OD readings important in predicting the likelihood of HIT
Particle Immunofiltration Assay [PIFA] Specificity High
Sensitivity High
Technically easy.
A negative test can rapidly exclude HIT as a cause of thrombocytopaenia

Lepirudin can be monitored using a variety of laboratory tests including the Ecarin Clotting Time and APTT. The APTT is widely available but may underestimate the degree of anticoagulation. However, Lepirudin is no longer available and therefore in this patient Fondaparinux has been selected to continue anticoagulation.

Unfortunately he needs develops a paraprosthetic valvular leak and 6 months after his original AVR he is scheduled for a replacement. You are asked to advise on how to manage him on bypass and in particular can he receive unfractionated heparin. What would you advise?

The ACCP Guidelines indicate that for a patient >100 days from the the diagnosis of HIT and with no evidence of HIT antibodies then surgery can safely be performed using unfractionated heparin for anticoagulation during bypass. If this was contraindicated e.g. <100 days since the diagnosis of HIT, then Bivalirudin would be a safe alternative.


Question 3

A 43-year-old man has a history of Heparin-Induced Thrombocytopaenia [Type II HIT] and is admitted with an extensive left proximal DVT.
1. How are are you going to manage this patient?
2. Depending on your choice of anticoagulant what tests will you employ to monitor this?

Click here for Part 2


1. You elect to treat him with lepirudin by continuous iv infusion. You monitor his anticoagulation by means of an Ecarin clotting time. 5 days into treatment his requirements for lepirudin begin to decrease. What do you think has happened?

Lepirudin is cleared through the kidney and should be avoided in patients with severe renal impairment [Creatinine clearance < 15 ml/min]. In cases of less severe renal impairment the dose of lepirudin will need to be adjusted. Some patients [as in this patient] develop antibodies to lepirudin and this leads to a decrease in lepirudin clearance prolonging the duration of lepirudin’s effect. In this situation the dose of lepirudin requires to be reduced to prevent over-anticoagulation.


Question 4

A 23-year-old woman is referred to you to discuss a pulmonary embolism she developed following a long-haul flight to the Arctic. The results of her thrombophilia screen [off all anticoagulants] are shown below:

Test Patient Reference Range
Antithrombin activity 92 U/dL >78 U/dL
Protein C activity 34 U/dL >63 U/dL
Protein S activity 35 U/dL >60 U/dL
Lupus anticoagulant Not detected  
IgG Anti-β2 GP1 antibody 2.9 units/ml 1-6 units/ml
1. What is the diagnosis?
2. Are there any other tests you would request and if so why?

Click here for Part 2

1. Investigations show that she is homozygous for the Factor Leiden mutation - is this significant in the terms of other aspects of the thrombophilia screen?

The initial thrombophilia tests show reduced levels of both Protein C and Protein S but it is important to note that these are clotting-based tests rather than chromogenic or immunological assays and therefore, both are sensitive to the presence of the factor V Leiden mutation.
The findings of combined Protein C and S deficiency is rare and suggests that this may be false positive due to some other problem. Vitamin K deficiency or a vitamin K inhibitor such as warfarin are also possible but we are told that the tests were performed when the patient was on no anticoagulants.


2. What additional tests might help you in this situation?

You can perform chromogenic Protein C assays and a free Protein S antigen assay. In this patient these additional tests were normal. It is also possible to adsorb out the Protein S and then repeat the clotting-based functional assay which will in this case would also be normal. It is the presence of the abnormal Factor V molecule that leads to the falsely low Protein C and S results.

In summary - this patient was homozygous for the Factor V Leiden mutation but did not have combined Protein C and S deficiency.


Question 5

An 8-year-old boy with sickle cell disease [Hb SS] develops a portal vein thrombosis. He has a thrombophilia screen performed which shows:

Test Patient Reference Range
Antithrombin activity 104 U/dL >78 U/dL
Protein C activity 35 U/dL >63 U/dL
Protein S activity 42 U/dL >60 U/dL
Free Protein S Ag 46 U/dL >61 U/dL
PT 12s 11.5 - 13.5s

1. Comment upon the results of these tests.
2. Do they provide an explanation for his portal vein thrombosis?

Click HERE for the answers

The laboratory assays suggest the presence of combined Protein C and Protein S deficiency. It would be important to exclude vitamin K deficiency but the PT is normal and so we can assume that this is not the cause of the low Protein C and Protein S.

