Fred, 11‐year‐old castrated male German Shephard dog
1.2 History
Current on vaccinations, receives monthly heartworm preventative/anthelminthic combination, and monthly flea and tick prevention. Receives yearly inhouse CBC/Biochemistry/UA, and combination ELISA test for Heartworm, Ehrlichia spp., Anaplasma spp., and Borrelia Burgdorferi. His previous laboratory work has always been within the reference intervals and his yearly infectious disease testing has previously been negative.
1.3 Presentation
Fred presents for recent onset of lethargy and anorexia.
Cardiopulmonary: Normal bronchovesicular sounds in all fields, a grade 2/6 systolic left‐sided heart murmur, and strong synchronous pulses.
Abdomen: Marked splenomegaly and hepatomegaly
Lymph: Mild peripheral lymphadenomegaly
HEENT: No abnormal findings
Urogenital: No abnormal findings
Integument: No abnormal findings
Neurologic: No abnormal findings
Musculoskeletal: No abnormal findings
Initial Data (History/Signalment/Physical Exam) Questions
Given the clinical data, what is the differential diagnosis?
What diagnostics ideally would you like to perform (given no resource boundaries) and why?
What low‐cost diagnostics could you perform in this patient that might give you similar information to your ideal list?
What information are you expecting to receive from these diagnostics? In other words, what differential do you expect to rule in or rule out with these diagnostics?
What results, given the patient’s signalment/history/clinical exam findings, would you expect in this patient?
Initial Data (History/Signalment/Physical Exam) Answers
Given the clinical data, what is the differential diagnosis?
Tachycardia, tachypnea, and pale mucous membranes with a normal CRT indicate the presence of anemia. A systolic murmur could be the result of anemia or the result of cardiac valvular insufficiency. Marked splenomegaly and hepatomegaly with the presence of anemia are supportive of infectious diseases (i.e. Mycoplasma spp., Leptospira spp., Babesia spp.), neoplasia, marked extramedullary hematopoiesis or immune‐mediated disease (i.e. IMHA). Acute lethargy and anorexia could be the result of numerous conditions and are vague clinical signs.
What diagnostics ideally would you like to perform (given no resource boundaries) and why?
Ideally performing a CBC, biochemical profile (including ALT, AST, GGT, ALP, total bilirubin, and bile acids if bilirubin is within the reference interval), urinalysis, radiographs, and abdominal ultrasound would be ideal to perform. Depending on the results, fine needle aspiration and or histopathology may be indicated.
What low‐cost diagnostics could you perform in this patient that might give you similar information to your ideal list?
PCV/TPP, blood film evaluation, BUN, urinalysis would be a good low‐cost starting point. From here, we can better target further diagnostics if needed.
What information are you expecting to receive from these diagnostics? In other words, what differential do you expect to rule in or rule out with these diagnostics?
Case Figure 1.1 Hematologic data. Absolute leukocyte values are based on WBC estimate and differential count.
PCV, TPP, and blood film are going to be helpful in assessing red blood cell mass (confirming anemia), leukocyte concentration, and differential (supporting inflammatory disease or neoplasia), evaluate for hemoparasites (i.e. Mycoplasma spp., or Babesia spp.), plasma protein status (possibly supporting inflammatory disease or neoplasia). BUN and urinalysis will help assess renal function (supporting or refuting Leptospira spp., or other diseases).
What results, given the patient’s signalment/history/clinical exam findings, would you expect in this patient?
In this patient, a decreased PCV would be expected with or without signs of regeneration on the blood film. We may also see leukocytosis depending on the underlying cause of the anemia. A stress leukogram caused by increased circulating endogenous glucocorticoids can be expected in sick patients. Otherwise, there are no other results that can be predicted at this point.
Diagnostic Data Interpretation Questions
Given the diagnostic results, what abnormalities do you identify? What is your interpretation of these findings?
Are any of these diagnostic results surprising/unexpected?
What are the broad mechanisms by which these abnormalities occur?
In this case, what is/are the top differential diagnoses based on the current diagnostic data?
What diagnostic results are most supportive for each of the differential diagnoses?
What additional diagnostics would you need to confirm/refute the top differentials for this case?
In patients with the condition depicted in this case, why is bicytopenia or pancytopenia a frequent finding?
Given the diagnostic results, what abnormalities do you identify? What is your interpretation of these findings?
Moderate to marked anemia (PCV 15%), marked leukocytosis with 93% of nucleated cells being large unclassified cells, and thrombocytosis. There is no evidence of erythroid regeneration (no polychromasia or nucleated erythrocytes). BUN is normal with an adequately concentrated USG is consistent with adequate renal function. Mild proteinuria is commonly seen in concentrated urine in the dog. Trace bilirubinuria is normal in dogs.
Are any of these diagnostic results surprising/unexpected?
There are very few cases where a marked leukocytosis is expected. In this case the estimated WBC count was 98,000/ul. In general, inflammatory leukograms are commonly associated with pyrexia, especially with leukocyte concentrations of this magnitude, which wasn’t seen in this case.
What are the broad mechanisms by which these abnormalities occur?
Marked leukocytosis, in this case, is the result of neoplastic hematopoietic cells circulating within the peripheral blood. Neoplastic cells proliferate in the bone marrow, begin circulating in peripheral blood, and can accumulate in other organs (i.e. spleen, liver, lymph nodes, etc.)
Anemia occurs for three primary reasons: erythrocytes are destroyed (hemolysis), they are used/consumed, or they are not adequately produced. In this case, there is no evidence of hemolysis (spherocytes, ghost cells, etc.) upon reviewing the blood film. There is also no evidence of loss or consumption since we do not see an indication of hemorrhage (i.e. clinical findings, decreased total plasma protein) in this patient. There is evidence of inadequate bone marrow response to anemia (lack of polychromasia or nucleated erythrocytes) supporting replacement of hematopoietic tissue by the neoplastic leukocytes.
