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Immune Mediated and Hematology > Immunology and Hematology CVT > Flashcards

Immunology and Hematology CVT Flashcards

1
Q

What is the MOA of cyclophosphamide?

A

o Alkylation of DNA during the S phase in cell cycle → Can be lethal to cell or produce miscoding errors (inhibit cell replication or DNA transcription)
§ Produces T- and B-cell lymphopenia
§ Suppresses both T-cell activity and antibody production

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2
Q

What are the indications for cyclophosphamide in dogs and cats?

A

· Indications in Dogs: Corticosteroid-resistant IMHA or IMTP, Rheumatoid arthritis; Polymyositis (in conjunction with corticosteroids)
· Indications in Cats: IMHA; Rheumatoid arthritis

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3
Q

What are the side effects of cyclophosphamide?

A

Myelosuppression; Gastroenteritis; Alopecia; Hemorrhagic cystitis

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4
Q

What is the MOA of azathioprine?

A

o Purine analog that is metabolized to ribonucleotide monophosphates → Poor conversion to diphosphates and triphosphates → ↑intracellular monophosphates → feedback inhibition of the enzymes required for biosynthesis of purine nucleotides
§ Triphosphate analogs formed → incorporated into DNA → ribonucleic acid miscoding and faulty transcription
§ Greater effect on humoral immunity

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5
Q

What are the indications of azathioprine in dogs?

A

Indications in Dogs: IMHA (administered in conjunction with steroids and/or cyclophosphamide); IMTP; Autoimmune skin disease; Chronic Hepatitis; Myasthenia Gravis; IM Glomerulopathy; Chronic Atrophic Gastritis; SLE; Inflammatory Bowel Disease

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6
Q

What are the indications of azathioprine in cats?

A

**VERY Myelotoxic in cats**

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7
Q

What are side effects of azathioprine?

A

Bone Marrow Suppression: Leukopenia, anemia, thrombocytopenia; Acute pancreatitis; Hepatotoxicity

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8
Q

What is the MOA of methotrexate?

A

o Competitively inhibits folic acid reductase (necessary for reduction of dihydrofolate →tetrahydrofolate) → affects production of purines and pyrimidines
§ Manifest during S phase (cell cycle)

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9
Q

What are the indications or methotrexate in dogs and cats?

A

Antineoplastic in lymphoma, carcinomas, sarcomas

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10
Q

What is the major side effect of methotrexate?

A

Gastrointestinal toxicity

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11
Q

How do glucocorticoids work?

A

o Glucocorticoids stabilize cell membrane of endothelial cells
o Inhibits:
§ Production of local chemotactic factors (¯ infiltration neutrophils, monocytes, and lymphocytes)
§ Secretion of destructive proteolytic enzymes (collagenase, elastase, and plasminogen activator; in allogeneic tissue)
§ Release of arachidonic acid from membrane phospholipids → prevents synthesis of prostaglandins, thromboxanes, and leukotrienes (major mediators of inflammation)
o Redistribute monocytes and lymphocytes from peripheral circulation to lymphatics/bone marrow (affects primarily T cells)
o Decrease T-cell activation and cytotoxicity
o Decrease Cytokine activity
o Alter macrophage function

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12
Q

What is the MOA of cyclosporine?

A

· Bound in cytosol (lymphocytes) by cyclophilins (cyclosporine-binding proteins)
o Cyclosporine-cyclophilin complexes → calcium-dependent calcineurin-calmodulin complexes → impede calcium-dependent signal transduction
§ Transcription factors → promote cytokine gene activation are direct or indirect substrates of the serine-threonine phosphatase activity of calcineurin
§ Enzymatic activity ¯ by association of cyclosporine-cyclophilin bimolecular complex with calcineurin
§ Inhibits early T-cell activation (G0 phase of the cell cycle)
§ Prevents synthesis of several cytokines (IL-2)
§ Without IL-2 → further T-cell proliferation is inhibited (T-cell cytotoxic activity ¯)
§ Stimulates cells to secrete transforming growth factor–β (TGF-β) protein → potent inhibitor of IL-2–stimulated T-cell proliferation and generation of antigen-specific cytotoxic lymphocyte
o NOT cytotoxic or myelotoxic

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13
Q

Which immunosupressant is specific for lymphocytes?

A

Cyclopsorine (specificity spares other rapidly dividing cells; allows nonspecific host defense to continue to function)

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14
Q

What is a potential reverse effect of cyclosporine in cats?

A

Can be nephrotoxic

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15
Q

What is the MOA of tacrolimus?