Protein C and S deficiency has been reported in cases of Sickle Cell Disease although the mechanism is unclear. It has been suggested that the abnormal red cell membrane adsorbs Protein C and Protein S from the plasma.


Question 6

A 4-year-old boy is admitted to hospital with what appears to be purpura fulminans. He has a thrombophilia screen performed which shows:
The only other history of note is that he had recently had a vesicular rash.

Test Patient Reference Range
Antithrombin activity 109 U/dL >78 U/dL
Protein C activity 82 U/dL >63 U/dL
Protein S activity 2 U/dL >60 U/dL
Free Protein S Ag 3 U/dL >61 U/dL
APCr 2.3 >2.20
Prothrombin G20210A G/G [Wild Type sequence]  

1. What is the diagnosis?
2. How will you manage this patient?

Click HERE for the answers

The laboratory tests show low Protein S levels and are strongly suggestive of Protein S deficiency. However, the vesicular rash suggests a diagnosis of Chicken pox and acquired Protein S deficiency secondary to an autoantibody directed again Protein S has been reported in several cases of Chicken pox. Chicken pox is a highly contagious illness caused by a primary infection with varicella zoster.

The management of such patients is complex and can involve plasma exchange, the use of fresh frozen plasma to replace Protein S, IVIG, steroids and intensive care support. The mortality is high.

Although acquired Protein S deficiency is well described in association with Chicken Pox, the development of auto-Protein S antibodies has been reported in association with other viral infections.


Question 7

A 45-year-old man develops an apparent spontaneous proximal DVT. He has some baseline pre-anticoagulant investigations performed:

Test Patient Reference Range
PT 23s 11.5-13.5s
APTT 72s 28-34s
Fibrinogen (Clauss) 3.9g/L 2-4g/L
Platelet count 189 x 109/L 150-400 x 109/L

1. What additional tests might you request?

Click here for Part 2

1. The APTT does not not correct in a mix with normal plasma.
2. What will you request next?

These tests suggest the presence of an inhibitor. As the patient presented with a DVT this suggests that the inhibitor may be a lupus anticoagulant i.e. an anti-phospholipid antibody. It is, however, unusual to see a prolongation of the PT in association with a lupus anticoagulant as the PT test contains large concentration so phospholipid which usually neutralises the anti phospholipid antibody. However they may do if the LA has anti-prothrombin activity as a small proportion do.

The clinical history in this case 'develops an apparent spontaneous...' - and so it is possible that the DVT is not a DVT but a large haematoma that is mimicking a DVT. An ultrasound scan would confirm or exclude a DVT.

So - logical tests would be a screen for a lupus anticoagulant [dRVVT and SCT] and also to measure Prothrombin [Factor II] levels. The PT is prolonged and the patient is not on a vitamin K antagonist. in some cases of a lupus anticoagulant, the LA can have anti-prothrombin activity leading to low prothrombin levels and a prolonged PT [and APTT although APTT is prolonged in this case due to LA.]

 

Click here for Part 3


1. You request a screen for lupus anticoagulant, the results of which are shown below:

Test Patient Reference Range
Silica Clotting Time [SCT] 2.97 <1.54
SCT + PL 54% <15%
Dilute Russell Viper Venom Time [DRVVT] 2.40 <1.20
DRVVT + PL 54.1% <15%

1. What is the diagnosis?
This patient has a lupus anticoagulant.

2. What else will you suggest?
a. Perform a Factor II [Prothrombin] assay.
b. Measure the PT using a variety of different reagents to see if you can identify one that generates a normal PT i.e. is insensitive to the LA. Of cause, if the Factor II [Prothrombin] assay is reduced this may not be possible.
c. You could also check the ANA, anti-cardiolipin antibody titre and anti-B2GPI titre.