Thrombocytosis occurs as a result of megakaryocyte stimulation to produce platelets. Thrombocytosis can be due to tumor associated inflammation with release of inflammatory cytokines that promote thrombopoiesis, the most common cause, or as a paraneoplastic syndrome due to tumor specific prothrombopoietic mechanisms.
In this case, what is/are the top differential diagnoses based on the current diagnostic data?
Acute leukemia with bone marrow suppression likely due to myelophthisis and infiltration of neoplastic cells into the spleen and liver.
What diagnostic results are most supportive for each of the differential diagnoses?
The most compelling finding is the extreme leukocytosis caused by large numbers of atypical nucleated cells. Although the large cells appear morphologically similar to lymphoid cells, their lineage cannot be definitively determined on a routinely stained blood film. A reactive lymphocytosis is very unlikely considering the absolute number and morphologic characteristics of these large unclassified cells.
What additional diagnostics would you need to confirm/refute the top differentials for this case?
In this case, there are several diagnostics that should be pursued to confirm the diagnosis of acute leukemia. Flow cytometry should be performed to identify the origin of the neoplastic cells (myeloid vs. lymphoid). Aspiration of the spleen and liver should be performed to confirm infiltration of neoplastic cells in these tissues. Bone marrow core biopsy should be performed to confirm that neoplastic cells have infiltrated the bone marrow resulting in myelopthisis. Bone marrow aspiration cytology is not as helpful as core biopsy due to the degree of leukocytosis in this patient and the amount of blood contamination in these samples. The same would hold true for the liver and spleen aspirates.
Case Figure 1.6 Biochemistry and urinalysis data. Urinalysis sample by cystocentesis.
In patients with the condition depicted in this case, why is bicytopenia or pancytopenia a frequent finding?
Patients with acute leukemias typically develop marked cytopenias due to myelophthisis. The replacement of normal hematopoietic tissue by neoplastic cells greatly reduces the ability to maintain normal blood cell concentrations in the peripheral blood.
2 Case #2
2.1 Signalment
Bella, 6‐year‐old spayed female Golden Retriever dog.
2.2 History
Current on vaccinations, does not currently receive heartworm preventatives, anthelminthics, or flea/tick preventatives. Currently receiving sulfamethoxazole‐trimethoprim antimicrobial therapy for a urinary tract infection. Today was the last treatment in a 14‐day course of the antimicrobials.
2.3 Presentation
Bella presents for acute collapse, lethargy, and panting.
Cardiopulmonary: No murmurs on auscultation, strong synchronous pulses, lungs auscultate normally. Abdomen: Moderate splenomegaly on palpation.
Lymph: No abnormal findings.
HEENT: Icteric sclera, pinnae, and oral mucosa.
Urogenital: Icteric vulvar mucosa.
Integument: No abnormal findings.
Neurologic: No abnormal findings.
Musculoskeletal: No abnormal findings.
Initial Data (History/Signalment/Physical Exam) Questions
Given the clinical data, what is the differential diagnosis?
What diagnostics ideally would you like to perform (given no resource boundaries) and why?
What low‐cost diagnostics could you perform in this patient that might give you similar information to your ideal list?
What information are you expecting to receive from these diagnostics? In other words, what differential do you expect to rule in or rule out with these diagnostics?
What results, given the patient’s signalment/history/clinical exam findings, would you expect in this patient?
Initial Data (History/Signalment/Physical Exam) Answers
Given the clinical data, what is the initial differential diagnosis?
The primary differentials in this case are:
Prehepatic icterus due to hemolytic anemia supported by pale yellow mucous membranes, tachycardia, and tachypnea, with strong peripheral pulses, normal CRT, and splenomegaly.
Hepatic or posthepatic icterus with secondary anemia supported by pale icteric mucous membranes.
*Differentiation of the primary cause of icterus cannot be determined by clinical findings alone and requires additional diagnostic tests. With the history of sulfonamide administration, idiosyncratic hepatocellular injury or secondary immune‐mediated hemolytic anemia should be considered.
What diagnostics ideally would you like to perform (given no resource boundaries) and why?
Ideally a CBC (including blood film review), biochemical profile, and urinalysis would be a good initial diagnostic plan. It is also beneficial to perform abdominal ultrasonography to examine the liver, biliary tract, and spleen. If there is evidence of erythrocyte aggregation on examination of the blood collection tube, a saline dispersion test should be performed to differentiate nonspecific aggregation from immune agglutination.
CBC would confirm anemia, determine the bone marrow response, and identify changes in other blood cell lineages.
Blood film review is critical in these cases! Erythrocyte morphology is the most direct way to identify the cause of anemia. The presence of spherocytes, ghost cells, Heinz bodies, and eccentrocytes can all be associated with hemolytic anemia. It is important to interpret all physical and laboratory findings together when evaluating blood cell morphology.
Biochemical profile is important in making the distinction between prehepatic, hepatic, or posthepatic icterus, as well as identifying potential causes.
Urinalysis is critical for adequate interpretation of the biochemistry profile and other clinical pathology data.
Abdominal ultrasonography is the best noninvasive way to differentiate hepatic from posthepatic icterus. In addition, ultrasonographic evaluation and fine needle aspiration is useful in identifying the cause in cases of hepatosplenomegaly.
*An important note, the Coombs test or Direct Antiglobulin may not be helpful in cases of hemolytic anemia due to low sensitivity and specificity of this test.
What low‐cost diagnostics could you perform in this patient that might give you similar information to your ideal list?
The low‐cost diagnostics that could be performed in this case would be PCV, TPP, blood film, BUN, and urinalysis.
What information are you expecting to receive from these diagnostics? In other words, what differential do you expect to rule in or rule out with these diagnostics?
