Date Published: February 20, 2018
Publisher: Public Library of Science
Author(s): Andrea Zoia, Michele Drigo, Christine J. Piek, Paolo Simioni, Marco Caldin, Salvatore V. Pizzo.
The primary objective of this study was to determine if activation of coagulation and fibrinolysis occurs in canine pleural effusions. Thirty-three dogs with pleural effusions of different origin were studied. Pleural effusion fibrinogen concentrations were significantly lower, while pleural fibrin-fibrinogen degradation products (FDPs) and D-dimer concentrations were significantly higher than those in plasma (P < 0.001 for all comparisons). These results show that, in canine pleural fluids, there is evidence of coagulation activation and fibrinolysis. The secondary aims of the current study were to determine if primary hyperfibrinolysis ([PHF] i.e., elevated plasma FDPs with a normal D-dimer concentrations), occurs in dogs with pleural effusion, and whether the presence of a concurrent inflammatory process may have activated the hemostatic cascade, with its intrinsically linked secondary hyperfibrinolysis, masking the concurrent PHF. The previously 33 selected dogs with pleural effusion (group 1) were compared to two control groups of 33 healthy (group 2) and 33 sick dogs without pleural effusion (group 3). Serum fibrinogen, FDPs, D-dimer, C-reactive protein (CRP), fibrinogen/CRP ratio, and frequency of PHF were determined. Fibrinogen, FDPs, D-dimer and CRP concentrations in group 1 were significantly increased compared to group 2 (P < 0.001 for all comparisons). FDPs and CRP concentrations in group 1 were also significantly increased compared to group 3 (P = 0.001 and P < 0.001, respectively). The fibrinogen/CRP ratio was significantly decreased in group 1 compared to groups 2 and 3 (P < 0.001 for both comparison). The frequency of PHF was significantly higher in group 1 compared to groups 2 (P = 0.004), but not compared to group 3. These results support the hypothesis that PHF occurs significantly more often in dogs with pleural effusion compared to healthy dogs. Nevertheless, the decrease in the fibrinogen/CRP ratio in group 1 compared to group 3, considering the higher FDPs and similar D-dimer concentrations, would suggest that PHF is also more frequent in dogs with pleural effusion compared to sick control dogs, and that this phenomenon is hidden due to concurrent secondary hyperfibrinolysis.
Fibrinolysis is the process whereby stable fibrin strands are broken down by plasmin . Localized fibrinolysis in response to thrombosis is necessary for the re-establishment of blood flow, and has been termed physiologic fibrinolysis . Pathologic hyperfibrinolysis occurs in disease syndromes that induce increased concentrations of plasminogen activators, decreased concentrations of plasminogen inhibitors, or a combination of both . Primary hyperfibrinolysis (PHF), also sometimes named primary hyperfibrinogenolysis [2,4,5], or pathologic fibrinolysis,  develops independently of intravascular activation of coagulation, and plasmin is formed without concomitant formation of thrombin . In PHF, the production of plasmin within the general circulation overwhelms the neutralizing capacity of the antiplasmins, causing generalized fibrinogenolysis, increased production of fibrin-fibrinogen degradation products (FDPs), degradation of coagulation factors V, VIII, IX, XI , and degradation of any pre-existing fibrin localized in thrombi and hemostatic clots [4,6,7], potentially leading to severe bleeding . Besides an excessive serum plasmin concentration, other enzymes such as serum tryptase or non-plasmic polymorphonuclear elastase have been reported as possible causes of PHF, when their serum concentration overwhelms the neutralizing capacity of the antiplasmins [8–10]. In humans, this has been associated with acute conditions, such as surgical procedures , shock , liver transplantation , acute leukaemia , or treatment with thrombolytic drugs. It can also be observed in chronic conditions such as tumours , chronic liver disease , or following peritoneovenous shunting [16–19]. Secondary or “reactive” hyperfibrinolysis, on the other hand, is a consequence of activation of coagulation causing generation of thrombin which stimulates the endothelium to produce an increased amount of tissue plasminogen activator . Secondary fibrinolysis is present in virtually every patient with disseminated intravascular coagulation (DIC), as it is an appropriate response to persistent thrombin generation . Because “cross-talk” between the inflammatory and hemostatic systems may be responsible for the activation of hemostasis associated with systemic inflammation [20,21], secondary or “reactive” hyperfibrinolysis, is often present in patients with inflammatory diseases.
The primary aim of this cohort study was to investigate whether coagulation and fibrinogenolytic/fibrinolytic activity occurs in any type of canine pleural effusion. The results of the current study show that a) in the pleural effusion of dogs, there is evidence of coagulation activation and fibrinolysis in every case, and b) this phenomenon occurs independently of the underlying mechanism that leads to pleural effusion formation.
In summary, we have shown that pleural effusions have fibrinolytic activity independent of the underlying mechanism of intra-thoracic fluid accumulation, and we also demonstrated that almost 40% of these dogs have systemic coagulative alterations suggesting PHF. The true frequency of PHF in dogs with pleural effusion could have been underestimated in this study due to the concurrent presence of secondary hyperfibrinolysis caused by the inflammatory disease underlying the cause of pleural effusion formation, as suggested from the significant decrease in fibrinogen/CRP ratio in the face of a higher FDPs and similar D-dimer concentrations in dogs with pleural effusions compared to control dogs. These results should support the screening of the systemic coagulative state in all dogs with pleural effusion in order to identify those with PHF. Future studies should assess the risk of bleeding in dogs with PHF and pleural effusion and should assess if these dogs may benefit from treatment with anti-fibrinolytic agents.