3. What anticoagulants would you suggest for this patient?
Initial treatment with a LMWH would with a logical approach. You could then use a vitamin K antagonist such as warfarin if you can identify PT reagents which are insensitive to the LA. If not it has been suggested that measuring FX levels may allow the monitoring of warfarin in patient with a LA.
Alternatively you could try one of the oral direct thrombin or direct Xa inhibitors. Other options would be to continue the LMWH or use the synthetic pentasaccharide Fondaparinux.


4. How will you monitor this patient if he requires long-term anticoagulation with a vitamin K antagonist e.g. warfarin .
See '2' above.


Question 8

Comment upon the results of the following blood tests.
What is the diagnosis?

Test Patient Reference Range
Silica Clotting Time [SCT] 2.77 <1.54
SCT + PL 39% <15%
Dilute Russell Viper Venom Time [DRVVT] 2.01 <1.20
DRVVT + PL 44.1% <15%
APTT 69s 28-34s

1. These results were obtained as part of a pre-operative screen in patient with a suspected colonic malignancy.
2. What advice would you give the surgeons regarding thromboprophylaxis?
3. The surgeons are concerned that this patient will bleed due to the prolonged APTT - what will you tell them.
4. Do patients with a lupus anticoagulant bleed?

Click HERE for the Answers

1. These results were obtained as part of a pre-operative screen in patient with a suspected colonic malignancy.
These results are consistent with the presence of a lupus anticoagulant.

2. What advice would you give the surgeons regarding thromboprophylaxis?
The risk of bleeding is small but the risk of thrombosis is potentially increased due to the the underling colonic malignancy, the requirement for abdominal surgery and the presence of a lupus anticoagulant. Thromboprophylaxis is clearly indicated for this patient.

3. The surgeons are concerned that this patient will bleed due to the prolonged APTT - what will you tell them.
You should reassure them that the greatest risk is of thrombosis rather than bleeding assuming the platelet count is normal. We are not given the PT but if this is normal then this would exclude a deficiency of Factor II [Prothrombin] which is the other reason that some patients with a LA can bleed.

4. Do patients with a lupus anticoagulant bleed?
See above.


Question 9

A 42-year-old woman has a history of 5 consecutive first trimester miscarriages. She has a screen for antiphospholipid antibodies performed and the results are show below:

Test Patient Reference Range
SCT 1.12 <1.54
DRVVT 1.09 <1.20
IgG Anticardiolipin antibody titre 3.2 GPLU/mL 1-12 GPLU/mL

1. Are there any other tests you might request?

Click here for Part 2

1. You request a screen for Anti-β2 glycoprotein I antibodies. The result is 221 units/ml with a reference range of 1-6 units/mL.

2 What is the explanation for these findings and how would you manage a future pregnancy in this lady?

The ELISA assay that is used to screen for Anticardiolipin antibodies used an extract of bovine heart muscle whereas the ELISA that is used to screen for Anti-β2 glycoprotein I antibodies uses recombinant human β2 glycoprotein I. There are slight epitope differences between the two antigens and in some individuals that antibodies will only be recognised by in the human β2 glycoprotein I.

These can be associated the problems in pregnancy and therefore current guidelines would suggest that such individuals should be managed with a combination of a LMWH and low dose aspirin.


Question 10

A 23-year-old man is admitted with suspected appendicitis. He has a pre-operative screen performed which shows:

Test Patient Reference Range
PT 12s 11.5-13s
APTT >120s 28-34s
Fibrinogen (Clauss) 5.1 g/L 2-4g/L
Thrombin Time 12s 11.8-13.2s

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

Click here for Part 2

1. He has no bleeding history despite removal of 4 wisdom teeth 2 years previously.
2. His FXII:C is <1 IU/dL.

What advice will you give the surgeons regarding FXII replacement therapy?
You need to reassure the surgeons that despite the APTT >120s this patient will not bleed and correcting the FXII is not necessary.