PCV would determine if the patient is anemic to help rule in or out prehepatic icterus. In addition, evaluation of buffy coat size might help identify the presence of leukocytosis or thrombocytosis.
TPP would help support hydration status findings. High total plasma protein may suggest nonspecific aggregation of erythrocytes versus immune agglutination.
Blood film review would identify spherocyte formation, or other RBC abnormalities consistent with hemolytic anemia and allow evaluation of leukocytes and platelets.
BUN is an evaluator of both renal glomerular filtration rate and hepatic function. In the icteric patient, a decreased BUN would suggest decreased hepatic function. Since a potential differential in the icteric dog is leptospirosis, renal injury is also a concern warranting BUN monitoring.
Urinalysis is critical in monitoring the renal function in any ill patient and adequate interpretation of the biochemical profile.
What results, given the patient’s signalment/history/clinical exam findings, would you expect in this patient?
In this case, bilirubinuria and icteric plasma is expected since the patient is grossly icteric. Given the tachycardia, tachypnea, slightly pale mucous membranes, normal CRT, and normal pulse quality, anemia is likely. Since the patient’s history of sulfonamide antimicrobial administration significantly increases the probability of an immune mechanism for the anemia, spherocyte formation would be an expected finding on the blood film. Because immune‐mediated hemolytic anemia is usually regenerative, polychromasia is an expected finding. Leukocytosis of varying magnitude can be expected due to either inflammation, increased circulating glucocorticoids, or both.
Case Figure 2.1 Hematologic data. *Absolute leukocyte values are based on WBC estimate and differential count.
Diagnostic Result Interpretation
Given the diagnostic results, what abnormalities do you identify? What is your interpretation of these findings?
Would the icterus in this patient be considered prehepatic, hepatic, or posthepatic in origin?
What are the broad mechanisms by which these abnormalities occur?
In this case, what is/are the top differential diagnoses based on the current diagnostic data?
What diagnostic results are most supportive for each of the differential diagnoses?
What additional diagnostics would you need to confirm/refute the top differentials for this case?
Why do we typically see signs of regeneration in cases of extravascular hemolytic anemia but not in intravascular hemolytic anemias? Does the presence of regeneration completely rule in or out either?
Case Figure 2.10 Biochemistry and urinalysis data. Urinalysis sample by cystocentesis.
Diagnostic Result Interpretation
Given the diagnostic results, what abnormalities do you identify? What is your interpretation of these findings?
There is moderate anemia present, with evidence of regeneration (2+ polychromasia, 15 nRBC/100WBC). There is moderate spherocytosis which is supportive of IMHA in this case. Mild leukocytosis with significant shift to immaturity (to metamyelocytes) is present supporting an inflammatory process, i.e. IMHA. Mild thrombocytosis is present, which is consistent with regenerative response to anemia or stimulation of thrombopoiesis by inflammatory cytokines.
The lack of hemoglobinemia and hemoglobinuria in the presence of icterus and spherocytes is consistent with extravascular hemolytic anemia.
BUN is within the reference interval and USG is within the range of adequate concentration, which supporting normal renal function.
Bilirubinuria and icteric plasma are consistent with the grossly evident icterus.
Would the icterus in this patient be considered prehepatic, hepatic, or posthepatic in origin?
In this case given the patient‘s history, physical exam findings, and evidence of hemolytic anemia, icterus is most likely of prehepatic origin.
What are the broad mechanisms by which these abnormalities occur?
In cases of extravascular immune hemolysis (i.e. IMHA) erythrocytes are removed from circulation by macrophages predominantly in the spleen and liver. As these macrophages phagocytose erythrocytes, hemoglobin is ultimately converted into unconjugated bilirubin and released for processing by the liver. The liver quickly becomes overwhelmed, which leads to significant hyperbilirubinemia, icterus, and bilirubinuria. The resulting anemia leads to decreased oxygen availability for the tissues and release of erythropoietin. Stimulation of the bone marrow erythroid lineage by erythropoietin results in a regenerative response to anemia. Erythropoietin has thrombopoietic effects and secondarily increases platelet numbers. Inflammatory cytokines stimulated by erythrocyte immune lysis leads to increased leukocyte production and subsequent leukocytosis and can stimulate thrombopoiesis.
In this case, what is/are the top differential diagnoses based on the current diagnostic data?
In this case, the primary differential diagnoses are:
Babesia spp., Leishmania spp., Dirofilaria immitis, Bartonella spp., and Anaplasma phagocytophilum have been associated with secondary IMHA in the dog.
What diagnostic results are most supportive of each of the differential diagnoses?
Currently, there is not enough evidence to allow the distinction between primary and secondary immune‐mediated hemolytic anemia. Since there is insufficient evidence, both mechanisms should be considered.
What additional diagnostics would you need to confirm/refute the top differentials for this case?
Additional diagnostics are required to determine the origin of IMHA in this patient. Serologic or molecular diagnostics would be beneficial in ruling out infectious causes since primary IMHA and secondary IMHA due to idiosyncratic drug reaction are both diagnoses of exclusion.
Given the history of the patient, administration of a potential IMHA inciting drug treatment should be ceased with continued monitoring. Resolution of disease with drug discontinuation is highly supportive of a drug reaction over primary IMHA.
Why do we typically see signs of regeneration in cases of extravascular hemolytic anemia but not in intravascular hemolytic anemias? Does the presence of regeneration completely rule in or out either?
It is important to remember it takes ~5 days to see evidence of regeneration from the bone marrow. Most commonly, the regenerative response is moderate to marked with extravascular hemolysis and nonregenerative or mildly regenerative with intravascular hemolysis. The main difference between the two types of hemolysis is the time point at which the disease is recognized by the owner. Patients with intravascular hemolysis usually have acute hemolytic crises with rapid onset of significant clinical disease. Because their clinical signs are acute, the bone marrow has not had time to respond prior to presentation. With extravascular hemolysis, the duration of the disease process is more chronic than intravascular hemolysis. There is a more gradual decrease in erythrocyte mass with extravascular hemolysis rather than the precipitous drop with intravascular hemolysis.
