{"id":1287,"date":"2013-07-01T18:39:27","date_gmt":"2013-07-01T18:39:27","guid":{"rendered":"http:\/\/phosdev.com\/todaysveterinarypractice\/?p=1287"},"modified":"2022-02-17T18:58:45","modified_gmt":"2022-02-17T18:58:45","slug":"diagnosis-of-immune-mediated-hemolytic-anemia","status":"publish","type":"post","link":"https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/hematology\/diagnosis-of-immune-mediated-hemolytic-anemia\/","title":{"rendered":"Diagnosis of Immune-Mediated Hemolytic Anemia"},"content":{"rendered":"<p><a href=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2016\/09\/T1307F04.pdf\"><img decoding=\"async\" class=\"alignnone size-full wp-image-9886\" src=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2011\/07\/pdf_button.png\" alt=\"pdf_button\" width=\"110\" height=\"27\" \/><\/a><\/p>\n<hr \/>\n<p><i>Todd Archer, DVM, Diplomate ACVIM, and Andrew Mackin, BSc, BVMS, Diplomate ACVIM<\/i><\/p>\n<p>Immune-mediated hemolytic anemia is one of the most common immune-mediated hematologic disorders in dogs and cats. Part 1 of this 2-article series discusses pathophysiology and diagnosis of IMHA, including patient predilection, history and clinical signs, physical examination, diagnostics, and differential diagnoses.<\/p>\n<hr \/>\n<p>Immune-mediated hemolytic anemia (IMHA) is one of the most common immune-mediated hematologic disorders in dogs and cats.<\/p>\n<p>In dogs, immune-mediated hemolytic anemia:<\/p>\n<ul>\n<li>Is commonly primary or idiopathic in origin<\/li>\n<li>Often affects particular breeds, including cocker spaniels, English springer spaniels, collies, poodles, and Irish setters<sup>1,2<\/sup><\/li>\n<li>Most commonly affects middle-aged female dogs<\/li>\n<li>Also occurs secondary to triggers, such as infectious, inflammatory, and neoplastic diseases; drugs; and vaccines (<strong>Table 1<\/strong>).<\/li>\n<\/ul>\n<p>In cats, there is no breed predilection for IMHA, and the condition is usually secondary to an underlying cause.<sup>3<\/sup><\/p>\n<div class=\"orange-box\">\n<h2><strong><span class=\"aquabold\">Pathophysiology<\/span><span class=\"aquabold\">\u00a0of IMHA<\/span><\/strong><\/h2>\n<p>IMHA is a\u00a0<span class=\"purple\">type II immune reaction<\/span>, where antibody and\/or complement formation against RBCs causes accelerated cell destruction and subsequent anemia. The anti-RBC antibodies can be either immunoglobulin G or M (IgG or IgM).<sup><span style=\"font-size: small\">4<\/span><\/sup>When the body is correctly responding to an immune reaction,\u00a0<span class=\"purple\">antibodies ensure an appropriate immune response<\/span>\u00a0while the\u00a0<span class=\"purple\">complement system enhances the ability of antibodies and phagocytic cells to clear pathogens<\/span>. However, in cases of IMHA:<\/p>\n<ul>\n<li>High levels of antibodies induce activation of the complement system and formation of the membrane attack complex; RBC destruction tends to be intravascular due to osmotic lysis.<sup><span style=\"font-size: small\">1<\/span><\/sup><\/li>\n<li>Macrophages within the spleen, liver, and other organs recognize the Fc portion of antibodies and\/or the C3b portion of complement bound to RBCs and prematurely remove cells from circulation and destroy them (<span class=\"purple\">extravascular hemolysis<\/span>).<sup><span style=\"font-size: small\">1,4<\/span><\/sup><\/li>\n<\/ul>\n<p>Classically, the bone marrow mounts an appropriate and strongly regenerative response. Less commonly, antibodies are also directed against marrow RBC precursors, resulting in nonregenerative anemia.