Case Answer
This cat was rapidly diagnosed on physical examination with aortic thromboembolism (ATE) or a saddle thrombus secondary to congestive heart failure (CHF). He was treated for pain and attempts to correct his acid base disturbances were made. His condition did not improve and he was humanely euthanized.
The saddle thrombus forms at the distal trifurcation of the aorta and causes partial or complete loss of blood supply to one or both of the hindlimbs. The loss of blood flow is often evident in a lack of a femoral pulse, hind limbs that are cool to the touch, and pale digital pads. This condition results in severe nerve and muscle damage. Upon cardiac auscultation, a murmur is often noted, as was the case in this cat. Middle-aged male cats are reportedly at an increased risk of developing this condition.1
The marked increase in CK supports severe muscle injury, which is the inciting cause of the majority of the biochemical changes observed (answer to question 1). There are few processes in small animals that cause this marked of an increase in CK and a saddle thrombus is one of them. The high AST and ALT activities are likely from muscle injury as well. Hypoxic injury to the liver secondary to additional thrombi may also have a minimal contribution to the increased AST and ALT activities. Rhabdomyolysis can release large amounts of K+ into circulation and this is likely the main contributor to this cat’s hyperkalemia. Additionally, reperfusion triggers over-activation of K/Ca2+ channels. Hyperkalemia is a main mortality risk for these cats over the first 2-3 days.2 Unfortunately, many cats with ATE are actually hypokalemic on a whole body level and aggressive treatment of the hyperkalemia can precipitate a hypokalemic state.
The cat has a severe primary, high anion gap titrational metabolic acidosis. The unmeasured anions are a combination of phosphates and sulfates accumulating secondary to a decreased glomerular filtration rate (GFR) and lactic acid formed as the result of decreased tissue oxygenation secondary to the occlusive thrombosis. The cat’s blood gases also show a respiratory acidosis which is compounding the metabolic acidosis. The cat was not reported to have vomited at home, nor was vomiting in the hospital observed. Thus, the corrected hypochloremia (108 mEq/L) is interpreted as the result of increased ammoniagenesis in the kidney as there is an attempt to excrete the acid load (as NH4Cl). In chronic respiratory acidosis, there will be increased regeneration of bicarbonate in the kidney. In this cat, even if there were time for this to occur, the effort to compensate might continue to be thwarted by the effects of titration if the cause of the metabolic acidosis is not corrected. (answer to question 2)
The azotemia is marked and is likely renal and prerenal in origin. Urine was not obtained, but the azotemia did not correct with fluid therapy. Renal infarction is not uncommon in cats with hypertrophic cardiomyopathy and may have contributed to renal injury in this case.1 Release of myoglobin and purine from damaged muscle cells can also cause tubular injury and if this cat’s kidneys are not already injured, he is at major risk of developing acute kidney injury and eventually failure. (answer to question 3) In people with crush injuries and skeletal muscle necrosis, alkaline diuresis ± dialysis are recommended to help ward off renal damage. The hyponatremia is secondary to the cat’s congestive heart failure (CHF) and dilution of the extracellular fluid compartment. This occurs in CHF as perceived poor perfusion triggers the renin-angiotensin system and creates a sodium-avid state. As the cat’s sodium level transiently increases, there is a thirst drive to promote water consumption and this expands the extracellular fluid. Unfortunately, this creates a vicious cycle because the cat’s circulatory system is not able to distribute the fluid evenly and third-spacing of fluids occurs. In cats, this most frequently manifests as a chylous pleural effusion. Acute necrosis of muscle may also be contributing to hyponatremia by causing a shift from the extracellular to the intracellular space. The hyperphosphatemia and hypermagnesemia could be explained by decreased GFR from the azotemia as well as release from injured skeletal muscle. Total calcium could be low secondary to renal azotemia, hypoalbuminemia or movement intracellularly into damaged muscles as postulated for equine myopathies. The normal ionized calcium may be due to the severe acidemia offsetting intracellular shifts or azotemia-associated changes. The mildly low albumin concentration could be attributed to dilutional effects (as described for sodium) and a negative acute phase response. The low iron concentration and % transferrin saturation can be attributed to inflammatory cytokines increasing hepcidin and sequestering iron and decreasing iron absorption.
Discussion
Most cats with ATE (arterial thromboembolism) have underlying cardiac disease with hypertrophic cardiomyopathy (HCM) being the most common.1,2 Cats with left atrial enlargement (LAE) are particularly predisposed. Analgesia is the primary goal of treatment and various surgical and enzymatic means of removing or dissolving the blood clot have been explored. Unfortunately, surgery has a high mortality rate and thrombolytics have not proven effective.3-6 Evaluation of anti-platelet and anti-coagulation treatments in cats with HCM as a preventative measure are ongoing. In a 2 year follow-up study of cats with HCM, 9% died from ATE.7
Treatment is confounded by the potential development of reperfusion injury. Reperfusion injury occurs when oxygen returns to a tissue that has suffered a period of ischemia. During the anoxic phase, anaerobic cellular metabolism and lactate accumulation cause a decrease in intracellular ATP and pH. Altered transport of ions across the cell and mitochondrial membranes results in cellular swelling and increased calcium within both the cell and mitochondria. Ultimately, cells undergo extensive endoplasmic reticulum and mitochondrial stress and will die under this duress. Irreversible damage is microscopically detectable after only 20 minutes of ischemia, and the consequences of this vary markedly across different tissue beds. Brain, kidney and heart are much more sensitive to ischemia than skeletal muscle and distal limb ischemia is fairly well tolerated.