3 Case #3
3.1 Signalment
Benji, a 2‐year‐old castrated male Staffordshire terrier mix dog
3.2 History
Current on all vaccinations, receives a monthly heartworm preventative/anthelminthic combination, but is not on flea/tick preventatives. Last week, Benji had his yearly physical exam, Heartworm/Ehrlichia/Anaplasma/Borellia ELISA testing, and updated his vaccinations.
3.3 Presentation
Benji presents today on emergency after his owners found him collapsed in their backyard and panting. Currently, the temperature outside is 106°F (41.1°C).
Cardiopulmonary: Adventitious lung sounds in the bronchovesicular regions bilaterally, fine crackles audible bilaterally. The heart auscults normally, peripheral pulses are rapid but weak.
Integument: Skin feels hot to the touch with diffuse erythema present.
HEENT: All mucosal surfaces are brick red/hyperemic, hypersalivation present, episcleral injection OU.
NIBP: 65 mmHg (systolic)
Questions for Part 1 of Case
Is echinocytosis commonly associated with dehydration? If so, why was echinocytosis not seen in this patient’s blood film?
Answers for Part 1 of Case
Is echinocytosis commonly associated with dehydration? If so, why was echinocytosis not seen in this patient’s blood film?
Echinocytosis can be associated with numerous causes such as EDTA artifact, envenomation, etc. However, dehydration is not commonly associated with echinocytosis.
Case Figure 3.1 Hematologic data. *Absolute leukocyte values are based on WBC estimate and differential count.
Follow‐up: After treatment for heat stroke, Benji’s temperature returned to a normal range, his mental status improved, and neurologic signs resolved. Benji’s respiratory effort has improved, and he is no longer dyspneic.
Cardiopulmonary: On auscultation, the heart auscults normally, and there are strong synchronous peripheral pulses. Adventitious lung sounds in the bronchovesicular region, improved
Integument: Petechiae and purpura noted on the ventrum
Lymph: No abnormal findings
Abdomen: Abdomen tense and painful.
Neuro: Patient is aware, but depressed. Ambulates normally and has normal conscious proprioceptive responses and nociceptive responses. A brief cranial nerve exam is within normal limits.
Musculoskeletal: No abnormal findings
HEENT: Petechiae noted on oral mucosa and pinna. Mild hyphema identified OS on ophthalmic exam.
Initial Data (History/Signalment/Physical Exam) Questions
Given the clinical data what is the differential diagnosis?
What diagnostics ideally would you like to perform (given no resource boundaries) and why?
What low‐cost diagnostics could you perform in this patient that might give you similar information to your ideal list?
Case Figure 3.6 Biochemistry and urinalysis data. Urinalysis sample by cystocentesis.
What results, given the patient’s signalment/history/clinical exam findings, would you expect in this patient?
Initial Data (History/Signalment/Physical Exam) Answers
Given the clinical data what is the differential diagnosis?
Given the clinical presentation and physical exam, the primary differential is heat stroke. Heat stroke patients present with a constellation of signs, severe hyperthermia, severe dehydration/hypovolemia, evidence of coagulopathy (typically petechiae), and gastrointestinal signs (typically diarrhea).
What diagnostics ideally would you like to perform (given no resource boundaries) and why?
In this patient performing a CBC, biochemical profile, arterial or venous blood gas analysis, lactate, urinalysis, coagulation profile (PT, aPTT, TCT, fibrinogen, antithrombin, FDPs, and D‐dimers), and blood pressure measurement would be ideal in this case.
CBC is especially important for evaluating erythrocyte morphology, leukocyte concentration, platelet concentration. Patients with heat stroke commonly have severe thrombocytopenia. It is important to monitor these parameters since DIC and Systemic Inflammatory Response Syndrome (SIRS) are common sequelae of heat stroke.
Serum biochemical profile is important because heat stroke can lead to severe metabolic derangements and multiorgan failure.
Blood gas analysis is important for initial stabilization and monitoring of these patients. Patients with heat stroke can present with metabolic acidosis, respiratory alkalosis, and mixed acid–base abnormalities
Lactate is usually elevated in patients with heat stroke and is often moderate to markedly increased.
Urinalysis is important because acute kidney injury is a common sequela to heat stroke due to acute tubular injury. Urinalysis is also critical to the adequate interpretation of a biochemical profile.
Coagulation profiles are valuable in managing heat stroke cases. Coagulopathy secondary to DIC is common sequelae of heat stroke.
Blood pressure measurement is important in the acute management of heat stroke cases. Marked dehydration and vascular injury in patients lead to severe hypovolemia and inadequate organ perfusion due to low blood pressure.
What low‐cost diagnostics could you perform in this patient that might give you similar information to your ideal list?
In this case, PCV/TPP, blood film evaluation, ACT, BUN, blood glucose, lactate, and urinalysis should be performed.
What results, given the patient’s signalment/history/clinical exam findings, would you expect in this patient?
In this patient we would expect to see hyperlactatemia, erythrocytosis/hemoconcentration, hyperproteinemia, azotemia, and hypoglycemia. We could also see thrombocytopenia or a prolonged activated clotting time.
NIBP: 115 mmHg (Systolic)
Case Figure 3.7 Hematologic data four hours post presentation. *Absolute leukocyte values are based on WBC estimate and differential count.
Given the diagnostic results, what is your interpretation of the abnormalities identified?
Are any of these diagnostic results surprising/unexpected?
What are the broad mechanisms by which the abnormalities in question 1 occur?
In this case, what is/are the top differential diagnoses based on the current diagnostic data?
What additional diagnostics would you need to confirm or refute the top differentials for this case?