<\/p>\n<\/div>\n<table style=\"height: 1620px\" border=\"1\" width=\"339\" cellspacing=\"0\" cellpadding=\"3\" align=\"right\">\n<tbody>\n<tr>\n<td class=\"GreenAqua\" align=\"center\">Table 1. Important Differential Diagnoses for Hemolytic Anemia<\/td>\n<\/tr>\n<tr bgcolor=\"#dbecf2\">\n<td class=\"references\" bgcolor=\"#ffffff\">CHEMICAL\/TOXIN INJURY<\/td>\n<\/tr>\n<tr>\n<td bgcolor=\"#dbecf2\">Castor bean<br \/>\nCopper<br \/>\nGarlic\/onion<br \/>\nMethylene blue<br \/>\nPropylene glycol<br \/>\nZinc<\/td>\n<\/tr>\n<tr bgcolor=\"#dbecf2\">\n<td class=\"references\" bgcolor=\"#ffffff\">IMMUNE-MEDIATED<\/td>\n<\/tr>\n<tr>\n<td bgcolor=\"#dbecf2\">Disseminated intravascular coagulation*<br \/>\nGlomerulonephritis*<br \/>\nIncompatible transfusions*<br \/>\nNeonatal isoerythrolysis*<br \/>\nPrimary IMHA*<br \/>\nSystemic lupus erythematosus*<\/td>\n<\/tr>\n<tr bgcolor=\"#dbecf2\">\n<td class=\"references\" bgcolor=\"#ffffff\">INFECTIOUS<\/td>\n<\/tr>\n<tr>\n<td bgcolor=\"#dbecf2\">Anaplasma species*<br \/>\nAncylostoma caninum*<br \/>\nBabesia canis*<br \/>\nBabesia gibsoni*<br \/>\nCytauxzoon felis*<br \/>\nDirofilaria immitis*<br \/>\nEhrlichia species*<br \/>\nFeLV*, FIP*, FIV*<br \/>\nHistoplasmosis*<br \/>\nLeishmaniasis*<br \/>\nLeptospirosis*<br \/>\nMycoplasma haemocanis*<br \/>\nMycoplasma haemofelis*<\/td>\n<\/tr>\n<tr bgcolor=\"#dbecf2\">\n<td class=\"references\" bgcolor=\"#ffffff\">INTRINSIC\/INHERITED RBC DEFECTS<\/td>\n<\/tr>\n<tr>\n<td bgcolor=\"#dbecf2\">Chondrodysplasia (in malamutes)<br \/>\nHereditary osmotic fragility<br \/>\nIdiopathic Heinz body anemia<br \/>\nMethemoglobin-reductase deficiency<br \/>\nPhosphofructokinase deficiency<br \/>\nPyruvate kinase deficiency<\/td>\n<\/tr>\n<tr bgcolor=\"#dbecf2\">\n<td class=\"references\" bgcolor=\"#ffffff\">MEDICATIONS<\/td>\n<\/tr>\n<tr>\n<td bgcolor=\"#dbecf2\">Acetaminophen*<br \/>\nCephalosporins*<br \/>\nChlorpromazine*<br \/>\nDipyrone*<br \/>\nHeparin*<br \/>\nLevamisole*<br \/>\nMethimazole\/propylthiouracil*<br \/>\nPenicillins*<br \/>\nPhenazopyridine hydrochloride*<br \/>\nProcainamide*<br \/>\nSulfonamides*<br \/>\nTopical benzocaine*<br \/>\nVitamin K*<br \/>\nQuinidine*<\/td>\n<\/tr>\n<tr bgcolor=\"#dbecf2\">\n<td class=\"references\" bgcolor=\"#ffffff\">NEOPLASIA<\/td>\n<\/tr>\n<tr>\n<td bgcolor=\"#dbecf2\">Diffuse sarcoma*<br \/>\nHemangiosarcoma*<br \/>\nLymphocytic leukemia*<br \/>\nLymphoma*<br \/>\nMultiple myeloma*<br \/>\nOther solid tumors*<\/td>\n<\/tr>\n<tr bgcolor=\"#dbecf2\">\n<td class=\"references\" bgcolor=\"#ffffff\">OTHER<\/td>\n<\/tr>\n<tr>\n<td bgcolor=\"#dbecf2\">Bee-sting envenomation*<br \/>\nRecent vaccination*<br \/>\nSevere hypophosphatemia<br \/>\nSnake-bite envenomation<\/td>\n<\/tr>\n<tr>\n<td bgcolor=\"#ffffff\"><span class=\"references\">*Denotes conditions that have been suggested to induce immunologic destruction of RBCs<\/span><\/td>\n<\/tr>\n<tr>\n<td><span class=\"references\">FeLV = feline leukemia virus; FIP = feline infectious peritonitis; FIV = feline immunodeficiency virus; IMHA = immune-mediated hemolytic anemia; RBC = red blood cell<\/span><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<h2><span class=\"bluboldheader\">PATIENT EVALUATION<\/span><\/h2>\n<h3><strong><span class=\"aquabold\">History<\/span><\/strong><\/h3>\n<p>When a patient presents with possible IMHA, history should include a detailed account of any recent medications or vaccines. Historical clues that suggest a possible underlying or triggering disease process should also be investigated (<strong>Table 1<\/strong>).<\/p>\n<h3><strong><span class=\"aquabold\">Clinical Signs<\/span><\/strong><\/h3>\n<p>Clinical signs seen in IMHA patients often include those associated with anemia and tissue hypoxia, including:<\/p>\n<ul>\n<li>Lethargy<\/li>\n<li>Weakness<\/li>\n<li>Tachypnea.<\/li>\n<\/ul>\n<p>When anemia is severe and acute in onset, patients tend to be the most significantly affected. When red blood cell (RBC) destruction is more chronic, patients may only be mildly affected despite marked anemia.<\/p>\n<h3><strong>Physical Examination<\/strong><\/h3>\n<p>Physical examination may reveal:<\/p>\n<ul>\n<li>Pale mucous membranes<\/li>\n<li>Tachycardia<\/li>\n<li>Bounding pulses<\/li>\n<li>Less commonly: Splenomegaly, hepatomegaly, lymph node enlargement, and fever.