When oxygen is rapidly returned, oxidative injury and inflammation ensue. Models of ischemia reperfusion injury were extensively used to elucidate the steps involved in leukocyte trafficking to sites of inflammation. If ischemia lasts for longer than 60 minutes, the breakdown of ATP results in the formation of hypoxanthine. The return of oxygen stimulates xanthine oxidase which results in the formation of superoxide and hydroxyl radicals. Nitric oxide produced as blood flow returns can led to the formation of peroxynitrite, which attacks membrane lipids and proteins causing even more damage. In later stages, leukocyte-derived NADPH oxidase produces further damaging radicals as do reactants produced by inflamed endothelial cells. Reperfusion itself can also initiate changes that induce a prothrombotic phenotype. Additionally, the post-ischemic blood can trigger what is known as remote organ injury which often manifests as respiratory distress.8
The mechanistic links between HCM and the development of a thrombus are multifactorial. The aberrant blood flow, which can be recognized by the development of spontaneous echocardiographic contrast (SEC), is thought to contribute to platelet activation, endothelial cell changes, and potentially dangerous aggregation of red blood cells. A number of studies have sought to determine if cats with cardiomyopathy have an underlying hypercoagulable state or biomarkers that might predict thrombotic risk. In one study, cats with LAE and SEC ± atrial thrombi, had higher fibrinogen concentrations compared to cats with only LAE. In the same study, only cats with ATE or SEC ± atrial thrombi had evidence of hypercoagulability. The SEC ± thrombi group was not further substratified to allow interpretation of the impact of the thrombi. Thus, it is not known at this time if SEC alone correlates to a hypercoagulable state.9 Cats with HCM have been reported to have higher circulating thrombin:antithrombin complexes.10 Unfortunately, many cats presenting with an ATE have no known history of cardiac disease.11 Thus, there is pressing need to identify early predictors of ATE, as well as effective means to decrease the risks in cats with HCM.
References
- Smith SA, Tobias AH, Jacob KA, Fine DM, Grumbles PL. Arterial thromboembolism in cats: acute crisis in 127 cases (1992-2001) and long-term management with low-dose aspirin in 24 cases. J Vet Intern Med. United States; 2003;17(1):73–83.
- Laste NJ, Harpster NK. A retrospective study of 100 cases of feline distal aortic thromboembolism: 1977-1993. J Am Anim Hosp Assoc. United States; 1995;31(6):492–500.
- Pion PD. Feline aortic thromboemboli and the potential utility of thrombolytic therapy with tissue plasminogen activator. Vet Clin North Am Small Anim Pract. United States; 1988 Jan;18(1):79–86.
- Reimer SB, Kittleson MD, Kyles AE. Use of rheolytic thrombectomy in the treatment of feline distal aortic thromboembolism. J Vet Intern Med. United States; 2006;20(2):290–6.
- Koyama H, Matsumoto H, Fukushima R, Hirose H. Local intra-arterial administration of urokinase in the treatment of a feline distal aortic thromboembolism. J Vet Med Sci. Japan; 2010 Sep;72(9):1209–11.
- Welch KM, Rozanski EA, Freeman LM, Rush JE. Prospective evaluation of tissue plasminogen activator in 11 cats with arterial thromboembolism. J Feline Med Surg. England; 2010 Feb;12(2):122–8.
- Payne JR, Borgeat K, Brodbelt DC, Connolly DJ, Luis Fuentes V. Risk factors associated with sudden death vs. congestive heart failure or arterial thromboembolism in cats with hypertrophic cardiomyopathy. J Vet Cardiol. Netherlands; 2015 Dec;17 Suppl 1:S318-28.
- Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell Biology of Ischemia/Reperfusion Injury. Vol. 298, Int Rev Cell Mol Biol. 2012. 229-317 p.
- Stokol T, Brooks M, Rush JE, Rishniw M, Erb H, Rozanski E, et al. Hypercoagulability in cats with cardiomyopathy. J Vet Intern Med. United States; 2008;22(3):546–52.
- Bedard C, Lanevschi-Pietersma A, Dunn M. Evaluation of coagulation markers in the plasma of healthy cats and cats with asymptomatic hypertrophic cardiomyopathy. Vet Clin Pathol. United States; 2007 Jun;36(2):167–72.
- Luis Fuentes V. Arterial thromboembolism: risks, realities and a rational first-line approach. J Feline Med Surg. England; 2012 Jul;14(7):459–70.