What is the significance of metarubricytosis in the absence of anemia?
Case Figure 3.13 Biochemistry and urinalysis data. Urinalysis sample by cystocentesis.
Why was it important to perform follow‐up diagnostics within a relatively short time frame?
Diagnostic Result Interpretation Answers
Given the diagnostic results, what is your interpretation of the abnormalities identified?
The patient on initial presentation had marked erythrocytosis/hemoconcentration, hyperproteinemia, azotemia, hypersthenuria, all of which are consistent with severe dehydration. Marked hyperlactatemia and hypoglycemia are consistent with the clinical presentation of heat stroke.
The changes from the initial diagnostics are persistent azotemia and hyperlactatemia despite appropriate fluid therapy, metarubricytosis, leukocyte shift to immaturity, evidence of a stress leukogram, precipitous decline in platelet count, glucosuria, cylindruria, and proteinuria.
Mild leukocytosis characterized by neutrophilia with a significant shift to immaturity, and monocytosis are consistent with inflammation. Lymphopenia and monocytosis is likely secondary to increased circulating glucocorticoids from stress. Marked thrombocytopenia is also present in this patient as well as prolonged ACT, consistent with coagulopathy. Persistent azotemia despite appropriate fluid therapy to correct for dehydration/hypovolemia, proteinuria, glucosuria, and cylindruria indicate acute kidney injury. Persistent hyperlactatemia in the presence of normal blood pressure suggests inadequate peripheral perfusion and persistent anaerobic metabolism.
Are any of these diagnostic results surprising/unexpected?
The leukocytosis is not surprising and is likely the result of stress considering the presence of lymphopenia and monocytosis. None of the other diagnostics on initial presentation are surprising or unexpected since they are common findings in patients with heat stroke.
The persistent azotemia despite correction of dehydration/hypovolemia is unexpected. We would expect that since our patient was significantly dehydrated and initially had adequate urine‐concentrating ability indicating prerenal azotemia that correction of the fluid deficiency should correct the azotemia. The same is true for the hyperlactatemia. Some of the patient’s leukogram changes are not entirely surprising (i.e. lymphopenia and monocytosis associated with stress) but the significant shift to immaturity is unexpected unless there is development of sepsis. The inappropriate metarubricytosis is not surprising due to hyperthermic injury to the splenic and bone marrow vasculature resulting in increased release of metarubricytes from the bone marrow and decreased clearing of metarubricytes from the blood by the spleen.
What are the broad mechanisms by which the abnormalities in question 1 occur?
Hypoglycemia resulting from heat stroke is likely multifactorial, resulting from increased consumption and decreased mobilization.
Increased PCV/TPP is the result of dehydration from increased water loss from the vascular space.
Azotemia is often both prerenal and renal in origin. For the prerenal aspect, severe dehydration decreases glomerular perfusion resulting in decreased GFR and increased serum concentration of nitrogenous waste products. For the renal aspect, injury to renal tubules from hyperthermia is likely multifactorial. Thermal injury, decreased tissue oxygen tension from decreased perfusion, and compounds released from injury to other tissues (i.e. myoglobin from rhabdomyolysis) are all potential contributors to renal injury.
Hyperlactatemia occurs as a result of increased anaerobic metabolism that is due to hypoxemia (primarily) and hypoglycemia. Inadequate oxygen prevents aerobic cellular respiration resulting in decreased ATP production through glycolysis producing lactic acid is a byproduct.
Thrombocytopenia is the result of severe platelet consumption, which has multiple causes. With severe hyperthermia, there is widespread vascular endothelial injury, which is a potent stimulus for platelet activation and clotting. In addition, tissue damage releases procoagulants from the tissue (i.e. Factor III), which further contributes to platelet and coagulation factor activation and consumption.
Prolongation of activated clotting time is caused by severe depletion of secondary hemostatic factors. This is a result of widespread activation of the coagulation cascade. Note: Platelet numbers needed to prolong activated clotting time are
extremely low (<10,000/μl).
Cylindruria is the result of renal tubular necrosis with sloughing of tubular epithelial cells and formation of cellular casts that are shed into the urine.
Glucosuria in the absence of hyperglycemia above the renal threshold is the result of renal tubular necrosis. Tubular injury prevents the reabsorption of glucose from renal filtrate and allows excretion in the urine.
Proteinuria occurs as a result of the proximal renal tubule‘s inability to reabsorb the small amount of protein normally found in the glomerular filtrate.
Inappropriate metarubricytosis in this case is the result of bone marrow and splenic sinusoidal injury from hyperthermia. Injured bone marrow and splenic sinusoids inappropriately releases immature cells (i.e. nRBCs) into circulation.
Leukocytosis characterized by neutrophilia, significant shift to immaturity, and toxic change indicate an inflammatory process. This could be the result of bacterial translocation from the GI tract secondary to hyperthermic injury, the result of inflammation secondary to tissue necrosis or direct bone marrow injury secondary to heat stroke. Injured bone marrow inappropriately releases immature cells (i.e. band neutrophils) into circulation.
In this case, what is/are the top differential diagnoses based on the current diagnostic data?
Disseminated intravascular coagulopathy, acute renal injury, and bone marrow injury secondary to heat stroke.
What additional diagnostics would you need to confirm or refute the top differentials for this case?
Based on the clinical presentation, there is enough information to confirm the clinical diagnosis of heat stroke.
No additional information would be needed to confirm acute kidney injury and bone marrow injury secondary the heat stroke. However, to provide the best supportive care and monitoring for additional changes in organ function, a full CBC, biochemical profile, urinalysis, and coagulation profile with d‐dimers should be performed.
What is the significance of metarubricytosis in the absence of anemia?