<\/li>\n<\/ul>\n<p>Other physical examination findings may include:<\/p>\n<ul>\n<li>Hemic murmur, which should resolve once anemia is corrected<\/li>\n<li>Jaundiced mucous membranes and tissues if there is acute severe hemolysis (<strong>Figure 1<\/strong>)<\/li>\n<li>Hemoglobinuria (&#8220;port wine&#8221; urine) in patients with intravascular hemolysis<\/li>\n<li>Petechiae, ecchymoses, and melena in patients with concurrent immune-mediated thrombocytopenia (Evan&#8217;s Syndrome)<\/li>\n<li>Signs that reveal the underlying cause of IMHA.<\/li>\n<\/ul>\n<p><span style=\"color: #333333\"><strong>Figure 1.<\/strong> Jaundice in a dog with severe IMHA<\/span><\/p>\n<div>\n<p><a href=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig01A.jpg\"><img fetchpriority=\"high\" decoding=\"async\" class=\"alignnone size-medium wp-image-2799\" src=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig01A-300x199.jpg\" alt=\"Archer_fig01A\" width=\"300\" height=\"199\" srcset=\"https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig01A-300x199.jpg 300w, https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig01A.jpg 452w\" sizes=\"(max-width: 300px) 100vw, 300px\" \/><\/a><\/p>\n<p><a href=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig01B.jpg\"><img decoding=\"async\" class=\"alignnone size-medium wp-image-2800\" src=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig01B-300x199.jpg\" alt=\"Archer_fig01B\" width=\"300\" height=\"199\" srcset=\"https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig01B-300x199.jpg 300w, https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig01B.jpg 452w\" sizes=\"(max-width: 300px) 100vw, 300px\" \/><\/a><\/p>\n<p><a href=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig01C.jpg\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-medium wp-image-2801\" src=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig01C-300x199.jpg\" alt=\"Archer_fig01C\" width=\"300\" height=\"199\" srcset=\"https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig01C-300x199.jpg 300w, https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig01C.jpg 452w\" sizes=\"(max-width: 300px) 100vw, 300px\" \/><br \/>\n<\/a><\/p>\n<\/div>\n<h2><span class=\"bluboldheader\">DIAGNOSTICS<\/span><\/h2>\n<p>Initial diagnostics in an anemic patient should focus on identifying the cause of the anemia.\u00a0<strong>A final diagnosis of IMHA is based on evidence of accelerated RBC destruction, with an underlying immune-mediated pathogenesis.<\/strong><\/p>\n<p>There is no single test that is definitively diagnostic for IMHA. Instead, evidence from various analyses is used to determine the diagnosis (<strong>Table 2<\/strong>). The following signs and results support a diagnosis of primary IMHA:<\/p>\n<ul>\n<li>Anemia<\/li>\n<li>Evidence of accelerated RBC lysis, including, but not limited to, hemoglobinemia\/hemoglobinuria (intravascular hemolysis) or bilirubinemia\/bilirubinuria<\/li>\n<li>Evidence of an immune-mediated process, such as autoagglutination, a positive Coombs&#8217; test, or increased numbers of circulating spherocytes<\/li>\n<li>Lack of other identifiable causes of anemia.<\/li>\n<\/ul>\n<table style=\"height: 1220px\" border=\"1\" width=\"688\" cellspacing=\"1\" cellpadding=\"10\">\n<tbody>\n<tr>\n<td>\n<table border=\"0\" width=\"100%\" cellspacing=\"1\" cellpadding=\"3\">\n<tbody>\n<tr>\n<td colspan=\"2\" align=\"center\"><span class=\"GreenAqua\">Table 2. Diagnostic Overview for Immune-Mediated Hemolytic Anemia<\/span><br \/>\n<span class=\"references\">No single test is definitively diagnostic for IMHA. Instead, evidence from various analyses is used to determine the diagnosis.