Acquired hypofibrinogenemia: current perspectives

Figures & data

Figure 1 Schematic structure of the fibrinogen molecule.

Table 1 Causes of hypofibrinogenemia and dysfibrinogenemia

Condition	Cause	Examples	Phenotype
Acquired hypofibrinogenemia	Reduced synthesis	Liver disease	Variable bleeding
	Increased consumption	tPA therapy, cancer, sepsis with DIC	Variable bleeding, may be prothrombotic or compensated asymptomatic
	Hemodilution	Massive transfusion	Variable bleeding
Acquired dysfibrinogenemia	Assay interference	Direct thrombin inhibitors (Dabigatran, Bivalirudin, Argatroban), other thrombin inhibitors (Heparin)	Variable – may be asymptomatic or have bleeding symptoms
	Posttranslational modification	Abnormal sialylation in liver disease	Variable – may be hemorrhagic or prothrombotic (eg, portal vein thrombosis)
	Autoantibody formation	MGUS or myeloma, autoimmune disease (eg, SLE), drug induced	Variable – may be asymptomatic or present with bleeding symptoms. May be associated with prothrombotic phenotype in SLE
	Paraneoplastic structurally abnormal fibrinogen production	Cervical endothelial cells, hepatoma cells in vitro	May predispose to thrombosis or bleeding. In vivo effect usually confounded and unclear

Abbreviations: DIC, disseminated intravascular coagulation; tPA, tissue plasminogen activator; MGUS, monoclonal gammopathy of uncertain significance; SLE, systemic lupus erythematosus.

Figure 2 A schematic representation of the formation of a fibrin clot including time to initiate coagulation, rate of formation of fibrin, formation of the stable clot, and strength of the clot once formed. Individual parameters available for the assessment of fibrinogen status are annotated.

Notes: Phases of fibrin polymerization and breakdown and the parameters that can be used in conventional clotting assays and viscoelastic assays to quantify the fibrin polymerization and lysis process.
Abbreviations: MCF, maximum clot firmness; MA, maximum amplitude; PT, prothrombin time; MAXV-t, time to maximum velocity; Fgn, fibrinogen; R time, CT, time to clot.

Figure 3 Determination of fibrinogen level (latex agglutination) during cardiopulmonary bypass in a patient anticoagulated with high-dose direct thrombin inhibitor (DTI – Bivalirudin).

Notes: No fibrinogen level was available when tested using the prothrombin-derived fibrinogen assay. Although a result was obtained using the Clauss method, it was substantially lower than that determined using the latex agglutination assay. This is due to DTI inhibition of thrombin in the Clauss assay. The latex assay was useful to ensure that consumption due to active bleeding was not being encountered although the activity of the fibrinogen infused is still under debate as the inhibition of the thrombin in the reagent would be expected to also be affecting the thrombin generation within the patient. ^*Not available.
Abbreviations: PT, prothrombin time; aPTT, activated partial thromboplastin time; Pre-op, preoperative; CPB, cardiopulmonary bypass; Fgn, fibrinogen; TT, thrombin time.

Figure 4 Schematic representation of a ROTEM/TEG FIBTEM/functional fibrinogen plot with parameters and the effect of drugs and deficiencies on the various phases and parameters of the assay.

Table 2 Impact of hypofibrinogenemia on important laboratory assays

Type of assay	Impact of acquired hypofibrinogenemia	Example (including but not limited to)	Comments
Clot based	Extensive	PT, aPTT, factor assays	Severe (<0.7 g/L) fibrinogen may lead to failure of the sample to clot
Immunological	Dependent on assay performed	Protein S, VWF, fibrinogen antigen assays	Fibrinogen antigen will be reduced
Chromogenic	Limited	Protein C, antithrombin (II based)	Dabigatran causes a falsely low fibrinogen and apparent acquired hypofibrinogenemia if it is not known that the patient is taking it. Additionally, spurious inhibition of thrombin in the antithrombin assay leads to a falsely elevated antithrombin level
Chemiluminescent	None	HIT screen, D-Dimer

Abbreviations: PT, prothrombin time; aPTT, activated partial thromboplastin time; VWF, von Willebrand factor; HIT, heparin-induced thrombocytopenia.