Inappropriate metarubricytosis is a clinicopathologic finding with relatively few differential diagnoses. Most commonly, this finding relates to bone marrow injury (i.e. heat stroke, lead poisoning, etc.), splenic dysfunction, or traumatic release into the vascular space (i.e. long bone fracture).
Why was it important to perform follow‐up diagnostics within a relatively short time frame?
Severe hyperthermia due to heat stroke directly injures multiple organs. The injury may not be evident in laboratory data early in the process. Although treatment returns the patient to a normothermic state, injury may be ongoing and does not stop once the patient is cooled or adequately rehydrated.
4 Case #4
4.1 Signalment
Mittens, a 10‐month‐old castrated male Siamese cat
4.2 History
Mittens is current on vaccinations and receives a monthly flea/tick preventative. Mittens was neutered at ~4 months of age by the shelter where he was adopted. Mittens came home from the shelter with severe diarrhea that resolved after three days.
4.3 Presentation
Patient presents for lethargy and hyporexia. The owners also report Mittens “feels hot”.
4.4 Physical Exam Findings
Temp: 104.9°F (40.5°C), HR: 212, RR: 32, MM: Pale Pink/Tacky, CRT: two seconds, Hydration status: ~5% Dehydrated, BCS: 3/9
Cardiopulmonary: No murmurs on auscultation, strong synchronous pulses, lungs auscultate normally.
Abdomen: Mild abdominal distension with fluid wave present and mild splenomegaly on palpation.
Lymph: No abnormalities identified.
HEENT: No abnormalities identified.
Urogenital: No abnormalities identified.
Integument: No abnormalities identified.
Neurologic: Patient is QAR, ambulates normally and has normal conscious proprioceptive responses and nociceptive responses. A brief cranial nerve exam is within normal limits.
Musculoskeletal: No abnormalities identified.
Initial Data (History/Signalment/Physical Exam) Questions
Given the clinical data what is the differential diagnosis?
What diagnostics ideally would you like to perform (given no resource boundaries) and why?
What low‐cost diagnostics could you perform in this patient that might give you similar information to your ideal list?
What information are you expecting to receive from these diagnostics? In other words, what differential do you expect to rule in or rule out with these diagnostics?
What results, given the patient’s signalment/history/clinical exam findings, would you expect in this patient?
Initial Data (History/Signalment/Physical Exam) Answers
Given the clinical data, what is the differential diagnosis?
From the clinical data the primary differential would be feline infectious peritonitis (FIP) due to the high fever, abdominal distension, and palpable fluid wave. Given the temperature and splenomegaly, hemotropic mycoplasma infection should be included as a differential. Fever indicates there is an inflammatory process occurring. Therefore, any compatible inflammatory diseases would be an appropriate differential. Otherwise, the clinical signs are nonspecific.
What diagnostics ideally would you like to perform (given no resource boundaries) and why?
It would be ideal to perform a CBC, biochemistry profile, urinalysis, FELV/FIV testing, and abdominocentesis w/fluid analysis. If fluid analysis is supportive of inflammation, bacterial culture and sensitivity, as well as, PCR for feline coronavirus would be ideal to perform. Depending on findings of the initial CBC, it may be beneficial to perform PCR for Mycoplasma spp., or other infectious organisms.
The CBC is part of any minimum database. The patient has pale pink mucous membranes, and slight tachycardia. It is important to evaluate if the patient is simply dehydrated or truly anemic. Leukogram evaluation may support an inflammatory process.
Biochemistry profile will help rule out or indicate potential causes of the abdominal effusion. Common differentials for abdominal effusion are inflammatory exudation (i.e. peritonitis), decreased vascular oncotic pressure (i.e. hypoproteinemia), and increased vascular hydrostatic pressure (i.e. heart failure). Biochemistry profile will evaluate plasma proteins, liver function, and renal function, important differentials for abdominal effusion. Serum bilirubin measurement is important and increases may raise suspicion for infection with hemotropic mycoplasmas or liver dysfunction.
Urinalysis is critical for adequate interpretation of a serum biochemistry profile and should always be performed.
FELV/FIV testing would help rule in or out retroviral infection in this patient. Retroviral status is important to establish in all feline patients with significant inflammatory disease.
Abdominal fluid analysis +/− infectious disease testing would be beneficial in this patient to investigate potential causes of effusion. The characterization of the fluid would help support the possibility of FIP.
Case Figure 4.1 Hematologic data. *Absolute leukocyte values are based on WBC estimate and differential count.
*Abdominal radiographs would be less helpful in this case because fluid within the peritoneal cavity obscures radiographic detail. Abdominal ultrasound and thoracic radiographs may be beneficial to perform.
What low‐cost diagnostics could you perform in this patient that might give you similar information provided by your ideal list of diagnostics?
PCV/TPP, blood film review, BUN, urinalysis, and abdominal fluid analysis would be appropriate low‐cost diagnostics.
What information are you expecting to receive from these diagnostics? In other words, what differential do you expect to rule in or rule out with these diagnostics?
PCV/TPP will confirm if the patient is anemic. If anemic, the total plasma protein can help determine the cause of the anemia. Total plasma protein may provide insight into disease process such as dehydration, hypoproteinemia, or inflammation.
Blood film evaluation can support evidence of an inflammatory process. Potentially, hemotropic mycoplasmas or other erythroparasites may be found to assist in determining the cause of anemia if present.
BUN will help support possible dehydration and may provide insight into the origin of the abdominal effusion if there is other evidence of renal insufficiency.
Urinalysis is necessary for adequate interpretation any biochemistry profile and BUN in this case. Urinalysis may also provide insight into potential causes of abdominal effusion if there is significant proteinuria.
Abdominal fluid analysis will classify the effusion and provide insight into potential causes of the effusion.
Case Figure 4.8 Biochemistry and urinalysis data. Urinalysis sample by cystocentesis.
What results, given the patient’s signalment/history/clinical exam findings, would you expect in this patient?