Question 11

A 39-year-old barrister is admitted with a proximal DVT. An enthusiastic doctor checks his fasting homocysteine and it is elevated at 220 µmol/L [reference range <16 µmol/L].

What are the possible explanations for this?
What questions might you ask this patient?
What tests might you request?
How will you manage this patient?

Click HERE for the Answers

What are the possible explanations for this?
The homocysteine is significantly elevated and this raises the possibility that this individual may have a deficiency of one of the enzymes involved in Hcy metabolism.

What questions might you ask this patient?
Any family history of note. What drugs is he/she taking. Ethnic origin.

What tests might you request?
You should repeat the test to confirm the abnormality. You should also check the levels of B12, folate and if possible B6. You could also check the renal function of this patient. More specialised assays of the enzymes [or the genes] involved in Hcy metabolism are possible and this may be necessary to establish the cause of the high Hcy.

How will you manage this patient?
1. You can manage the DVT as you would for any patient.
2. You can start the patient on B12, folate and B6 supplements and this often reduces the Hcy levels. In some cases supplementing the diet with Betaine can reduce Hcy levels
.


Question 12

A 2-day-old baby is diagnosed with neonatal purpura fulminans. The results of Protein C assays are shown below:
Comment upon the results of these tests

Test Patient Reference Range
Protein C Antigen 23 U/dL >63 U/dL
Protein C Activity [Chromogenic] 21 U/dL >60 U/dL
Protein S Activity 46 U/dL >61 U/dL


Click here for Part 2


1. You request family studies and these are shown below:

                  

Test Mother Father Brother Reference Range
Protein C Antigen 47 U/dL 80 U/dL 55 U/dL >63 U/dL
Protein C Activity [Chromogenic] 54 U/dL 79 U/dL 53 U/dL >60 U/dL
Protein S [Free Protein S Antigen] 74 U/dL 79 U/dL 82 U/dL >61 U/dL

Comment upon these tests.
The tests in the affected child [II:2] do not support a diagnosis of neonatal purpura fulminans due to homozygous PC deficiency. However, the PC assay is a chromogenic assay and you should repeat the test using a functional, clotting-based assay. Remember, the PC chromogenic assay will not identify all cases of PC deficiency and will be normal for example, if the mutation is in the GLA domain.

Are there any additional tests you would request?
See above.

 

Click here for Part 3


You request a clotting-based functional Protein C assay - the results of which are shown below:

Test Patient Mother Father Brother Reference Range
Protein C Activity
[Clotting Assay]
<1 U/dL 54 U/dL 51 U/dL 54 U/dL >60 U/dL


                  

Comment upon these tests.
The tests in the affected child [II:2] support a diagnosis of neonatal purpura fulminans due to homozygous PC deficiency. Both the mother and father have low PC levels consistent with heterozygous PC deficiency although you cannot be certain of this without genetic testing.

What is the diagnosis and how do you explain the results of all of the tests?
II:2 has homozygous PC deficiency. His mother has a mutation identified by the chromogenic assay but his father has a mutation in the GLA domain - the latter is not detected by the chromogenic assay and only by the functional clotting-based assay.


Question 13

Fill in the missing blanks in the following table:

Snake Venom Which Snake Tests used with this venom
Ancrod Agkistrodon rhodostoma [also known as Calloselasma rhodostoma Defibrinating agent - rarely used today.
Reptilase Bothrops atrox  Clots fibrinogen in the presence of unfractionated heparin. Used to establish if prolonged thrombin Time or APTT is due to the presence of unfractionated heparin.
Botrocetin Bothrops jararaca Induces binding of von Willebrand factor to the platelet GpIb receptor - historically used as a functional VWF activity assay similar to the ristocetin cofactor assay.
Ristocetin Ristocetin is an antibiotic obtained from the bacterium Amycolatopsis lurida Forms the basis for a functional Von Willebrand Factor assay
Botox Botox is a toxin produced from the bacterium Clostridium botulinum None - at least as far as the authors are aware
Protac Agkistrodon contortrix  Protein C activator and used in functional PC and PS assays and well as the APC resistance assay.
Russell Viper Venom Daboia russelii  Forms the basis for the dRVVT which is used to screen for the presence of a Lupus Anticoagulant. RVV can also be used to assay Factor X in plasma.
Ecarin Echis carinatus  Forms the basis of the the Ecarin Clotting Time which can be used to monitor direct thrombin inhibitors and also to screen for a lupus anticoagulant.
Textarin Pseudonaja textilis Activates prothrombin in the presence of phospholipid and so will be prolonged if antiphospholipid antibodies [Lupus anticoagulant] are present.

