Sep 052021




The point-of-care blood gas analysis showed an alkalemia due to a primary respiratory alkalosis, with a mild concurrent metabolic acidosis. The anion gap was normal (20 mEq/L, RI, 13-25 mEq/L), but could be lowered by a presumptive concurrent hypoalbuminemia. The metabolic acidosis was likely a primary disturbance, presumably due to titration of bicarbonate by an accumulating acid (considering the absence of changes in the strong ions, sodium and chloride), although lactate concentrations measured 15 minutes later were normal. It is possible a mild lactic acidosis was present earlier. The acute nature of the dog’s illness would preclude the metabolic acidosis being a renal compensatory response to the dominating respiratory alkalosis (insufficient time for the kidney to compensate, plus one would expect a disproportionally higher chloride than sodium with a renal compensatory response to a primary respiratory alkalosis). The decreased pO2 suggested mild hypoxemia, likely due to alterations in blood flow to the lungs (e.g. thrombosis) or pulmonary edema. The primary respiratory alkalosis could be attributed to pain, pulmonary edema (stimulation of mechanoreceptors in the lungs), and hypoxemia (Question 1).

The hemogram results from blood taken the day after admission showed a mild normocytic normochromic anemia with no evidence of regeneration and a hypoproteinemia, which was due to a decrease in both albumin and globulins, based on the biochemical panel. The decrease in hematocrit versus the PCV on admission (taking into account the different methods used for measurement) and worsening hypoproteinemia can be attributed to acute gastrointestinal hemorrhage (bloody diarrhea) and a dilutional effect of overnight fluid therapy (Question 2). The panhypoproteinemia was more severe than the anemia, supporting concurrent protein exudation from altered vascular permeability (supported clinically by the edema in abdominal organs and ascites). Increased epinephrine concentrations may also be causing concurrent splenic contraction, which would increase the PCV and hematocrit disproportionally to the protein concentration. The anemia was considered too acute to be regenerative. There was also a mild inflammatory leukogram, characterized by a mild left shift and toxic change, despite a normal total leukocyte and neutrophil count, with a concurrent stress leukogram (lymphopenia and eosinopenia). Based on the presenting clinical signs and biochemical abnormalities, the inflammation may be occurring in the gastrointestinal tract and liver. The low MCHC was not considered a clinically relevant finding. In summary, the hemogram showed evidence of acute hemorrhage, inflammation and stress (Question 3).

The biochemical panel showed markedly increased hepatocellular injury enzyme activities (ALT and AST, as well as LDH) and a moderately increased CK activity, indicating acute liver and muscle injury, respectively. Muscle injury would also increase AST and LDH activity. The high ALP activity could be due to endogenous stress (corticosteroid response) and cholestasis, with the latter being supported by the minimally increased total and direct bilirubin concentrations. The increased GGT activity may also be due to cholestasis or potentially biliary necrosis. There was a roughly proportional increase in sodium and chloride concentrations, which were attributed to overnight fluid therapy. The mild acidosis appeared to have resolved, which was confirmed on a repeat blood gas analysis. The hypocalcemia was likely due to the hypoalbuminemia, but a concurrent ionized hypocalcemia was possible (ionized calcium was not measured). The increased glucose concentration at admission and the next day was due to stress (endogenous corticosteroids, epinephrine and/or norepinephrine), supported by the hemogram results. The mild increase in lipase activity may be secondary to pancreatitis (hypoxic injury from altered blood flow, thrombosis or vascular permeability), whereas the mildly decreased cholesterol concentration could be due to inflammation or hepatic dysfunction from injury. The mild decrease in TIBC concentration can be attributed to exudative losses with albumin (Question 2). Pathologic processes identified from the biochemical panel are acute liver injury, muscle injury, mild cholestasis, stress, and protein exudation/loss, with possible mild pancreatitis (Question 3).

The coagulation panel revealed prolonged prothrombin (PT) and activated partial thromboplastin times (APTT). These findings, along with the moderate thrombocytopenia on the hemogram, are supportive of disseminated intravascular coagulation (overt likely thrombotic phase, since the dog did not demonstrate clinical signs of excessive hemorrhage) with consumption of platelets and coagulation factors. The prolonged thrombin clot time (TCT) could be explained by hypofibrinogenemia (consumption), although high concentrations of fibrinogen degradation products could also inhibit thrombin-mediated conversion of fibrinogen to fibrin (Questions 2 and 3).

Taken the acute onset of the dog’s illness and the marked liver injury on the biochemical panel with bloody diarrhea, ascites and gall bladder edema, acute anaphylaxis was likely (Question 4).