<\/span><\/td>\n<\/tr>\n<tr>\n<td valign=\"bottom\" bgcolor=\"#eff8fa\" width=\"23%\"><strong class=\"purple\">Diagnostic Process<\/strong><\/td>\n<td valign=\"bottom\" bgcolor=\"#dbf0f4\" width=\"77%\"><strong class=\"purple\">Results That May Indicate IMHA<\/strong><\/td>\n<\/tr>\n<tr>\n<td valign=\"top\" bgcolor=\"#eff8fa\"><strong>Predilection<\/strong><\/td>\n<td valign=\"top\" bgcolor=\"#dbf0f4\">\n<ul>\n<li>Often affects particular breeds*<\/li>\n<li>Commonly affects middle-aged female dogs<\/li>\n<li>In cats, no breed predilection<\/li>\n<\/ul>\n<\/td>\n<\/tr>\n<tr>\n<td valign=\"top\" bgcolor=\"#eff8fa\"><strong>History<\/strong><\/td>\n<td valign=\"top\" bgcolor=\"#dbf0f4\">\n<ul>\n<li>Infectious, inflammatory, or neoplastic disease<\/li>\n<li>Drug or vaccine administration<\/li>\n<li>In cats, IMHA usually secondary to underlying cause<\/li>\n<\/ul>\n<\/td>\n<\/tr>\n<tr>\n<td valign=\"top\" bgcolor=\"#eff8fa\"><strong>Clinical Signs<\/strong><\/td>\n<td valign=\"top\" bgcolor=\"#dbf0f4\">\n<ul>\n<li>Lethargy<\/li>\n<li>Weakness<\/li>\n<li>Tachypnea<\/li>\n<\/ul>\n<\/td>\n<\/tr>\n<tr>\n<td valign=\"top\" bgcolor=\"#eff8fa\"><strong>Physical Examination<\/strong><\/td>\n<td valign=\"top\" bgcolor=\"#dbf0f4\">\n<ul>\n<li>Pale mucous membranes, tachycardia, bounding pulses, and hemic murmur<\/li>\n<li>Splenomegaly, hepatomegaly, enlarged lymph nodes, and fever<\/li>\n<li>Signs related to the underlying cause<\/li>\n<li>Acute severe hemolysis: Jaundiced mucous membranes and tissues<\/li>\n<li>Intravascular hemolysis: Hemoglobinuria (&#8220;port wine&#8221; urine)<\/li>\n<li>Immune-mediated thrombocytopenia: Petechiae, ecchymoses, and melena<\/li>\n<\/ul>\n<\/td>\n<\/tr>\n<tr>\n<td valign=\"top\" bgcolor=\"#eff8fa\"><strong>Blood Analysis<\/strong><\/td>\n<td valign=\"top\" bgcolor=\"#dbf0f4\">\n<ul>\n<li><strong>CBC\/blood smear:<\/strong> Anemia, accelerated RBC lysis, spherocytosis, neutrophilia<\/li>\n<li><strong>Agglutination (anti-RBC antibodies): <\/strong>Macroagglutination, microagglutination<\/li>\n<li><strong>Direct Coombs&#8217; test:<\/strong> Positive result<\/li>\n<li><strong>Serum biochemistry: <\/strong>Hyperbilirubinemia, increased liver enzymes<\/li>\n<\/ul>\n<\/td>\n<\/tr>\n<tr>\n<td valign=\"top\" bgcolor=\"#eff8fa\"><strong>Coagulation Tests<\/strong><\/td>\n<td valign=\"top\" bgcolor=\"#dbf0f4\">\n<ul>\n<li><strong>PT &amp; aPTT:<\/strong> Disseminated intravascular coagulation, thromboembolic disease<\/li>\n<\/ul>\n<\/td>\n<\/tr>\n<tr>\n<td valign=\"top\" bgcolor=\"#eff8fa\"><strong>Urinalysis<\/strong><\/td>\n<td valign=\"top\" bgcolor=\"#dbf0f4\">\n<ul>\n<li>Bilirubinuria<\/li>\n<li>Hemoglobinuria (intravascular hemolysis)<\/li>\n<\/ul>\n<\/td>\n<\/tr>\n<tr>\n<td valign=\"top\" bgcolor=\"#eff8fa\"><strong>Additional Testing<\/strong><\/td>\n<td valign=\"top\" bgcolor=\"#dbf0f4\">\n<ul>\n<li><strong>Bone marrow evaluation:<\/strong> Indicated if persistant nonregenerative anemia or pancytopenia is present on blood analysis.<\/li>\n<li><strong>Infectious disease identification:<\/strong> Indicated if infectious cause of hemolysis is suspected based on signalment, clinical signs, and geographic location.<\/li>\n<li><strong>Imaging:<\/strong> Indicated when identifying underlying causes of IMHA<\/li>\n<\/ul>\n<\/td>\n<\/tr>\n<tr>\n<td class=\"references\" colspan=\"2\" valign=\"top\"><em>* Cocker spaniels, English springer spaniels, collies, poodles, and Irish setters<\/em><br \/>\naPTT = activated partial thromboplastin time; CBC = complete blood count; IMHA = immune-mediated hemolytic anemia; PT = prothrombin time; RBC = red blood cell<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>&nbsp;<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<h3><strong><span class=\"aquabold\">Complete Blood Count &amp; Blood Smear Analysis<\/span><\/strong><\/h3>\n<p>In IMHA patients, complete blood count (CBC) with blood smear analysis often reveals anemia and RBC changes, which are suggestive of a regenerative response, such as polychromasia, anisocytosis, and nucleated RBCs.<\/p>\n<h3><strong><span class=\"purple\">Reticulocytes<\/span><\/strong><\/h3>\n<ul>\n<li>An increased absolute reticulocyte count (&gt; 60,000\/mcL, dogs; &gt; 50,000\/mcL aggregate reticulocytes, cats) or corrected reticulocyte percentage (&gt; 1%, dogs; &gt; 0.5%, cats) documents a regenerative marrow response.