Algorithm of Cunningham et al for Laboratory Testing in a Patient with Suspected Dysfibrinogenemia

 

Patient selection: Bleeding or thrombosis not explained by other more common disorders (exclusion), or the finding of a prolonged thrombin time.

 

Testing (variable depending on findings):

(1) fibrinogen activity (functional assay)

(2) thrombin time

(3) reptilase time

(4) fibrinogen antigen, with determination of the activity to antigen ratio

(5) liver function tests

(6) molecular analysis of fibrinogen protein and gene

 

Initial evaluation:

(1) fibrinogen activity

(2) thrombin time

(3) exclude exposure to heparin, dextran or hydroxyethyl starch

Thrombin Time	Additional Test	Assessment
normal	reptilase time	if reptilase time prolonged follow protocol below; else discontinue
prolonged	exclude heparin exposure	pursue protocol below
shortened	exclude exposure to dextran or starch	evaluate for inherited dysfibrinogenemia

 

Protocol:

(1) Measure the fibrinogen activity to antigen ratio.

(2) Perform liver function tests.

 

Fibrinogen Activity to Antigen Ratio	Liver Function Tests	Assessment
normal	NA	perform thrombin time mixing study
decreased	elevated	if there is no evidence of inherited dysfibrinogenemia suspect acquired dysfibrinogenemia
decreased	normal	evaluate for inherited dysfibrinogenemia

 

The thrombin time mixing study consists of performing a thrombin time on the following mixtures:

(1) mixture 1: 1:1 mix of patient plasma with pooled normal plasma

(2) mixture 2: 1:1 mix of defibrinated patient plasma with pooled normal plasma (defibrination achieved by heating to 56°C for 10 minutes).

(3) mixture 3: control of 1:1 mix buffered saline and pooled normal plasma.

A patient with an acquired dysfibrinogenemia will have a prolonged thrombin time in mixture 1 but normal mixture 2, since the acquired dysfibrinogen interferes with fibrin clot formation in mixture 1 but is not available to do so in mixture 2.

 

Inherited dysfibrinogenemia workup:

(1) Evaluate other family members.

(2) Perform fibrinogen protein analysis (usually starting with electropheresis).

(3) Perform fibrinogen gene analysis.

 

The molecular workup is expensive and is warranted in those with significant symptoms or to establish a familial disorder.

 

Serum Fibrinogen Activity	Term with dysfibrinogenemia
decreased	hypodysfibrinogenemia
normal	dysfibrinogenemia
increased	hyperdysfibrinogenemia