Disorders of fibrinolysis can result in thrombosis (if fibrinolysis is deficient or inhibited) or hemorrhage (accelerated fibrinolysis). Due to the difficulties with confirming fibrinolysis and the fact that fibrinolysis will be, in large part, dictated by the strength of the fibrin clot that forms initially (thin fibers formed under conditions of low thrombin are more susceptible to fibrinolysis versus thicker clots which form under higher thrombin concentrations). The extent of our knowledge of fibrinolytic disorders has been impaired by the relative lack of tests that are specific for fibrinolysis. Although D-dimer, a marker of breakdown of crosslinked fibrin, is a readily available test for fibrinolysis, D-dimer concentrations can also be increased if there is decreased clearance (e.g. hepatic synthetic failure with decreased Kupffer cell function as presumably Kupffer cells clear D-dimer) or enzymes other than those normally associated with fibrinolysis (e.g. tissue or urokinase plasminogen activator; tPA or uPA) breakdown fibrin instead, e.g. neutrophil or bacterial proteases. However, with the advent of tissue plasminogen activator (tPA)-triggered fibrinolysis with thromboelastographic viscoelastic-based testing (e.g. TEG) and thromboelastometric viscoelastic-based testing (e.g. ROTEM), fibrinolysis can now be evaluated, particularly when excessive, in dogs and cats (Dengate et al 2013, Spodsberg et al 2013, Fletcher et al 2014, Jeffery et al 2017, Sigrist et al 2018). Note that clot retraction can mimic fibrinolysis (Marly-Voquer et al 2017) when tPA is not added.
Although fibrinolysis has been distinguished as a primary disorder (e.g. independent of thrombin activation) or secondary to activation of hemostasis, it can be difficult to distinguish between these scenarios.
Excess fibrinolysis
This will predispose an animal to hemorrhage. This could be due to the following mechanisms (or a combination thereof):
- Increased release or activity of plasminogen activators (tPA or uPA): This will result in excessive conversion of plasminogen to plasmin and could be due to physiologic stimuli (e.g. endothelial injury, bradykinin liberated from kallikrein after activation of the contact pathway of hemostasis) or pathologic (or pathogen)-related variables, e.g. physical injury of endothelial cells, such as by filarial worms (Sigrist et al 2017).
- Deficient inhibitors: Inhibition or deficiency of plasminogen activator inhibitor (PAI-1) will result in increased activity in tPA or uPA. A genetic defect in English Springer Spaniels with excessive hemorrhage appears to be due to a deficiency of PAI-1 based on genetic studies. High concentrations of activated protein C are thought to underly the pathogenesis of hyperfibrinolysis and bleeding in trauma patients (activated protein C inhibits PAI-1). Neutrophil proteases can also cleave PAI-1. A deficiency of α2-anti-plasmin, the main inhibitor of plasmin, was uncovered as the cause of delayed bleeding in Scottish Deerhounds (Court et al 2023).
Excessive fibrinolysis has been reported with cancer, infection with Angiostrongylus vasorum in dogs, various types of liver disease, and trauma. In most studies of excessive fibrinolysis in dogs, the affected dogs also had hypocoagulable profiles so it is not known if they had primary fibrinolysis (Dengate et al 2013, Spodsberg et al 2013, Fletcher et al 2014, Jeffery et al 2017, Sigrist et al 2017, Sigrist et al 2018). It is also unclear if such animals would benefit from fibrinolytic inhibitors. At Cornell University, we have seen individual cases of dogs with excessive hemorrhage that respond to fibrinolytic inhibitors, such as ε-aminocaproic acid. These dogs do not have hypocoagulable TEG profiles or abnormal coagulation results, so they do appear to have a primary fibrinolytic disorder, the exact cause of which is unclear. Similarly, some Greyhounds suffer from excessive hemorrhage, which responds to ε-aminocaproic acid, suggesting they too have an, as yet uncharacterized, fibrinolytic defect (Couto, personal communication).
Insufficient fibrinolysis
This will predispose an animal to thrombosis and can be caused by the following mechanism:
- Excess PAI-1: This occurs with trauma and endotoxemia in humans and contributes to the thrombotic phase of DIC secondary to endotoxemia. High PAI-1 is also seen in horses with colic and endotoxemia (Collatos et al 1994). Bacterial and platelet polyphosphates and extracellular histones and DNA form a stronger fibrin clot and can inhibit fibrinolysis directly (e.g. inhibiting the action of tPA, act as a cofactor for fibrinolytic inhibitors) (Alhamdi and Toh 2017).
- Formation of a stronger clot with thicker fibrin fibrils: This will occur with excessive prodution of thrombin, which also activates thrombin-activatable fibrinolytic inhibitor, which inhibits clot breakdown by competing with plasminogen binding to lysine residues in fibrin. In fact, the fibrinolytic inhibitor, ε-aminocaproic acid, provides lysine residues to compete with plasminogen. Histone, extracellular DNA, polyphosphates and neutrophil constituents, such as α-defensins, can also increase stability and strength of the clot, thus inhibiting fibrinolysis and promoting thrombosis.
Insufficient fibrinolysis is thought to underpin thrombosis that occurs in DIC with bacterial sepsis in humans and horses. We can use pharmacologic agents (tPA and streptokinase) to break down large clots.