<sup>5<\/sup><\/li>\n<li>Since a regenerative response takes approximately 3 to 5 days to mount, acute cases may initially appear poorly regenerative.<\/li>\n<li>A nonregenerative response may also suggest the presence of antibodies directed against marrow precursors.<\/li>\n<\/ul>\n<h3><strong><span class=\"purple\">Spherocytes<\/span><\/strong><\/h3>\n<p>Spherocytes may also be seen on blood smears. Spherocytes are small RBCs with a loss of central pallor produced by incomplete destruction of RBCs by macrophages (<strong>Figure 2<\/strong>). Spherocytosis is very suggestive of IMHA.<\/p>\n<div id=\"attachment_2802\" style=\"width: 310px\" class=\"wp-caption alignnone\"><a href=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig02.jpg\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-2802\" class=\"wp-image-2802 size-medium\" src=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig02-300x225.jpg\" alt=\"Archer_fig02\" width=\"300\" height=\"225\" srcset=\"https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig02-300x225.jpg 300w, https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig02.jpg 400w\" sizes=\"(max-width: 300px) 100vw, 300px\" \/><\/a><p id=\"caption-attachment-2802\" class=\"wp-caption-text\">Figure 2. Marked spherocytosis observed on a Wright&#8217;s-stained blood smear from a dog with IMHA; spherocytes are recognized as smaller RBCs that lack central pallor. They form when macrophages remove a segment of RBC membrane without loss of intracellular contents; the remaining cell membrane must form a globoid sphere in order to stretch over and contain the cytoplasm.<\/p><\/div>\n<h3><strong><span class=\"purple\">Other Findings<\/span><\/strong><\/h3>\n<p>The blood smear should also be carefully evaluated by an experienced clinical pathologist for:<\/p>\n<ul>\n<li><strong>Presence of RBC parasites<\/strong>, such as\u00a0<em>Mycoplasma haemofelis<\/em>\u00a0(formerly\u00a0<em>Haemobartonella<\/em>) and\u00a0<em>Babesia<\/em><\/li>\n<li><strong>Neutrophilia<\/strong>, often with a left shift, is commonly seen in IMHA patients<\/li>\n<li><strong>Extreme leukocytosis<\/strong>\u00a0(&#8220;leukemoid response&#8221;) occurs in some dogs with IMHA and has been associated with severe tissue injury<sup>6<\/sup><\/li>\n<li><strong>Thrombocytopenia<\/strong>\u00a0will be observed in animals with Evan&#8217;s Syndrome.<\/li>\n<\/ul>\n<h3><strong><span class=\"aquabold\">Anti-RBC Antibodies<\/span><\/strong><\/h3>\n<h3><span class=\"purple\">Spontaneous Autoagglutination<\/span><\/h3>\n<p>High levels of anti-RBC antibodies sometimes result in their attachment to more than one cell, causing spontaneous RBC agglutination. Agglutination may be appreciated as red speckles when blood is placed in an EDTA tube (<strong>Figure 3<\/strong>) or onto a microscope slide.<\/p>\n<div id=\"attachment_2803\" style=\"width: 310px\" class=\"wp-caption alignnone\"><a href=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig03.jpg\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-2803\" class=\"wp-image-2803 size-medium\" src=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig03-300x199.jpg\" alt=\"Archer_fig03\" width=\"300\" height=\"199\" srcset=\"https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig03-300x199.jpg 300w, https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig03.jpg 452w\" sizes=\"(max-width: 300px) 100vw, 300px\" \/><\/a><p id=\"caption-attachment-2803\" class=\"wp-caption-text\">Figure 3. Autoagglutination observed as red speckles in EDTA-anticoagulated blood from a dog with severe IMHA.<\/p><\/div>\n<h3><strong><span class=\"purple\">Slide Agglutination Test<\/span><\/strong><\/h3>\n<p>The slide agglutination test can be easily performed in practice, and is used to differentiate true autoagglutination from rouleaux formation (nonimmune RBC adhesion).