Follow up

The dog was treated for acute anaphylaxis on the night of admission with epinephrine and antihistamines. The dog responded well to the aggressive treatment administered during hospitalization, with resolution of the organ edema and ascites, and was discharged into the care of the owner 3 days after admission. Repeat clinical pathologic testing on the day of discharge showed a worsening anemia (26% at discharge, no evidence of regeneration), continued thrombocytopenia (64 x 103/μL at discharge) but resolving inflammation (mild rebound neutrophilia of 10.6 x 103/μL with no left shift or toxic change). Transaminase and CK activities had decreased and the LDH and lipase activities and protein (albumin and globulin) and cholesterol concentrations were within reference intervals. There was ongoing evidence of cholestasis (persistently increased total and direct bilirubin concentrations, slightly higher ALP and GGT activities). The total calcium concentration was still decreased, supporting an ionized hypocalcemia (unclear cause). The PT and APTT were lower than the initial measurements but still prolonged (17 and 25 seconds, respectively), but the TCT had normalized (7.5 seconds) when measured 2 days after admission.


Anaphylaxis is an acute, severe, frequently life-threatening, systemic hypersensitivity reaction. It has occurred throughout the ages, being recorded in ancient Greek and Chinese literature. The term anaphylaxis was first coined by an investigator, Charles Richet, who recognized it as a “new disease” after a colleague, Paul Portier, induced fatal anaphylaxis in two unfortunate dogs via injections of extracts from the jellyfish, the Portuguese man-of-war (in experiments that would not obtain institutional animal care and use committee approval nowadays). Richet modified the Greek word “aphylaxis” meaning “negation” (thinking the reaction was due to lack of immunization against the extract, which was the purpose of the experiment) to anaphylaxis and won a Nobel Prize for this effort.2 Anaphylaxis is also known as a secondary mast cell activation disorder, with clonal mastocytosis representing a primary mast cell activation disorder.3

We now know that anaphylaxis is usually elicited by the binding of IgE antibodies to high affinity IgE receptors (FcεR1) on mast cells and basophils (although mast cells are considered the main cell culprit), with subsequent degranulation, in response to triggers, such as food allergies (e.g. peanuts in peoples), insect bites (bee and wasp stings), drugs and other allergens. The IgE is produced upon sensitization of T helper cells, which drive a TH2 response through interleukin (IL)-4 and -13. Mast cells release preformed vasoactive mediators, including histamine and tryptase, which cause vasodilation and increased vascular permeability, resulting in edema with protein exudation, and subsequent hypotension and hemodynamic shock. These mediators also cause constriction of smooth muscle cells in various organs, including the airways and gastrointestinal tract, resulting in dyspnea and vomiting, diarrhea and abdominal cramps. Other mediators that have important roles in anaphylaxis are platelet-activating factor, prostaglandins, leukotrienes and bradykinin. These are produced and released directly by mast cells upon activation (platelet-activating factor, prostaglandins, leukotrienes) or generated through actions of mast cell mediators, such as tryptase and heparin, on other systems, such as cleavage of the contact factors of coagulation (FXII, prekallikrein), which liberate bradykinin, a potent vasodilator, smooth muscle constrictor and permeability factor. Anaphylactic reactions can also be triggered via non-IgE dependent and even non-mast cell-dependent pathways, which used to be called anaphylactoid reactions, however the term anaphylactoid has become controversial and is no longer in common use.4 A consensus statement from the European and American Academies of Allergy and Clinical Immunology used the terms IgE- and non-IgE-mediated endotypes in describing the different types of anaphylaxis.5 The precise mechanisms and cells responsible for non-IgE-mediated anaphylaxis are unclear, however it may involve drug, immunoglobulin G or immune complex binding to Fcγ receptors and activation of macrophages, mast cells, neutrophils (with subsequent release of neutrophil extracellular traps or NETosis) and endothelial cells.6-8 Complement-based anaphylatoxins, C3a and C5a, and drugs can also directly induce mast cell degranulation/activation and bradykinin can be produced via drug-induced activation of the kinin-kallikrein system, manifesting as non-immune-mediated anaphylaxis.9-10 Mast cell-dependent and -independent mechanisms are potentially distinguished by measurement of histamine and tryptase, however these compounds have a short half-life, which reduces test sensitivity, and their measurement is not routine. Newer more stable serum and urinary biomarkers, such as leukotriene and prostaglandin metabolites, hold promise for diagnosis of anaphylaxis.5 The term idiopathic anaphylaxis has been applied to recurrent bouts of clinical anaphylaxis, without an inciting cause.3

Anaphylaxis has been described in dogs in response to various drugs, including antimicrobials, vaccines, and anesthetic agents, food allergies and insect (usually wasp or Hymenoptera) stings.10-12 The liver and gastrointestinal tract are the “shock” organs in dogs, as seen in this case, where clinical signs and laboratory findings were dominated by vascular permeability (severe acute fluid shifts cause rapid collapse along with bradycardia), manifesting as abdominal organ edema, ascites, hypotension, decreased venous return to the heart, hemorrhagic diarrhea and liver injury.10,12,13 Dogs are typically acidemic due to a lactic acidosis and can have increased GGT activity, hypocalcemia and hyperbilirubinemia,13 as seen in this case. The liver injury is attributed to vascular permeability and venous congestion, reducing portal blood flow and resulting in hypoxic injury, with increased transaminase activities10,11 Dyspnea can result from bronchoconstriction or upper airway edema.