A

Binds in cytosol (lymphocytes) with an immunophilin, FK-binding protein (FKBP) → tacrolimus-FKBP complex binds to calcineurin and inhibits its phosphatase activity→ directly and indirectly inhibits de novo expression of nuclear regulatory proteins and T-cell activation genes o Transcription of cytokines (IL-2, IL-3, IL-4, IL-5, interferon-γ, TNF-α, and granulocyte-macrophage colony-stimulating factor) responsible for lymphocyte activation is suppressed
o ¯ IL-2 and IL-7 receptors
o Inhibits B-cell proliferation/production of antibody (unknown mechanism)

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16
Q

What are the indications of tacrolimus in vet med?

A

o Topically: 0.1% solution, controlled discoid lupus erythematosus and pemphigus foliaceus in dogs (Rosenkrantz et al., 2004)
o Topical 0.02% aqueous suspension for the effective treatment of dogs with KCS (Berdoulay, English, and Nadelstein, 2005)

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17
Q

What is the MOA of sirolimus?

A

· Macrocyclic antibiotic with a structure similar to tacrolimus → binds in cell cytosol to FKBP
o Affect different and distinct sites in the signal transduction pathway
o Immunosuppressive → sirolimus-FKBP complex blocking activation of target of rapamycin, (mTOR)
§ mTOR is serine/threonine protein kinase →regulation of cell proliferation through the initiation of gene translation in response to AA, growth factors, cytokines, and mitogens
§ Kinase activity of cyclin-dependent kinase-2 and cyclin-dependent kinase-4 (cell cycle regulators) also inhibited
§ Blocks IL-2 and other growth factor–mediated signal transduction (signal 3 of the allograft rejection response) and the calcium-independent CD28/B7 (CD80/CD86) costimulatory pathway
□ Cyclosporine and tacrolimus block T-cell cell cycle progression at the GO to G1 stage
□ Sirolimus prevents cells from progressing from G1 to the S phase
® Blocks T-cell activation by IL-2, IL-4, and IL-6 and stimulation of B-cell proliferation by lipopolysaccharide
® Directly inhibits B-cell immunoglobulin synthesis caused by interleukins

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18
Q

What are potential side effects of sirolimus?

A

hyperlipidemia, thrombocytopenia, delayed wound healing, delayed graft function, mouth ulcers, pneumonitis, and interstitial lung disease

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19
Q

What is the MOA of mycophenolate?

A

o Prodrug hydrolyzed by liver esterases → mycophenolic acid
o MOA:
§ Cytostatic for lymphocytes → inhibition of inosine monophosphate dehydrogenase → enzyme necessary for de novo purine biosynthesis
o Relatively selective inhibitor of T- and B-cell proliferation during the S phase of the cell cycle via its ability to prevent guanosine and deoxyguanosine biosynthesis

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20
Q

What is the MOA of leflunomide?

A

· Synthetic organic isoxazole → intestinal mucosa metabolizes to active form = A77 1726
· Part of its antiproliferative activity during the S phase (cell cycle) → inhibiting de novo pathway of pyrimidine biosynthesis
o Target: enzyme dihydroorotate dehydrogenase

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21
Q

What is a potential side effect of leflunomide in dogs?

A

o GI toxicity (dogs) → accumulation of metabolite trimethylfluoroanaline (TMFA)
§ Cats: TMFA does not present the toxicity problem encountered

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22
Q

What is FTY 720?

A 
from myriocin (fungus-derived sphingosine analog)  o After phosphorylation, FTY 720 engages lymphocyte sphingosine-1-phosphate receptors and profoundly alters lymphocyte trafficking → acting as a functional sphingosine-1-phosphate antagonist
  o Sequesters naïve and activated CD4+ and CD8+ T and B cells from the blood into lymph nodes and Peyer's patches (without affecting function)
  o Does not impair cellular or humoral immunity to systemic viral infection nor does it affect T-cell activation, expansion/proliferation, or immunologic memory
  o Synergizes effectively with inhibitors of T-cell activation and proliferation to prevent allograft rejection
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23
Q

Is there alloantibody production in dogs?

A

NO! · No clinically important alloantibodies (isoantibodies) present before sensitization with a transfusion
· Pregnancy does not cause sensitization because of a complete placenta in dogs → NO alloantibody production

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24
Q

What is the most antigenic blood type in dogs?