<\/p>\n<ul>\n<li>A single drop of EDTA-anticoagulated blood is placed onto a microscope slide and mixed with saline (1\u20132 drops in dogs; 3\u20134 drops in cats due to their greater propensity to develop rouleaux).<\/li>\n<li>The slide is rocked back and forth; then evaluated for the formation of macroagglutination (obvious agglutination to the naked eye) (<strong>Figure 4<\/strong>).<\/li>\n<li>A coverslip can then be placed on the mixture, and the slide evaluated under a microscope for microagglutination (4 or more RBCs in a cluster) (<strong>Figure 5<\/strong>).<\/li>\n<li>True agglutination appears as &#8220;clusters of grapes&#8221; while rouleaux appear as &#8220;stacks of coins&#8221; (<strong>Figure 6<\/strong>).<\/li>\n<li>Rouleaux can further be differentiated from autoagglutination by adding additional saline and by RBC washing techniques; extra saline often disperses rouleaux but will not disperse true autoagglutination.<\/li>\n<\/ul>\n<p><em>Since autoagglutination is only seen with high antibody levels, a negative slide agglutination test does not rule out IMHA.\u00a0<\/em><\/p>\n<div id=\"attachment_2804\" style=\"width: 310px\" class=\"wp-caption alignnone\"><a href=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig04.jpg\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-2804\" class=\"wp-image-2804 size-medium\" src=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig04-300x210.jpg\" alt=\"Archer_fig04\" width=\"300\" height=\"210\" srcset=\"https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig04-300x210.jpg 300w, https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig04.jpg 428w\" sizes=\"(max-width: 300px) 100vw, 300px\" \/><\/a><p id=\"caption-attachment-2804\" class=\"wp-caption-text\"><br \/>Figure 4. Positive slide agglutination test in a dog with IMHA, demonstrating obvious macroagglutination. Since false positives can also occur, the Coombs&#8217; test should be carefully interpreted in each individual patient.<\/p><\/div>\n<div id=\"attachment_2805\" style=\"width: 310px\" class=\"wp-caption alignnone\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-2805\" class=\"wp-image-2805 size-medium\" src=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig05-300x225.jpg\" alt=\"Archer_fig05\" width=\"300\" height=\"225\" srcset=\"https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig05-300x225.jpg 300w, https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig05.jpg 400w\" sizes=\"(max-width: 300px) 100vw, 300px\" \/><p id=\"caption-attachment-2805\" class=\"wp-caption-text\">Figure 5. Microagglutination observed on a standard Wright&#8217;s-stained blood smear from a dog with IMHA; RBCs are strongly adhered to one another by a high level of anti-RBC antibodies that are attached to more than one cell.<\/p><\/div>\n<div id=\"attachment_2806\" style=\"width: 310px\" class=\"wp-caption alignnone\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-2806\" class=\"wp-image-2806 size-medium\" src=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig06-300x225.jpg\" alt=\"Archer_fig06\" width=\"300\" height=\"225\" srcset=\"https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig06-300x225.jpg 300w, https:\/\/navc.sitepreview.app\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/Archer_fig06.jpg 400w\" sizes=\"(max-width: 300px) 100vw, 300px\" \/><p id=\"caption-attachment-2806\" class=\"wp-caption-text\">Figure 6. Rouleaux observed on a Wright&#8217;s-stained blood smear from a cat with a serious systemic illness. RBCs can form stacks in conditions associated with high plasma protein levels; while these stacks can appear as speckles to the naked eye, cell-to-cell bonding is weak and easily dispersed by saline.