The diagnosis of anaphylaxis is based on a rapid onset of clinical signs of dyspnea, cardiovascular dysfunction (e.g. acute collapse, bradycardia, hypotension) and gastrointestinal signs, including abdominal pain, salivation, diarrhea, which may be frankly bloody, and vomiting.10,14 In one study of 67 patients, cardiovascular compromise and gastrointestinal injury were seen more frequently (100 and 94%, respectively) than respiratory or cutaneous symptoms (67% and 27%, respectively).14 In a study of 96 dogs, increased ALT activity (>80-100 U/L) and gall bladder edema (> 3 mm thickened wall or alternating echolucent and echogenic areas, representing subserosal edema and also called a “striated” wall) were sensitive (85-93%) and specific (98%) tests to discriminate between mild acute allergic reactions (n=40) and acute anaphylaxis (n=56).11 In other studies, increased ALT activity and gall bladder edema were seen in 94%14 and 20%, 75%, 84% of cases, respectively.13,15 Since ALT activity cannot be measured as a quick assessment test, a FAST scan of the abdomen with recognition of gall bladder edema can be used as a rapid ante-mortem diagnostic test for anaphylaxis in dogs,11 although neither increased ALT activity nor gall bladder edema is specific for anaphylaxis, also being seen with cardiac disease and sepsis.15,16

The mechanism for the ascites in the dog of this report was not ascertained because abdominal fluid was not aspirated.  In two studies, the ascites was usually due to hemoperitoneum, although the cause of hemorrhage was unclear (most dogs had normal coagulation profiles in one study13, but not the other14). Other effusions were classified as high-protein transudates,14 although these effusions could also have been poorly cellular exudates, considering the alterations in vascular permeability that occur with anaphylaxis. Transudative effusions were seen in 5 of 6 dogs in another study, with only one dog having a hemorrhagic effusion.15

Hemostatic abnormalities have been described in human and canine patients with anaphylaxis, including DIC-like syndromes.17-18 Coagulation abnormalities are commonly seen; a prolonged PT and/or APTT were seen in 37/39 dogs in which coagulation testing was performed.14 Mast cell constituents can affect different aspects of hemostasis directly or indirectly.6 For instance, heparin can inhibit coagulation and thrombin generation, prolonging the PT, APTT and TCT, as seen in the dog of this report. However, the persistent increases in the PT and APTT support ongoing hemostatic dysfunction, such as that due to DIC. Tryptase can cleave fibrinogen, resulting in hypofibrinogenemia, and platelet-activating factor, released by activated mast cells and other cell types in IgE- and non-IgE-mediated anaphylaxis, is associated with laboratory evidence of DIC in experimentally-induced anaphylaxis in mice.19 Activated complement components (C3a, C5a) and histamine can upregulate tissue factor expression on endothelial cells, potentially triggering DIC independently of mast cells in anaphylaxis.20-22

Treatment of anaphylaxis includes epinephrine (the first line of treatment) and antihistamines, with fluid therapy in hypotensive patients,10 as done in this case. Beta-blockers and glucocorticoids are also concurrently administered, the former in dyspneic patients to promote bronchodilation. Biphasic reactions do occur so patients should be monitored for 3 days.10 The mortality rate of anaphylaxis in dogs in one study was 15%; a serum phosphate concentration >12 mg/dL, hypoglycemia (<80 mg/dL) at any time during hospitalization, and a PT that was prolonged by >50% of the upper reference limit were negative prognostic indicators.14 Differential diagnoses for anaphylaxis include severe asthma, hemorrhagic gastroenteritis (not typically associated with increased transaminase activities, hypoproteinemia or thrombocytopenia23), acute toxicity, and sepsis.  In one study of 10 dogs with acute anaphylaxis and 22 dogs with acute sepsis, acute collapse was the only clinical sign seen in more dogs with anaphylaxis than sepsis. Dogs with anaphylaxis had lower temperatures than those with sepsis (37 versus 39°C) and on clinical pathologic testing had lower mean pH (7.30 versus 7.37 units in sepsis; due to lactic acidemia) and globulin concentrations (2.1 versus 3.1 g/dL) and higher mean glucose concentration (152 versus 87 mg/dL in sepsis) and ALT activity (456 versus 71 U/L),15 although there was overlap between both groups and numbers of animals in the groups was low. Gall bladder edema was only seen in 2/10 dogs with anaphylaxis and with sepsis.15


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