A

DEA 1.1

Anti-DEA 1.1 antibodies will develop after 4 days

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25
What is the universal blood donor in dogs?
DEA 1.1 Negative
26
Does pregnancy sensitize dogs to develop alloantibodies?
No!!
27
What is the most common DEA in dogs?
DEA 4 - Positive in >98% of dogs
28
What is the universal blood donor in cats?
There is NO universal blood donor in cats
29
What are the 3 major blood types of cats?
o Type A (a/a or a/b) o Type B (b/b) § 40% British shorthaired, Devon rex (A-B incompatibility → heterozygous kittens) § None in Siamese o Type AB (rare): 3rd allele (AB), recessive to “a” and codominant to “b” – both expressed § Purebred and DSH known to have type B blood (DNA tests available) → < 1%
30
Do cats have alloantibodes to blood types?
Yes! o Cats lacking certain antigen in RBC may have naturally occurring/induced alloantibodies (isoantibodies) against the missing type → acute hemolytic transfusion rxn and anti-A mediated hemolysis of newborn (neonatal isoerythrolysis)
31
What is another RBC antigen in cats?
o Mik antigen: Most but not all DSH o Mik-positive blood to cats lacking Mik antigen → acute hemolytic transfusion reactions o Naturally occurring anti-Mik alloantibodies documented in several Mik-negative cats
32
When blood typing a cat that is severely anemia, but there is no agglutination on the card what could be happening?
Severely anemic cats may not agglutinate → excess antibody present compared to the number of red cells → prozone effect
33
What is the big difference between dogs and cats in blood typing?
Cats possess naturally occurring alloantibodies against the blood type antigen they lack o All type B cats: strong anti-A antibodies with high hemolysin and agglutinin titers (>1:32) after a few weeks of age o Type A cats: weak anti-B alloantibodies with low anti-B titers of 1:2
34
Which species can have neonatal isoerythrolysis?
Cats! o Kittens (Type A, AB) receiving anti-A alloantibodies through colostrum from type B queens (including primiparous queens), during the first 16 hours of life → neonatal isoerythrolysis § Dark pigmenturia, anemia, icterus, anorexia, and sudden death (first week of life) § Survivors may develop tail tip necrosis
35
Why is crossmatching important?
§ Reveal blood group antigens on RBC surface → serologic compatibility/incompatibility btwn donor and recipient o Check for presence/absence of naturally occurring/induced alloantibodies in serum (or plasma) o Abs may be hemolysins and/or hemagglutins (directed against known blood groups or other RBC surface antigens)
36
Describe a major crossmatch.
Alloantibodies in recipient's plasma against donor RBCs o Incompatibility→ greatest importance: predicts that transfused donor cells will be attacked by antibodies in patient's plasma → acute hemolytic transfusion rxn (can be life threatening, with as little as 1 ml)
37
Describe a minor crossmatch.
Alloantibodies in donor's plasma against the recipient's RBCs o Incompatibility → lesser concern: donor's plasma volume is small (esp pRBCs) and plasma markedly diluted in the patient
38
What can be added to a crossmatch to enhance the reaction?
Coomb's reagent (anti-IgG, anti-IgM, anti-C3)
39
What can occur in a dog that is receiving its first transfusion?
should be compatible (No clinically important naturally occurring alloantibodies) → May omit a crossmatch if 1st transfusion (as long as the donor has also not be transfused)
40
What should occur in a dog that has received a previous blood transfusion?
§ Compatible crossmatch does NOT prevent sensitization of patient against donor cells (in 1-2 wks) □ Thus previously transfused dogs should ALWAYS be crossmatched (even if receiving blood from same donor) ® This transfused dog should NEVER be used as a donor
41
What is the time span from initial transfusion to incompatibility?
4 days (risk may last for years due to alloantibodies)
42
What should occur in a cat that is receiving its first transfusion?
§ First crossmatch may be incompatible (naturally occurring alloantibodies) → Due to anti-A alloantibodies, anti-B alloantibodies, Mik alloantibodies, or rxn to other RBC antigens = Needs crossmatch
43
What should be considering when thinking about giving a plasma transfusion in a cat?