In this patient, a normal BUN with a USG in the hypersthenuric range (patient is ~5% dehydrated) is expected. An inflammatory leukogram, stress (glucocorticoid) leukogram, or both would be expected considering the presence of fever in this patient. Abdominal effusion may reveal an exudate or protein‐rich effusion considering the presence of fever. However, a transudate or protein‐poor cellular infiltrate could be possible. Given the patient‘s pale mucous membranes and slight tachycardia, the PCV may be decreased. Given the abdominal effusion and fever, the total plasma protein may be high due to increased inflammatory proteins, possible dehydration. Since there is no clinical evidence of blood loss, hypoproteinemia is less likely. However, hypoproteinemia due to protein loss through the gastrointestinal tract or kidney is possible.
Diagnostic Result Interpretation Questions
Given the diagnostic results, what abnormalities do you identify? What is your interpretation of these findings?
Are any of these diagnostic results surprising/unexpected?
What are the broad mechanisms by which these abnormalities occur?
Is rouleaux normally seen in cats? If so, is it ever of diagnostic value when present?
How can we distinguish rouleaux from erythrocyte agglutination? Why is it important to make the distinction between the two?
What is the reason we see bilirubinuria and mildly icteric plasma in this patient? Is bilirubinuria ever normal in cats?
In this case, what is/are the top differential diagnoses based on the current diagnostic data?
What diagnostic results are most supportive for each of the differential diagnoses?
What additional diagnostics would you need to confirm/refute the top differentials for this case?
Diagnostic Result Interpretation Answers
Given the diagnostic results, what abnormalities do you identify? What is your interpretation of these abnormalities?
The PCV is within the reference interval, indicating the patient‘s pale mucous membranes are more likely due to poor perfusion and not anemia.
The total plasma protein is markedly increased. Considering the inflammatory process evident in the fluid analysis, the markedly increased total plasma protein is most likely due to inflammation. A less likely possibility would be an immunoglobulin producing plasma cell neoplasm. The degree of dehydration is unlikely to cause this degree of hyperproteinemia.
The WBC estimate is mildly decreased, the neutrophil count is within the reference interval. The mild leukopenia is likely the result of lymphopenia, and monocytopenia. Lymphopenia is likely secondary to increased circulating glucocorticoid (cortisol) concentration. Monocytopenia is not a clinically significant finding.
The BUN is normal and urine specific gravity shows adequate urine‐concentrating ability. Therefore, the patient likely has normal renal function.
There is mild bilirubinuria, which supports the mildly icteric plasma appearance. Bilirubinuria in combination with icteric plasma confirms that this patient is hyperbilirubinemic. In this case, the increase in plasma bilirubin concentration is not of a magnitude that is resulting in grossly evident jaundice. There is not enough information to definitively determine the cause of icterus in this patient.
The abdominal fluid analysis shows a very high‐protein effusion. There are predominantly large, activated macrophages with low numbers of neutrophils and lymphocytes and no infectious agents identified. This finding is very consistent with chronic inflammation and is commonly seen in patients with feline infectious peritonitis (FIP).
Are any of these diagnostic results surprising/unexpected?
The icteric plasma and bilirubinuria was unexpected, but not surprising. It was unexpected because the patient did not have gross evidence of icterus. Generally, serum bilirubin concentrations have to be >2.5 mg/dL to be visibly evident as icteric mucous membranes. However, increased plasma bilirubin concentration is a common finding in cats with FIP.
The markedly increased total plasma protein was also unexpected but not surprising. In cats, marked immunologic responses, can be common with certain inflammatory conditions. This degree of hyperglobulinemia is common with FIP. Feline infectious peritonitis is a major differential to consider in cases of marked hyperproteinemia caused by markedly increased globulin concentration.
In this case, the relatively normal leukogram is surprising because of the presence of significant fever and inflammatory abdominal effusion. However, it is important to remember that even in cases of significant tissue inflammation you may not see leukocytosis or neutrophilia.
What are the broad mechanisms by which these abnormalities occur?
In this case, prehepatic icterus is unlikely since the PCV is within reference interval. The icterus is most likely hepatic in origin, although a posthepatic component cannot definitively be ruled out without abdominal ultrasound. Icterus of hepatic origin is likely the result of vasculitis and subsequent hepatocellular injury, a common sequela of FIP.
Lymphopenia is the result of increased plasma glucocorticoid (cortisol) concentration. Glucocorticoids have many effects on lymphocytes: induction of lympholysis, reduced egress from lymph nodes, and decreased lymphocyte proliferation. All of these can contribute to lymphopenia due to glucocorticoid (cortisol) response.
Increases in total plasma protein can have several mechanisms including increased production of proteins or loss of plasma water effectively concentrating proteins. It is unlikely that this patient‘s hyperproteinemia is the result of the dehydration present. Hyperproteinemia in this case is most likely the result of increased production of immunoglobulins and acute phase proteins such as fibrinogen, C‐reactive protein, Serum Amyloid A, and other alpha and beta globulins.
High‐protein, low cell effusion is the result of cavitary protein and water exudation, but little loss of cells into the fluid. Widespread vasculitis is a common cause of protein and fluid loss from the vascular space into the cavitary space. Fluid cellularity can be mild to moderate, mainly due to the adhesion of inflammatory cells to endothelium and inflammation secondary to necrosis. The inflammatory cell population is predominantly activated macrophages, which in the case in FIP occurs as a result of virus‐mediated macrophage proliferation.
Is rouleaux normally seen in cats? If so, is it ever of diagnostic value when present?
Rouleaux can be a normal finding in cats when examining the blood film; however, rouleaux to the degree seen in this case is abnormal. This degree is supportive of a markedly increased plasma protein concentration. Increased plasma proteins lead to increased erythrocyte attraction by altering surface charge. If there is marked rouleaux and markedly increased plasma protein, there are relatively few conditions that should be considered depending on clinical signs (i.e. Plasma cell neoplasia, severe inflammatory response, etc.).
