Introduction
Whereas glomerular diseases (GD) are typically considered prothrombotic, tubule-interstitial "uremic" renal diseases such as chronic kidney disease (CKD) and acute kidney injury (AKI) are mostly referred to as antithrombotic with increased risk of uremic bleeding. Accurate assessment of the hemostatic status of animals with renal diseases is essential for the safe performance of diagnostic procedures and to guide therapeutic interventions. However data on prevalence and types of hemostatic disorders and the diagnostic value of available tests are sparse.
Evaluation of Hemostasis in Small Animals with Renal Disease
Despite a severe lack of clear data concerning the respective value of individual tests available to assess the function of the hemostatic system, a thorough evaluation of the renal patient should aim to assess at least the primary and the secondary hemostasis. This is of particular interest in animals planned for more invasive diagnostic procedures (i.e., renal biopsy) or therapeutic interventions (i.e., renal replacement, interventional urological procedures). Despite all the limitations associated with the interpretation of the in vitro testing of hemostasis and the complexity of the interactions between primary and secondary hemostasis, this artificial division is still useful for the stepwise evaluation of the hemostatic system, as long as we realize that this simplified scheme cannot be transferred as such to the in vivo situation.
Primary Hemostasis
Platelet count, platelet function, vascular function and von Willebrand factor activity typically define together the primary hemostasis. Platelet function can be evaluated with various tools including the platelet function analyzer (i.e., PFA-100) in which citrated blood is aspirated at high shear rates through an aperture in a membrane coated with collagen and either epinephrine or ADP. These agonists induce platelet adhesion, activation and aggregation and lead to a rapid occlusion of the aperture termed the closure time. Clinically, however, the primary hemostasis is most often evaluated globally using the buccal mucosal bleeding time (BMBT) after having made sure that the platelet count is normal. By making a standard incision in the buccal mucosa, the time necessary for the formation of a primary clot is recorded. Cessation of bleeding within less than 3 minutes is considered normal. In a study including 10 normal dogs and 63 dogs with AKI or CKD, both groups of disease showed approximately doubled BMBT compared to the normal dogs. This was in most dogs the only evidence of uremic bleeding and was at least not clearly correlated with the level of azotemia. Measurement of von Willebrand factor was not useful in the diagnostic evaluation of the hemostasis in these dogs.
Secondary Hemostasis
Evaluation of both arms of the coagulation cascade with the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) has been well established in small animal medicine and provides, together with the fibrinogen concentration, a reasonable first evaluation of the secondary hemostasis. These 3 tests and the measurement of individual factors do not seem to be of strong relevance in the renal patient, with the exception of AKI where DIC or liver failure may be involved. Abnormal secondary hemostasis is otherwise rare in renal diseases and reflects more the polysystemic nature of AKI, including a wide array of underlying etiologies.
Additional Tests
The most often cited other test of hemostasis in dogs with GD is probably antithrombin, a protein almost the size of albumin that is lost in the urine of animals with protein-losing nephropathy. Loss of antithrombin has been associated with the risk of thrombosis and it has been suggested that its concentration parallels that of albumin. Dogs with a serum albumin concentration < 20 g/L often have a significantly decreased antithrombin activity and are considered at risk of thrombosis. This cutoff has, however, recently been challenged and it seems more likely that all dogs with protein-losing nephropathy have a certain risk of thrombosis. Antithrombin has also been shown to be decreased in some dogs with AKI, participating to the commonly encountered hypercoagulable or mixed hyper-hypo-coagulable condition of these dogs. D-dimer measurement may be used to evaluate dogs with suspect DIC (therefore mostly dogs with AKI), although the true value of this assay in the renal patient is difficult to assess, many dogs yielding positive results after surgery or other bleeding episodes.
Thromboelastography or thromboelastometry refers to a viscoelastic method for the global in vitro evaluation of hemostasis. It investigates the interaction of coagulation factors, their inhibitors, platelets and other blood cells during clotting and fibrinolysis. In small animal medicine, it is typically considered as one of the main methods to assess hypercoagulability in clinical patients. Using this method, it has been shown that dogs with GN, but also dogs with AKI and CKD have marked prothrombotic features.
Main Clinical Disorders of Hemostasis in Dogs with Renal Disease
Uremic Platelet Dysfunction
Uremic platelets develop an acquired dysfunction, possibly causing bleeding complications. The pathogenesis of this hemostatic disorder is multifactorial and includes effects of circulating toxins, alterations of the vessel wall, anemia and other factors. The correction of the azotemia with hemodialysis usually decreases uremic bleeding but fails to correct it completely, supporting the complex pathogenesis of this uremic manifestation. Petechiation, bruising and mucosal bleeding are often observed in severely uremic animals and sometimes contribute to the anemia of the renal patient.
GN-Associated Hypercoagulability
The animal with GN is typically hypercoagulable, the degree of this complication being related to the severity of the proteinuria. Glomerular loss of antithrombin, platelet activation and sometimes thrombocytosis, as well as microvascular disease all contribute to this feature of GN in dogs. A study from Cook et al. described thrombotic complications as main cause of death in 22% of 137 dogs with GN, emphasizing the need for anticoagulation therapy in these dogs. The recently published consensus on the therapy of glomerular disease clearly recommends therapy with low-dose aspirin in affected dogs.
CKD and AKI
In a recent study performed by the author, approximately 70% of dogs with CKD demonstrated clear evidence of a prothrombotic condition. The only evidence or uremic bleeding was seen in the BMBT in some dogs, with 20% of the dogs showing mixed pro- and anticoagulatory features.
Dogs with AKI had the widest spectrum of hemostatic disorders with approximately 1/3 being hypercoagulable, 1/3 hypocoagulable and 1/3 showing mixed features. The most extreme hemostatic abnormalities in both directions were encountered in this group of dog.
In light of this discussion, it appears that the simple associations proteinuria-hypercoagulation or uremia-hypocoagulation are too simplistic and that a correct assessment of individual dogs requires an individual thorough evaluation of their hemostasis.
Although no single test predicts fully the hemostatic status of individual dogs, the simple BMBT seems to best evaluate a potential hypocoagulable status, whereas plasma fibrinogen concentration and thromboelastometry seem to be adequate for assessing an elevated thrombotic risk in dogs with renal disease. The magnitude of the observed disorders probably indicates further that the simplified classification of renal patients as hypo- or hypercoagulable may need further refinements.
Therapeutic intervention is at this stage certainly warranted for dogs with clear hypocoagulability (typically some dogs with AKI) and in dogs with GN-associated hypercoagulability. Interventions in other dogs or cats with renal diseases cannot be recommended at this stage due to the lack of available data.
References
1. IRIS Canine GN Study Group, Standard Therapy Subgroup, Brown SA, et al. Consensus recommendations for standard therapy of glomerular disease in dogs. J Vet Intern Med. 2013;27(S1):S27–43.
2. Francey T et al. Evaluation of hemostasis in 256 dogs with renal disease. ACVIM; 2013. Abstract.
3. Escolar G et al. Uremic platelet dysfunction: past and present. Curr Hematol Rep. 2005;4:359–367.