§ Naturally occurring alloantibodies → impacts plasma transfusions, thus only AB plasma can be safely transfused in cats □ Additional naturally occurring alloantibodies may exist in plasma unit → consider crossmatching plasma
44
What precluded blood-typing, crossmatching, and Coomb's testing?
o True (persistent) autoagglutination precludes blood-typing, crossmatching, and Coombs’ testing
45
What are the top breeds of cats that are Type B?
Devon Rex and exotics
46
What type of hypersensitvity reaction occurs with IMHA?
RBCs destroyed (type II hypersensitivity rxn) → extravascular or intravascular hemolysis
47
How does extravascular hemolysis occur in IMHA?
o Extravascular hemolysis: Ig or complement-coated RBCs removed by phagocytic cells (reticouloendothelial system/mononuclear phagocyte system)
48
How does intravascular hemolysis occur in IMHA?
RBCs coated with enough IgG or IgM to fix complement (10-20% of dogs)
49
What is the difference between primary and secondary IMHA, what is most common?
§ Primary IMHA: True autoimmune rxn against RBCs → 60% to 75% dogs (since no underlying etiology identified) § Secondary IMHA: RBCs destroyed as “innocent bystanders” of immune rxn against some foreign protein that may be adherent to RBC surface (most common form in cats) o Trigger protein: Viral or bacterial infection, drug administration, or neoplastic processes
50
Name 4 causes of inherited causes of hemolytic anemia.
1. Pyruvate kinase deficiency 2. Phosphofructokinase deficiency 3. Chrondrodysplasia/anemia 4. Nonspeherocytic hemolytic anemia
51
Name 4 causes of IM (primary) hemolytic anemia.
1. Primary (idiopathic) IMHA 2. IMHA assoicated with SLE 3. Neonatal isoerythrolysis 4. Incompatible transfusion
52
Name 1 metabolic cause of hmeolytic anemia.
Hypophosphatemia
53
What 2 cancers are the most likely to result in hemolytic anemia?
Microangiopathic anemia associated with hemangiosarcoma and lymphoma
54
Name 8 causes of infectious hemolytic anemia?
1. Babesia (canis and gibsoni) 2. Mycoplasma (haemominutum, haemofelis, haemocanis) 3. Dirofilaria immitis 4. Bacterial endocarditis 5. FeLV 6. Leptospirosis 7. Cytauxzoon felis 8. Ehrlichia canis
55
Name 9 toxin or drug related causes of hemolytic anemias.
1. Onion toxicity 2. Zine toxicity 3. Methylene Blue 4. Copper toxicity 5. Propylthiouracil 6. Methimazole 7. Sulfa drugs 8. Penicillins and cephalosporins 9. Quinidine
56
What is the signalment of IMHA in dogs?
``` Middle age (median 6-7 yrs) Females Any breed (overrepresented breeds: cocker spaniels, English springer spaniels, collies, poodles, Old English sheepdogs, and Irish setters) ```
57
Which breeds are over-represented in IMHA in dogs?
Overrepresented breeds: cocker spaniels, English springer spaniels, collies, poodles, Old English sheepdogs, and Irish setters
58
What is leukocytosis in dogs with IMHA correlated with?
Correlation btwn leukocytosis in dogs with IMHA and tissue necrosis, specifically centrilobular hepatic necrosis, presumably secondary to hypoxemia (McManus and Craig, 2001)
59
What is the sensitivity and specificity for Coomb's test for IMHA? What percentage of IMHA dogs are +?
Detects antibodies and/or complement on RBC surface (Positive: 35% to 60% of IMHA dogs) o Sensitivity: 53%; Specificity: 100%
60
What does a direct Coomb's test detect?
§ Detects antibodies and/or complement on RBC surface (Positive: 35% to 60% of IMHA dogs)
61
What is a more sensitive test than Coomb's test for antibodies/complement on RBCs surface?
Flow cytometry of RBCs: More sensitive 92%; Specificity: 100%
62
What can cause false + Coomb's test in dogs?
False-positive: Concurrent disease (neoplasia, mycoplasmosis, babesiosis, bacterial infections, administration of certain drugs, previous transfusion, improper antisera preparation, and nonspecific adsorption of serum proteins on damaged RBCs)
63
What is thought to be the major therapeutic effect of glucocorticoids for IMHA?
· Major therapeutic effect: ¯ Fc receptor-mediated RBC destruction within mononuclear/phagocyte system Inhibit complement activation and ↓ circulating levels of cytokines → ↓ amplification of immune response
64
What is thought to be the major therapeutic effect of mycophenolate for IMHA?
Converted to mycophenolic acid → inhibits purine synthesis primarily in B and T lymphocytes→ decrease autoantibody production
65
What is thought to be the major therapeutic effect of IV Ig for IMHA?
