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The Hong Kong Association of Blood Transfusion and Haematology

BLEEDING TENDENCY IN DYSFIBRINOGENAEMIA
Dr. Kate Leung*, Dr. Herman Liu**, Dr. Raymond Chu***

* Medical Officer, Haematology Division, Department of Pathology, Queen Mary Hospital
** Medical Officer, Department of Medicine, Pamela Youde Nethersole Eastern Hospital
*** Consultant Haematologist, Department of Pathology, Pamela Youde Nethersole Eastern Hospital

Case presentation:

A 74-year old man presented with a spontaneous large buttock haematoma after slipped and fell.Detailed questioning revealed a subjective weight loss of 10 pounds recently.He also complained of constipation and a recent colonoscopy was performed that showed normal finding. 

Past medical history includes: (1) Hypertension on Betaloc zok 200mg daily & Plendil 5 mg daily, (2) Right pleural effusion with pleuordesis done for years, (3) Benign renal mass with excision done in 1997 at a private hospital, (4) Inguinal hernia operated in 1998 at a private hospital, (5) Benign prostate hypertrophy with TURP done in 1999 at a private hospital. Currently he was put on anti-hypertensives, anti-cholinergics (detrusitol 1 mg OM) and fibre. He denied taking any herbal medicine. 

Physical examination was unremarkable apart from the large haematoma over the thigh and buttock region, around 10 cm in diameter, tender on palpation.Blood pressure was 147 / 79 mm Hg and pulse rate was regular at 75 beats per minute.Examination of other systems was unremarkable. 

Complete blood picture: haemoglobin 15.1 g/dL, white blood cell 11.9 x 109/L, platelet 208 x 109/L. Clotting screen: prothrombin time (PT) 51.0 seconds, INR 3.9, activated partial thromboplastin time (APTT) 41.3 seconds.Blood biochemistry: sodium 142 mmol/L, potassium 3.3 mmol/L, urea 4.1 mmol/L, creatinine 90 mmol/L, albumin 35 g/L, globulin 28 g/L and bilirubin 35 mmol/L, alkaline phosphatase 106 U/L, alanine transferase 28 U/L. 

Clotting profile was repeated and the results were: PT >120 seconds, INR >8, APTT 39 seconds, thrombin time (TT) >50 seconds, D-dimer <0.5 mg/L.Four units of fresh frozen plasma and 10 mg vitamin K were given intravenously.Clotting profile after treatment showed PT 20.5 seconds, INR 1.8, APTT 36.9 seconds. 

The coagulation profile was again repeated using different reagents and the results were tabulated in Table 1.

 Table 1. Coagulation assays on the patient.  
Patient 
Reference range
Prothrombin time (RecombiPlasTin* by Ortho Diagnostic Systems Inc.)
>120 secs
8.0 - 12.0 secs
Prothrombin time (Thromborel S* by Dade Behring)
16.6 secs
11.3 - 13.2 secs
Activated partial thromboplastin time (Automated APTT reagent by Organon Teknika)
39.0 secs
24.0 - 38.0 secs
Activated partial thromboplastin time (Thrombosil I by Ortho Diagnostic Systems Inc.)
35.9 secs
27.6 - 37.6 secs
Thrombin time (Thromboquik by Organon Teknika)
> 50 secs
Control TT 13 secs
Thrombin time (Thrombin by Sigma) 
> 110 secs
Control TT 14 secs
Correction with 25 mg protamine sulfate
> 110 secs
Fibrinogen (by Clauss functional method)
< 0.1 g/L
2.0 - 4.0 g/L
Fibrinogen (by Clauss functional method)
0.13 g/L
1.46 - 3.38 g/L
D-dimer (Fibrinosticon by Organon Teknika)
< 0.5 mg/ml
< 0.5 mg/ml
D-dimer (FDP-Slidex direct by bioMérieux)
< 0.5 mg/L
0 - 0.5 mg/L

* RecombiPlasTin consists of recombinant human tissue factor; and Thromborel S consists of human placental thromboplastin

A 1:1 mixing study with normal plasma was performed on the thrombin time, which showed a partial correction of the clotting time (56.1 secs), with a control 1:1 mix thrombin time of 14.0 secs.The fibrinogen level of the 1:1 mix of patient and normal plasma was 0.76 g/L, while that of normal plasma was 2.6 g/L. Factor assay curves of factors II, V, X and VII were all in parallel and levels were within normal range.

When manual tilt-tube method of prothrombin time was performed using the RecombiPlasTin, no end-point detection was obtained.

As dysfibrinogenemia was suspected in this case, so the antigenic measurement of the fibrinogen level was also checked, and was found to be normal (around 3 g/L).A final diagnosis of dysfibrinogenemia was made.A family study was indicated, but unfortunately, he had only one brother in Hong Kong, and the others were in China.All the clotting tests and fibrinogen level (both functional & antigenic) was normal in his brother.

Six units of fresh frozen plasma were given but without much improvement in the clotting times.But there were no new bruises developed. The patient was discharged and followed up in out patient clinic.

Discussion:
 
The exact incidence of dysfibrinogenemia has not been determined, though both hereditary and acquired forms of dysfibrinogenemia are known to be rare conditions.Structural defects in the fibrinogen molecule can lead to either thrombosis (20%) or bleeding (25%), but majority of the reported families of dysfibrinogenemias (around 55%) are clinically asymptomatic.Many of them are alarmed by an abnormal laboratory test, usually a prolonged thrombin time or reptilase time.
Low or discordant fibrinogen levels, together with an abnormal clotting time, are sufficient for a diagnosis of fibrinogen dysfunction.However, in most laboratories, only the functional assay of fibrinogen level is employed.

Prothrombin time is widely use coagulation screening test, and it is also widely known that the variable sensitivities in the different thromboplastins used.But generally, the results could be converted to comparable values by means of the International Sensitivity Index (ISI), especially for patients on oral anticoagulants.A discrepancy between mechanical and spectrophotometric clot detection method found in a new fibrinogen variant has been reported before.The postulated mechanism of the fibrinogen defect is affecting the fibrin polymerization enough to effect light scatter interpretation, while there is enough polymerization to increase plasma viscosity to yield an end point using an electromechanical analyzer.

More significantly, as in our case, the discrepancy between human tissue derived thromboplastin and recombinant human tissue factor is seen.Perhaps the difference in protein concentrations or ionic strength may affect the degree of fibrin polymerization in dysfibrinogenemia.Hence the end-point detection can be detected in some clotting systems (like human tissue derived thromoboplastin PT or APTT system) but not in the other systems (like recombinant human tissue factor PT or thrombin time).Unfortunately, we were unable to prove this.

The above case should alert us the possible discrepancies between the various reagents used in PT.Furthermore, in screening a case of suspected clotting disorders, different clotting based systems should be used, otherwise, we might missed the defect.

References:

1.Dysfibrinogenemia and other disorders of fibrinogen structure and function. From Haemostais and Thrombosis: Basic Prinicples and Clinical Practice, 3rd edition, Colman & Hirsh, Chapter 16.

2.Fibringogen Longmont: A dysfibrinogenemia that causes prolonged clot-based test results only when using an optical detection method. American Journal of Hematology 63: 149-155 (2000).

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