Question 14

A 19-year-old woman develops a cerebral venous sinus thrombosis. investigations show that she is heterozygous for the Prothrombin G20201A mutation. Is this significant and why?

Click HERE for the Answers

The use of oral contraceptives is more frequent amongst women with cerebral-vein thromboses than controls. For women who take the oral contraceptive pill and who have the prothrombin-gene mutation the odds ratio for cerebral-vein thrombosis rises to ~150.

Martinelli et al N Engl J Med 1998;338(25):1793-1797.


Question 15

A 23-year-old male is admitted and a diagnosis of TTP is made. Your 'Boss' requests an ADAMTS-13 assay and he quizzes you on the various tests available for measuring ADAMTS-13. What methods currently exist for measuring ADAMTS-13?

Click HERE for the answers
1. See the section on ADAMTS13 assays to refresh your knowledge.


Question 16

Look at the following TEG traces and decide what they show:
1.


2.


3.


Click HERE for the Answers

1. The first trace shows a hypercoagulable TEG from a patient who was pregnant.

2. The second trace shows a hypocoagulable trace for a patient with moderate Haemophilia A.

3. The third trace is from a patient with hyperfibrinolysis due to liver disease.


Question 17

A 46-year-old woman is admitted under the care of the surgeons with a mesenteric vein thrombosis. A thrombophilia screen is requested - she was on no anticoagulants at the time of testing.
Comment upon the results of these tests.

Test Patient Reference Range
PT 13s 11.5-13s
APTT 33s 28-34s
Fibrinogen (Clauss) 4.1 g/l 2-4g/L
Platelets 689 x 109/L 150-400 x 109/L

1. Are there any other tests you might request?

Click here for Part 2


You request a JAK2 screen which shows her to be heterozygous for the JAK2 V617F mutation. Do you think this provides an explanation for her mesenteric vein thrombosis? If so why?

The elevated platelet count may be primary or secondary. However, increasingly the JAK2 mutation is recognised as a risk factor for mesenteric vein thromboses. In some cases the JAK2 mutation can be associated with relatively normal counts.


Question 18

A 59-year-old man is admitted for surgery and found to have a prolonged APTT. Comment upon the results of these investigations and suggest additional tests that you might request

Test Patient Reference Range
PT 13s 11.5-13s
APTT 67s 28-34s
Fibrinogen (Clauss) 4.1 g/l 2-4g/L
Platelets 299x 109/L 150-400 x 109/L


Click HERE for Part 2

1. You request FVIII, FIX and FXI assays all of which of are normal.
You also took a very careful bleeding history which was negative.
2. You suspect a lupus anticoagulant and request a dRVVT and a SCT.


Show below are the raw data for these tests. What do these suggest and are the results consistent with the presence of a lupus anticoagulant?

Sample SCT Clotting Time [s] Ratios
Patient Plasma 339.8 s [Patient Plasma]/[Reference Plasma] = 5.20
Reference Control [Normal] Plasma 65.2 s
Patient Plasma + Phospholipid 118.6 s [Patient Plasma + Phospholipid]/Reference Control [Normal] Plasma +  Phospholipid] = 1.90
Reference Control [Normal] Plasma +  Phospholipid 62.2 s
% Correction = 63.5%


Sample dRVVT Clotting Time [s] Ratios
Patient Plasma 149.6 s [Patient Plasma]/[Reference Plasma] = 4.01
Reference Control [Normal] Plasma 37.3 s
Patient Plasma + Phospholipid 51.6 s [Patient Plasma + Phospholipid]/Reference Control [Normal] Plasma +  Phospholipid] = 1.65
Reference Control [Normal] Plasma +  Phospholipid 31.3 s
% Correction = 58.9%

These results confirm the presence of a lupus anticoagulant. Both the dRVVT and the SCT are prolonged in the patient plasma sample and both show significant correction with exogenous phospholipid.