MOA: Blockade of macrophage Fc receptors and possibly antiidiotypic down-regulation of autoantibody production → Suppresses immune destruction of RBCs
66
What is thought to be the major therapeutic effect of liposome encapsulated clodronate for IMHA?
· Deplete splenic macrophages and block clearance of Ig-coated RBCs · Used in IMHA in dogs: Well tolerated, prelim evidence suggests its ability to rapidly block clearance of opsonized RBCs in normal dogs and dogs with IMHA → resulting in improved survival (Mathes, Jordan, and Dow, 2006)
67
What are potential complications in IMHA patients?
``` Refractory anemia Hemorrhage (GI) Bacteria and fungal infections (immunosuppression) Acute Renal Failure PTE (32% of dogs that died from IMHA) ```
68
Name 4 risk factors of PTE in dogs with IMHA.
o Risk factors for PTE: Hyperbilirubinemia, hypoalbuminemia, intravenous catheter placement, and severe thrombocytopenia (<50,000/μl) (Klein et al., 1989; Carr, Panciera, and Kidd, 2002)
69
Which prophylactic therapy to prevent thrombosis is recommeneded in IMHA?
Heparin - Failed to show a benefit on survival (Fryer, McMichael, and Slater, 2005; Breuhl, Scott-Moncrieff, and Brooks, 2005) Aspirin - significantly improved survival rate in dogs receiving azathioprine and aspirin in conjunction with glucocorticoids compared to those receiving azathioprine and glucocorticoids or azathioprine, heparin, and glucocorticoids (Weinkle et al., 2005)
70
What disease should be tested for that can result in secondary suppression of erythropoiesis?
1. Infectious/inflammatory diseases 2. Neoplasia 3. Chronic renal disease 4. Chronic liver disease 5. Hypothyroidism 6. Hypoadrenocorticism
71
What infectious diseases can result in nonregenerative anemias/multiple cytopenias?
1. Ehrlichia 2. Anaplasma pagocytophilum 3. Parvovirus 4. FeLV 5. FIV
72
Name 5 drugs that result in hematologic dyscrasias.
``` o Chemotherapeutic agents o Estrogenic compounds (dogs) o Phenylbutazone o Acetaminophen o Aspirin o Trimethoprim/sulfadiazine o Phenobarbital (dogs) o Propylthiouracil (cats) o Methimazole (cats) o Griseofulvin o Others: cephalosporins, carprofen, meclofenamic acid, chloramphenicol, primidone, phenytoin, metronidazole, levamisole, albendazole, fenbendazole, thiacetarsemide, amiodarone, captopril, quinidine, colchicine, and mitotane ```
73
What are the hallmarks of microangiopathic hemolytic anemia?
Schistocytes and keratocytes
74
What is a common finding with FeLV anemia?
MACROCYTIC - But non-regenerative
75
What is pure red cell aplasia?
Severe nonregenerative, normocytic, normochromic anemia and marked erythroid hypoplasia in bone marrow
76
What should you think if you see pyogranulmatous inflammation in the BM?
dog/cat → disseminated histoplasmosis
77
What should you think if you see granulmatous inflammation in the BM?
dog → systemic fungal infections
78
Define hemophagocytic syndrome?
· Benign proliferative disorder of macrophages o Must be differentiated from malignant proliferation of histiocytes (malignant histiocytosis) o Criteria for diagnosis: bicytopenia or pancytopenia in blood and < 2% hemophagocytic macrophages BM § If concurrent myelonecrosis, myelofibrosis, or marrow inflammation → excluded because hemophagocytic macrophages likely a result of these conditions and not primary o Dogs: IMHA, SLE, sepsis, E. canis infection, blastomycosis, lymphoma, and myelodysplastic syndromes Idiopathic (20% of cases)
79
What are myelodysplastic syndromes?
· Acquired clonal proliferative disorders due to genetic mutation in hematopoietic stem cells o Differentiating an MDS from acute leukemia based on % myeloblasts in bone marrow § Leukemias: > 30% myeloblasts § MDS: < 30% myeloblasts (more recent: 20%) o 2 Major categories: Differentiated based on % myeloblasts in bone marrow
80
What are the 2 major categories of myelodysplastic syndromes?
Differentiated based on % myeloblasts in bone marrow 1. MDS with refractory cytopenias (MDS-RC) → < 6% myeloblasts · Less ill, better response to tx, longer survival · Responsive to EPO therapy (50-2000 U/kg SQ 3 times/week) · Dogs: moderate-severe normocytic, normochromic, nonregenerative anemia; dysplastic features in BM limited to erythroid line · Cats: macrocytic normochromic anemia, and many pancytopenic o metarubricytosis and autoagglutination (could confused with IMHA) o Dysplasia is seen frequently in all cells lines in bone marrow (unlike dogs) 2. MDS with excess myeloblasts (MDS-EB) → 6-30% myeloblasts · Survival short · Tx: EPO and other hematopoietic growth factors, chemo (hydroxyurea, low-dose cytosine arabinoside, and low-dose aclarubicin = limited success) · Dogs/Cats: Bicytopenia or pancytopenia · BM: dysplastic features in all cell lines