<\/p><\/div>\n<h3><strong><span class=\"aquabold\">Direct Coombs&#8217; Test<\/span><\/strong><\/h3>\n<p>The direct Coombs&#8217; test is also known as the direct antiglobulin test (DAT) and identifies antibodies or complement adhered to RBCs. IMHA patients that do not demonstrate autoagglutination may still test positive on the Coombs&#8217; test. However, diagnostic sensitivity of the Coombs&#8217; test ranges from 60% to 89%, so a negative test does not exclude IMHA.<\/p>\n<h3><strong><span class=\"aquabold\">Additional Diagnostics<\/span><\/strong><br \/>\n<strong><span class=\"purple\">Serum Biochemical Profile<\/span><\/strong><\/h3>\n<p>Common serum biochemistry changes in IMHA patients include hyperbilirubinemia and increased liver enzymes.<\/p>\n<p><em><strong>Hyperbilirubinemia<\/strong><\/em><\/p>\n<ul>\n<li>With accelerated RBC destruction, increased bilirubin production by macrophages can overwhelm hepatic processing capacity, resulting in hyperbilirubinemia. However, it may also be due to concurrent hepatobiliary disease.<\/li>\n<li>Normal bilirubin levels are often seen in mild or chronic cases of IMHA because a healthy liver can still handle the extra bilirubin.<\/li>\n<\/ul>\n<p><em><strong>Increased Liver Enzymes<\/strong><\/em><\/p>\n<ul>\n<li>Liver enzyme elevation, especially alanine aminotransferase, may be present due to hypoxic liver damage.<\/li>\n<li>Azotemia may sometimes occur due to either prerenal causes (dehydration) or renal causes (hemoglobin-induced renal damage).<\/li>\n<\/ul>\n<h3><strong><span class=\"purple\">Coagulation Tests<\/span><\/strong><\/h3>\n<p>Coagulation tests, such as the 1-stage prothrombin time (PT) or activated partial thromboplastin time (aPTT), are indicated to assess for hemostatic disorders, such as:<\/p>\n<ul>\n<li>Disseminated intravascular coagulation (DIC)<\/li>\n<li>Thromboembolic disease.<\/li>\n<\/ul>\n<p>D-dimer concentration or antithrombin activity may be needed to characterize DIC or thrombotic diseases. Both conditions can be common and serious complications of IMHA.<\/p>\n<h3><strong><span class=\"purple\">Bone Marrow Evaluation<\/span><\/strong><\/h3>\n<p>Marrow evaluation is indicated if there is a persistent (beyond 3\u20135 days) nonregenerative anemia or pancytopenia is present on blood analysis.<\/p>\n<h3><strong><span class=\"purple\">Infectious Disease<\/span><\/strong><\/h3>\n<p>Testing for infectious causes of hemolysis, such as Mycoplasma haemofelis, Babesia canis, or Babesia gibsoni should be considered in individual patients based on signalment, clinical signs, and geographic location.<\/p>\n<h3><strong><span class=\"purple\">Urinalysis<\/span><\/strong><\/h3>\n<p>Urinalysis often reveals bilirubinuria or, with intravascular hemolysis, hemoglobinuria.<\/p>\n<h3><strong><span class=\"purple\">Imaging<\/span><\/strong><\/h3>\n<p>Diagnostic imaging is indicated to identify underlying causes of IMHA, such as neoplasia.<\/p>\n<ul>\n<li>Thoracic radiographs, abdominal radiographs, and abdominal ultrasound should be considered.<\/li>\n<li>Aspirates and histologic biopsies should be performed on any masses\/abnormal-appearing organs found on imaging.<\/li>\n<li>Abdominal radiographs are also indicated to exclude zinc foreign bodies, since zinc toxicosis can mimic IMHA.<\/li>\n<\/ul>\n<p><em>Part 2 of this series\u2014Management of Immune-Mediated Hemolytic Anemia\u2014will be published in the September\/October 2013 issue of Today&#8217;s Veterinary Practice.<\/em><\/p>\n<p><span class=\"references\">aPPT = activated partial thromboplastin time; CBC = complete blood count; DAT = direct antiglobulin test; DIC = disseminated intravascular coagulation; IgG = immunoglobulin G; IgM = immunoglobulin M; IMHA = immune-mediated hemolytic anemia; PT = prothrombin time; RBC = red blood cell<\/span><\/p>\n<h3><strong>References<\/strong><\/h3>\n<ol>\n<li>Balch A, Mackin A. Canine immune-mediated hemolytic anemia: Pathophysiology, clinical signs, and diagnosis. <em>Compend Contin Educ Pract Vet<\/em> 2007; 29:217-225.<\/li>\n<li>Carr AP, Panciera DL, Kidd L. Prognostic factors for mortality and thromboembolism in canine immune-mediated hemolytic anemia: A retrospective study of 72 dogs. J <em>Vet Intern Med<\/em> 2002; 16:504-509.