Question 19

A 56-year-old man has a history of Hodgkin's Lymphoma and is in remission following chemotherapy. He is revised in clinic because of sudden onset of bruising, epistaxes and gum bleeding. Examination apart from a number of large bruises was unremarkable. There was no evidence that his Hodgkin's Lymphoma had relapsed.
You request some basic clotting tests, the results of which are shown below:

Test Patient Reference Range
PT 13s 11.5-13s
APTT 32s 28-34s
Fibrinogen (Clauss) 4.1 g/l 2-4g/L
Platelets 299 x 109/L 150-400 x 109/L

Click HERE for Part 2

1. You request a PFA-100 as a screen of platelet function:

PFA-110 Patient Control
ADP-Collagen cartridge > 300s <113s
ADP-Epinephrine cartridge > 300s <112s

What additional tests would you now request?
Platelet aggregation testing

Are there any questions you might ask the patient?
It is sensible to enquire about any drugs this patient may be taking


Click HERE for Part 3

1. The patient had not taken any anti-platelet drugs and had not consumed any foodstuffs that would account for the PFA-100 abnormalities.

2. You request formal platelet aggregation studies and these are show below:

Platelet agglutination with Ristocetin
Platelet aggregation with ADP, Collagen and Adrenaline

What do these results suggest?
The aggregation tests show no agglutination with low dose ristocetin but normal agglutination at higher dose. There is however, defective aggregation with other agonists and the results are suggestive of Glanzmann's Thrombasthenia [GTT].

Are their any additional tests you might request?
Flow cytometry may be useful in this case. Incubating patient plasma with normal platelets may show blocking of the GpIIb/IIIa receptor.


Click HERE for Part 4
Shown below are the results of platelet aggregation traces 3 months later [with no treatment].

What do these suggest?

Platelet aggregation with ADP, Collagen and Adrenaline

The problem has now resolved and we assume that this is a case of transient acquired anti-IIb/IIIa antibodies.


You may wonder why this question is in the section on Thrombophilia Tests? Its here so that you do not focus exclusively on Thrombophilia Testing!



Question 20

A 34-year-old male presents to your local Emergency Department with a 2-day history of a painful swollen left leg. You suspect a DVT and arrange an urgent ultrasound which confirms an extensive proximal DVT extending into the iliac veins.

Test Patient Reference Range
PT 13s 11.5-13s
APTT 22s 28-34s
Fibrinogen (Clauss) 4.1 g/l 2-4g/L
Platelets 356 x 109/L 150-400 x 109/L

Are there any additional tests you might request or questions you might ask?

 

Click HERE for Part 2

1. There are no obvious risk factors that you can elicit for this individuals to develop a DVT
2. There is no family history of note.

You are surprised by the the short APTT and repeat this and it is again short at 21.5s. What additional tests might you request?
In this situation the most likely explanation is a high FVIII level and so you should measure Factors VIII [IX, XI and XII].

 

Click HERE for Part 3

You request Factor VIII, Factor IX, Factor XI and Factor XII assays.

What do you think might be the explanation for this.
See below - this is a very rare problem.

How will you manage this patient?
Conventional treatment with initially a low molecular weight heparin followed by anticoagulation with a vitamin K antagonist is effective.

The Factor assays are normal apart from the Factor IX which is 4.56 IU/m [reference 0.5 1.5 IU/mL].

This patient has Factor IX Padua - an X-linked disorder due to a missense mutation as position 31134 [G→ T] that results in the substitution of a leucine for the normal amino acid at position 338. This substitution lead to a significant increase in FIX clotting activity. This region of Factor IX appears to be important in the binding binding of Factor X [the substrate for FIX] and increases the efficiency of this binding significantly.




Click HERE to to return to the top of the page