81
What is the most frequently diagnosed neoplastic condition in BM of dogs?
Lymphoma Need to differentiate disseminated lymphoma (lymphoblasts in other locations, LNs/organs) from acute lymphoblastic leukemia
82
What is the second most frequently diagnosed neoplasia in BM?
Multiple myeloma
83
Name 5 things that suggest multiple myeloma.
Large # atypical plasma cells in BM with or without presence of hypercalcemia, osteolytic lesions, monoclonal gammopathy, or light-chain proteinuria
84
Name 3 things that can result in reactive plasma cell hyperplasia in the BM?
Infectious disease, Ehrlichosis, FIP
85
How do you differentiate hemophagotic syndrome from maligant histiocytosis?
Malignant Histiocytosis · Differentiating it from hemophagocytic syndrome → > 30% histiocytic cells in BM, high nuclear-to-cytoplasmic ratio, and multinuclearity, and rarely confined to BM
86
What is the most common inherited bleeding disorder in dogs?
von Willebrand's disease = Due to lack of von Willebrand's factor (vWF)
87
What is von Willebrand's factor?
Adhesive glycoprotein produced by endothelial cells and megakaryocytes 95% constituitively secreted and 5% stored in Weibel-Palade bodies
88
What is the function of von Willebrand's factor?
Promote adhesion of platelets to exposed subendothelium (esp areas of high shear stress, ex arteries) o Via binding to the glycoprotein (GP)Ib α-receptor on platelets o Role in platelet-to-platelet aggregation in conjunction with GPIIb/IIIa complex (integrin αIIbβ3) and fibrinogen Form a tightly bound complex with factor VIII (prolong T1/2 of factor VIII; less important in dogs)
89
What receptor on platelets does von Willebrane interact with?
glycoprotein (GP)Ib α-receptor on platelets
90
How many types of von Willebrand's disease are there and describe each type?
o Type I vWD: All multimers present but ¯ quantity (most common) § Heterogeneous group of dzs with marked breed variation § > 50 breeds (with hemorrhagic tendency): Doberman pinscher, standard poodle, Shetland sheepdog, and German shepherd · Bleeding (variable) → ↑ bleeding associated with surgical procedures or after trauma, spontaneous bleeding seen occasionally (epistaxis, urogenital), or stressors to hemostasis (ie transient thrombocytopenia dt vaccination or NSAID inhibiting platelet activity); spontaneous hemorrhage (can be seen) § Some dogs ¯ vWF, but bleeding tendency does not seem to exist o Type II vWD: Larger, more effective multimers are absent, and bleeding can be severe § German shorthaired and German wirehaired pointers o Type III vWD: All multimers are absent, most severe form → life-threatening hemorrhagic episodes § Scottish terriers, Chesapeake Bay retrievers, Dutch kooikers, and Shetland sheepdogs
91
What is the most common form of vWD?
Type I = All multimers present but decreased quantity
92
Name 3 breeds that commonly have Type 1 vWD?
Type I = All multimers present but decreased quantity | Doberman pinscher, standard poodle, Shetland sheepdog, and German shepherd
93
In which type of vWD is bleeding severe and why?
Type III vWD: All mutimers are absent = MOST SEVERE FORM = Life-threatening hemorrhagic episodes
94
What 2 breeds get Type II vWD?
German shorthaired and German wirehaired pointers
95
What breeds get Type III vWD?
Type III vWD: All mutimers are absent = MOST SEVERE FORM = Life-threatening hemorrhagic episodes § Scottish terriers, Chesapeake Bay retrievers, Dutch kooikers, and Shetland sheepdogs
96
How do you diagnosis vWD?
Determination of vWF levels | ELISA: Concentration expressed as vWF:antigen (Ag), do not determine biologic activity or multimeric distribution
97
What are the cut-off established by Cornell for vWD?
Normal: 70% to 180% vWF: Ag → Free from vWD, unlikely to transmit the dz Borderline: 50% to 69% vWF: Ag Abnormal: 0% to 49% vWF: Ag → Carriers of vWD, can transmit to offspring
98
Why may multiple measurements of vWF:antigen may be needed?
Daily variation in vWF: Ag concentration can be high
99
How can you determine the multimeric distribution in a vWD dog?
Perform electrophoresis
100
What is the global test for primary hemostasis and what components does it test for?