<\/li>\n<li>August J. Immune-mediated hemolytic anemia. <em>Consultations in Feline Internal Medicine, vol 6<\/em>. St. Louis: Saunders, 2006, pp 617-627.<\/li>\n<li>McCullough S. Immune-mediated hemolytic anemia: Understanding the nemesis. <em>Vet Clin North Am Small Anim Pract<\/em> 2003; 33:1295-1315.<\/li>\n<li>BF Feldman, Zinkl JZ, NC Jain. <em>Schalm&#8217;s Veterinary Hematology<\/em>, 5th ed. Baltimore: Lippincott Williams &amp; Wilkins, 2000, pp 110-116.<\/li>\n<li>McManus PM, Craig LE. Correlation between leukocytosis and necropsy findings in dogs with immune-mediated hemolytic anemia: 34 cases (1994-1999). <em>JAVMA<\/em> 2001; 218(8):1308-1313.<\/li>\n<\/ol>\n<p><span class=\"author-bio\"><strong><a href=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/f04_Archer.png\"><img loading=\"lazy\" decoding=\"async\" class=\"alignleft size-full wp-image-7152\" src=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/f04_Archer.png\" alt=\"f04_Archer\" width=\"100\" height=\"124\" \/><\/a>Todd M. Archer<\/strong>, DVM, Diplomate ACVIM, is an assistant professor of small animal medicine in the Department of Clinical Sciences at Mississippi State University College of Veterinary Medicine. Dr. Archer&#8217;s clinical interests include hematology, immunology, and endocrine disorders as well as interventional radiologic procedures. His research has primarily focused on T-cell responses in dogs to cyclosporine using both flow cytometry and qRT-PCR. Dr. Archer has spoken at national, state, and local meetings and also published research articles regarding his work with cyclosporine. He received his DVM and completed an internship and residency at Mississippi State University.<\/span><\/p>\n<p>&nbsp;<\/p>\n<p><span class=\"author-bio\"><strong><a href=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/f04_Mackin.png\"><img loading=\"lazy\" decoding=\"async\" class=\"alignleft size-full wp-image-7153\" src=\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2013\/07\/f04_Mackin.png\" alt=\"f04_Mackin\" width=\"100\" height=\"124\" \/><\/a>Andrew Mackin<\/strong>, BVMS, DVSc, Diplomate ACVIM, is currently professor and Ward Chair of Medicine at Mississippi State University College of Veterinary Medicine. His clinical and research interests focus on hematology, hemostasis, immunosuppressive therapy, and transfusion medicine. Dr. Mackin received the 2006 Carl Norden-Pfizer Distinguished Teacher Award. He received his veterinary degree from Murdoch University in Western Australia; then completed an internship and residency in small animal medicine at University of Melbourne as well as an internal medicine residency at Ontario Veterinary College.<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Todd Archer, DVM, Diplomate ACVIM, and Andrew Mackin, BSc, BVMS, Diplomate ACVIM Immune-mediated hemolytic anemia is one of the most common immune-mediated hematologic disorders in dogs and cats.<\/p>\n","protected":false},"author":1,"featured_media":2766,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"iawp_total_views":33237,"footnotes":""},"categories":[373],"tags":[13],"class_list":["post-1287","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-july-august-2013","tag-peer-reviewed","column-features","clinical_topics-hematology"],"acf":{"hide_sidebar":false,"hide_sidebar_ad":false,"hide_all_ads":false},"yoast_head":"<!-- This site is optimized with the Yoast SEO Premium plugin v24.7 (Yoast SEO v27.3) - https:\/\/yoast.com\/product\/yoast-seo-premium-wordpress\/ -->\n<title>Diagnosis of Immune-Mediated Hemolytic Anemia | Today&#039;s Veterinary Practice<\/title>\n<meta name=\"description\" content=\"Immune-mediated hemolytic anemia is one of the most common immune-mediated hematologic disorders in dogs and cats.\" \/>\n<meta name=\"robots\" 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