How can we distinguish rouleaux from erythrocyte agglutination? Why is it important to make the distinction between the two?
Erythrocyte agglutination and rouleaux can be challenging to distinguish by morphology alone.
Performing a saline agglutination test allows for distinction between the two entities. When performed, the dilution of the plasma protein will usually allow the erythrocyte surface charge to become more normal. This allows the stacked erythrocytes to “disperse” from each other. In the case of true erythrocyte agglutination, the saline will not disperse the cells, and they will remain aggregated.
It is critical to distinguish these two entities from each other. Erythrocyte agglutination has more significant implications than rouleaux. Erythrocyte agglutination indicates immune‐mediated hemolytic anemia, where rouleaux can be normal or simply indicate increased plasma protein concentration.
What is the reason we see bilirubinuria and mildly icteric plasma in this patient? Is bilirubinuria ever normal in cats?
In cats, bilirubinuria is never “normal” and by itself is indicative of hyperbilirubinemia. The bilirubinuria and mildly icteric plasma are both consistent with hyperbilirubinemia. In cats with no signs of jaundice on physical exam, a positive urine bilirubin should be confirmed, to ensure the result is not erroneous. In this case, the presence of icteric plasma confirms the urinalysis result is correct.
*Note: Bilirubinuria is normal in dogs because they have a lower renal threshold for bilirubin and can conjugate and secrete bilirubin in the kidney.
In this case, what is/are the top differential diagnoses based on the current diagnostic data?
FIP is the primary differential. Other differentials to consider are FELV, FIV, Hemotropic Mycoplasma, or other infectious diseases. Concurrent diseases cannot be ruled out.
What diagnostic results are most supportive for each of the differential diagnoses?
The most likely differential is FIP, supported by the marked hyperproteinemia, high‐protein and mild cellularity effusion, and evidence of hepatic disease. Other causes of vasculitis should be considered as well. FELV/FIV should always be considered in ill patients with evidence of inflammatory or infectious disease. Hemotropic mycoplasma infection also cannot be entirely ruled out at this time because of the observed splenomegaly and icteric plasma. The anemia associated with hemotropic mycoplasmas can be periodic. Currently, we don‘t have enough information to rule in other disease, that may be more apparent with a full minimum database.
What additional diagnostics would you need to confirm/refute your top differentials for this case?
In this case, complete fluid analysis with quantification of the nucleated cell count and Feline Coronavirus PCR on the abdominal effusion would assist in confirming or refuting the diagnosis of FIP. It is important in a case like this to rule out other potential causes i.e. FELV, Mycoplasma, etc. therefore, PCR testing for a variety of infectious agents may be helpful in efficiently identifying a cause for the patient‘s signs. It would also be helpful to perform serum protein electrophoresis to differentiate a monoclonal gammopathy (secondary to neoplasia) from a polyclonal gammopathy (secondary to marked inflammation). Infectious diseases typically result in a polyclonal gammopathy; however, in rare cases, infectious disease may result in monoclonal gammopathies (i.e. Ehrlichiosis in dogs and FIP in cats).
5 Case #5
5.1 Signalment
Star, a 9‐week‐old intact female Australian Shepherd dog
5.2 History
Star was adopted by her family yesterday from an online ad. She came with no documentation of vaccinations, previous veterinary visits, or fecal examination.
5.3 Presentation
Star presents for a wellness exam and vaccinations. This morning the owners noticed that Star was not acting like she was yesterday. She is depressed, will not eat, has bloody diarrhea and is vomiting.
Cardiopulmonary: No murmurs on auscultation, strong synchronous pulses, lungs auscultate normally. Abdomen: Abdomen appears painful on palpation, patient moans when attempted.
Lymph: No abnormalities identified.
HEENT: No abnormalities identified.
Urogenital: No abnormalities identified.
Integument: No abnormalities identified.
Neurologic: Patient is QAR, ambulates normally and has normal conscious proprioceptive responses and nociceptive responses. A brief cranial nerve exam is within normal limits.
Musculoskeletal: No abnormalities identified.
Initial Data (History/Signalment/Physical Exam) Questions
Given the clinical data what is the differential diagnosis?
What diagnostics ideally would you like to perform (given no resource boundaries) and why?
What low‐cost diagnostics could you perform in this patient that might give you similar information to your ideal list?
What information are you expecting to receive from these diagnostics? In other words, what differential do you expect to rule in or rule out with these diagnostics?
What results, given the patient’s signalment/history/clinical exam findings, would you expect in this patient?
Initial Data (History/Signalment/Physical Exam) Answers
Given the clinical data what is the differential diagnosis?
Canine parvoviral enteritis, canine distemper virus, giardiasis, or intestinal parasitism are the top differentials.
What diagnostics ideally would you like to perform (given no resource boundaries) and why?
Ideally in this patient, a CBC, biochemistry profile, urinalysis, fecal direct smear, fecal flotation, and rapid antigen testing for Canine parvovirus (CPV) and Giardia would be ideal.
The CBC is important to assess for evidence of inflammation. If this patient has a CPV infection, leukocyte concentration is an important prognostic indicator.
A biochemical profile would be valuable in assessing electrolyte/acid–base status. It will also be important for treatment monitoring and adjustment based on changes in parameters related to renal function and hydration status (i.e. BUN and creatinine).
Urinalysis is critical for adequate interpretation of the serum biochemical profile and they should always be performed together.
Fecal direct smear will allow us to evaluate for motile parasites (i.e. Giardia) and the population of microorganisms present.
Fecal flotation would allow evaluation for the presence of GI parasites, which are common in puppies. It is needed to rule out the possibility of hookworms, roundworms, and whipworms as a cause of the diarrhea
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