BMBT = vWD, thrombocytopenia, platelet function defects, vasculitis = Prolonged BMBT
101
What is normal for BMBT?
Less than 4 mins
102
Is there an association between hypoT4 and vWD in dogs?
No! Thyroid supplementation to euthyroid Dobermans with vWD does not increase vWF concentration or activity (Heseltine, Panciera, and Troy, 2005)
103
Name products that can be used for vWD and their benefit?
1. Fresh Plasma: vWF level ↑ but NO improvement in BMBT 2. Fresh Frozen Plasma 3. Cryoprecipitate: Increased vWf within 30 mins and BMBT rapidly improved 4. Human Recombinant vWF: Minimal effect in dogs 5. Desmopressin acetate: Effects to promote hemostasis: Release of stored vWF from endothelial cells
104
What can be administered to blood donor dogs prior to donation to increased vWF levels and how does it work?
Desmopressin acetate → Release of stored vWF from endothelial cells
105
What is hemophilia A?
§ Factor VIII deficiency (most common inherited coagulation factor deficiency in dogs, X-linked recessive disease) o Female is carrier, only males express CS of dz (but carrier female + affected male = affected females)
106
What is the most common inherited coagulation factor deficiency in dogs?
Factor VIII deficiency = Hemophilia A
107
What breed has a high prevalence of hemophilia A?
Hemophilia A = Factor VIII def | GSD
108
What portion of the coagulation pathway is affected when factor VIII is deficient?
Factor VIII → intrinsic coagulation pathway → activated clotting time (ACT) and activated partial thromboplastin time (APTT) prolonged
109
What is Hemophilia B?
Factor IX deficiency (Christmas disease): X–linked recessive mode
110
What portion of the coagulation pathway is affected when factor VIX is deficient?
Factor IX → intrinsic coagulation pathway → ACT and APTT are prolonged in dogs
111
Which hereditary coagulopathy is most common in Saint Bernard dogs?
Hypofibrinogenemia (factor I deficiency) → Saint Bernard dogs o Prolonged one-step prothrombin time (OSPT; extrinsic pathway of coagulation)
112
Which hereditary coagulopathy is most common in Boxer?
§ Factor II (prothrombin) deficiency o Autosomal-recessive, family of boxers o Prolonged OSPT
113
Which hereditary coagulopathy is most common in Beagle?
§ Factor VII deficiency o Beagles: Autosomal-dominant disease o Bleeding rare, but prolonged OSPT
114
Which hereditary coagulopathy is most common in Cocker Spaniel?
§ Factor X deficiency o Cocker Spaniels: Autosomal-dominant variable expression of bleeding (severely affected do not survive) § Both APTT and OSPT prolonged
115
Which hereditary coagulopathy is most common in Kerry blue terriers, Great Pyrenees, and English springer spaniels?
§ Factor XI deficiency o Kerry blue terriers, Great Pyrenees, and English springer spaniels: autosomal-recessive trait o Prolonged APTT and variable bleeding tendency
116
Which hereditary coagulopathy is most common in cats?
§ Factor XII (Hageman factor) deficiency o Miniature poodles but more commonly in cats o Prolonged APTT, but it is not associated with a bleeding tendency"
117
When blood is stored which factors become inactive?
Factor VIII, vWF, and factor V
118
When blood is stored which factors retain activity?
Vitamin K–dependent factors (factor II, VII, IX, and X)
119
What is fresh plasma and what factors does it contain?
Plasma harvested from whole blood within 6 hr of collection → fresh plasma All vital coagulation protein activity is retained) o Also contains albumin, complement proteins, antithrombin III, and immunoglobulins
120
What is fresh-frozen plasma and what factors does it contain?
§ Rapid separation from whole blood preserves the activity of factors V and VIII and vWF § Plasma frozen within 6 hrs of collection → fresh-frozen plasma o Stored frozen (−70° C) and retain its coagulation activity for 1 year
121
What is stored or frozen plasma and what factors does it contain?
§ Plasma is separated from RBCs more than 6 hrs after collection § Deficient in factors V and VIII and vWF activity § Other coagulation factors present (including factor IX) § Not used to treat coagulopathies
122
What is cryoprecipiate?
