A male patient in his 20s attends A&E after experiencing excessive bleeding during a routine dental procedure. The patient does not take any anticoagulants and has no past history of haemorrhages. In A&E, an FBC and clotting screen were requested. The results of the FBC were unremarkable.
Q1: From which derivative curve shown above would the APTT value determined?
APTT would be determined from the peak of the second derivative curve, where the rate of conversion of fibrinogen to fibrin is represented.
The patient’s APTT result resembled the plot shown above.
Q2: Which abnormal feature is present in this curve? What could this feature indicate?
A biphasic curve (or double-peak) is shown in the plot above. These are often associated with coagulation disorders such as positive lupus anticoagulant, FVIII and FIX deficiency, and Von Willebrand Disease.
The results from the patient’s clotting screen are:
| Patient’s Result | Reference Range |
PT (s) | 13.0 | 11.0-15.0 |
APTT (s) | 44.0 | 23.0-37.0 |
Fibrinogen (g/L) | 3.68 | 1.50-5.00 |
The APTT was found to prolonged. Following this, a mixing study was performed.
Q3: If the mixing study does not correct the prolonged APTT, what could this mean is causing the prolonged APTT?
If the APTT does not correct in a mixing study this means that there is no factor deficiency, and the cause of the prolonged APTT is likely the result of an inhibitor in the patient’s plasma.
Q4: Why is a lupus anticoagulant performed in cases of unexplained prolonged APTT?
Patient’s with antiphospholipid syndrome may produce lupus anticoagulant antibody. These autoantibodies target the epitopes of phospholipids bound in cell membranes. This leads prothrombotic effects in vivo but prolonged APTT results in vitro.
The mixing study corrected the APTT value therefore the sample was sent to be tested for intrinsic pathway factors: FVIII, FIX, FXI, and FXII. The results are shown below:
| Patient’s Result | Reference Range |
FVIII (IU/dL) | 52 | 50-200 |
FIX (IU/dL) | 136 | 60-150 |
FXI (IU/dL) | 144 | 70-160 |
FXII (IU/dL) | 144 | 50-200 |
Q5: Do these results explain the patient’s bleeding episode? What role does FVIII have in haemostasis?
These results show the patient’s FVIII level is borderline. FVIII is a coenzyme responsible for accelerating the generation of FXa and subsequently thrombin (which cleaves fibrinogen to fibrin). FVIII is also responsible for stabilising VWF. Reduced FVIII is associated with bleeding tendency.
Q6: Based on these results and clinical history, is Haemophilia A or Von Willebrand Disease more likely? What tests could be performed to differentiate Haemophilia A from Von Willebrand Disease?
This case may suggest VWD as patients with VWD often receive a diagnosis later in life than compared to Haemophilia A patients. This is due to most cases of VWD causing only mild disease. The following tests are often required to diagnose VWD:
FVIII:C – a measure of the functional FVIII as FVIII activity is reduced in some VWD types.
VWF Ag – the level of functional (and non-functional) VWF. VWF concentration and functionality is reduced in VWD.
VWF:GPIbB – a measure of platelet glycoprotein activity, decreased activity represents the failure of VWF to bind to glycoproteins present on platelet membranes.
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