§ Fresh-frozen plasma is slowly thawed (at 4 °C), a precipitate is formed → CP § Factor VIII, fibrinogen, and vWF in the plasma is contained in the CP (most of it) § 1/10 the volume of the original plasma, remainder of plasma → cryo-free plasma or cryosupernatant (contains most of other active coagulation factors and plasma proteins) o CP: vWF about 4-20X that in original plasma (Stokol and Parry, 1995; Ching et al., 1994) § CP and cryosupernatant can be frozen again, stored for 1 year
123
What are the most common platelet disorders in dogs?
5% primary IM, 13% neoplasia, 23% infectious/inflammatory dz, and 59% other or multifactoral causes (Grindem et al., 1991)
124
What are the most common platelet disorders in cats?
2% primary IM, 20% neoplasia, 29% infectious diseases, 7% cardiac diseases, 22% multiple etiologies, and 20% unknown causes (Jordan, Grindem, and Breitschwerdt, 1993)
125
Name two breeds that have a pseudothrombocytopenia.
Cavalier King Charles Spaniels | Greyhounds (other sighthounds)
126
What are the 4 mechansims of thrombocytopenia and Ddx for each?
1. ↓ production a. Suppression/destruction of megakaryocytes due to IM dz, drugs, infectious agents, whole body irradiation, and myelophthisic disorders 2. ↑ consumption/destruction a. Primary or secondary IM dz, drugs, DIC (vascular damage, septicemia, endotoxemia, massive tissue necrosis/damage, or release of procoagulant substances), disseminated neoplasia, and infectious diseases 3. Sequestration (marked thrombocytopenia not typical, often transient) a. Splenic congestion/splenomegaly, hepatomegaly, neoplasia, severe hypothermia (dogs), and experimentally induced endotoxemia 4. Excessive loss a. Massive blood loss (hemorrhage due to rodenticide toxicity, but often platelets N to ↑)
127
What 2 infectious disease are the most common to result in secondary IMTP?
Ehrlichia canis and RMSF
128
What drug is known to form a hapten that results in immune mediated targeting of platelets?
TMS (dogs)
129
What is the prevalence of E. canis infections in thrombocytopenic dogs in an endemic region?
63.1% of dogs with a platelet count < 100,000/μl but only 21% of dogs with platelet 100,000-200,000/μl; nonthrombocytopenic dogs had an infection rate of 1.4% (Bulla et al., 2004)
130
What is the classic signalment for primary IMTP in dogs?
middle-aged female dogs o Breeds: Cocker spaniels, German shepherds, poodles, and Old English sheepdogs o Risk of bleeding ↑ platelet counts ¯ below 20,000/μl (spontaneous bleeding atypical)
131
How can you estimate a platelet count?
platelet count estimated (plt/mL): Mean platelet count in ten 100× fields (in monolayer) X 15,000
132
Name 3 organisms that can result in thrombocytopenia and hemolytic disease.
Babesia Cytauxzoon, and Mycoplasma (may be seen in RBCs)
133
What organism is likely if you see morulae in neutrophils?
Acute canine granulocytotropic ehrlichiosis and anaplasmosis
134
What organism is likely if you see morulae in monocytes?
Monocytotrophic ehrlichiosis
135
What organism is likely if you see morulae in platelets?
Anaplasma platys
136
What would be suggestive of hemorrhage from rodeniticide toxicity?
Markedly prolonged PT and APTT with normal FDPs or D-dimer levels § Proteins inhibited by vitamin K antagonism or absence (PIVKA) test to confirm rodenticide
137
Discuss the use of platelet transfusions for thrombocytopenia?
Platelet transfusions: limited use, since hard to get large enough # platelets to exert a clinical benefit + short circulating T1/2 of transfused platelets (platelet concentrates, platelet-rich plasma, or whole blood) o Provide transient improvement in hemostasis
138
What has been associated with shorter hospitalization times in dogs with IMPT?
``` o Vincristine (0.02 mg/kg intravenously once) § Associated with shorter hospitalization times (Rosanski EA et al., 2002) ```
139
Is the severity of the thrombocytopenia a significant prognostic indicator for IMPT?
NO!
140
What is the mortality rate of IMPT dogs?
Mortality rates: 25%-30% (most severe cases)
141
What hypersenstivity reactions occur in SLE?
Type III = Immune complex formation induce tissue damage Type II = Direct antibody-mediated cytotoxicity Type IV = Cell-mediated autoimmunity
142
What are the most common syndromes recognized in dogs with SLE?
IMPA, IM skin dz, glomerulonephritis, IMHA, IMTP
143
What is a LE cell?
A specific test for SLE Neutrophil that has phagocytized nuclear material (found in mashed clotted blood or other body fluids) - Lacks sensitivity

Immune Mediated and Hematology (4 decks)

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