Hematology Flashcards
Cyclosporine use as immunosuppressive
Primarily IMHA, but also RA, ITP, myositis
Azathioprine MOA?
Purine analog, metabolized to ribonucleotide mono phosphates. Accumulation of mono phosphates leads to negative feedback on enzymes required for purine synthesis
Does aza have a better effect on humoral or cell- mediated immunity?
HUMORAL.
What is major side effect of aza in cats
Myelosuppression
MOA of methotrexate
Inhibits folic acid reductase resulting in decreased purine and pyrimidine synthesis
S phase specific
What cancer is methotrexate used to treat?
Lymphoma, carcinoma, sarcoma
What are the MOAs of steroids?
Stabilize endothelial cell membranes, inhibit production of local chemo tactic factors, decrease infiltration of neutrophils, monocytes, lymphocytes.
Inhibit release of amino acids from membrane phospholipids- no synthesis of membrane prostaglandins, thromboxanes, leukotrienes
Suppress T cell activation and cytotoxicity, suppress cytokines activity and alter macrophage function
MOA of cyclosporine?
Inhibits calcineurin to inhibit calcium dependent signal transduction
Bound in cytosol of lymphocytes by cyclophilins. Cyclosporine- cyclophilins complexes associate with calcium- dependent calcineurin calmodulin complexes to impede calcium dependent signal transduction. Transcription factors that promote cytokines gene activation are indirect or direct substrates of calcineurin. This results in inhibition of early T cell activation (G0 cell cycle) and prevents synthesis of IL-2, resulting in inhibition of T-cell proliferation and decreased T cell cytotoxic activity.
Also stimulates Tgf- B production which is an inhibitor of IL2 stimulated T cell proliferation and generation of antigen- specific cytotoxic lymphocytes
Which suspension is 4% bioavailable in dogs? Sandimmune or neoral
Sandimmune. It is a oil suspension and sucks. Neoral is a micro emulsion and more bioavailable
When to measure cyclosporine blood levels?
12 hour trough level
In humans they do 2 hrs post administration
Side effects of cyclosporine?
Hepatotoxicty- when waaaay high blood levels are present. RARE.
Nephrotoxic- RARE in cats. Super super rare in dogs.
Can promote development of neoplasia especially lymphoma ESP when used w pred
In dogs: severe gingival hyperplasia, fibropapillomas, severe or fatal pyoderma
Side effects of aza?
Bone marrow suppression, pancreatitis, hepatotoxicty
Cyclophosphamide MOA
Alkylating agent- S phase specific
Tacrolimus MOA
This is a calcineurin inhibitor too- lymphocyte specific
Binds in the cytosol to an immunophilin, FK-binding protein
The tacrolimus FKBP complex binds to calcineurin and inhibits its phosphatase activity (cycle does this too but in a diff way). This results in inibition of de novo expression of nuclear regulatory proteins and T cell activation genes. The transcription of cytokines (IL- 2, IL-3, IL-4, IL-5, interferon gamma, tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor) are suppressed, as is suppression of IL-2 and IL-7 receptors.
Tacrolimus is 50-100x potent compared to cyclosporin. IT inhibits B cell proliferation and production of antibody- MOA unknown.
Toxicities of tacrolimus
super toxic! vasculitis leading to myocardial infarction, liver failure, intussusception, anorexia
MOA sirolimus, rapamycin, everolimus
These are macrocyclic antibiotics with a structure similar to tacrolimus that bind in the cell cytosol to FKBP. Sirolumus works by blocking activation of mTOR- a serine/threonine protein kinase involved in regulation of cell proliferation
Prevents cell from progressing from G1 to S phase, and blocks T cell activation by IL-2, IL-4, IL-6 and stimulation of B cell proliferation by lipopolysaccharide. Sirloins also directly inhibits B cell immunoglobulin synthesis caused by interleukins.
These inhibit the proliferation of fibroblasts, endothelial cells, hepatocytes, and smooth muscle cells induced by growth factors such as platelet-derived growth factor and fibroblast growth factors.
Toxicity of sirolimus
When given with cyclosporine, increased risk of nephrotoxicity, hemolytic uremic syndrome, hypertension. Hyperlipidemia, thrombocytopenia, delayed wound healing, delayed graft function, mouth ulcers, pneumonitis, and interstitial lung disease.
Mycophenolate MOA
hydrolyzed in the liver to mycophenolic acid. Cytostatic to lymphocytes due to inhibition of inosine monophosphate dehydrogenase, an enzyme necessary for de novo purine biosynthesis. It’s a relatively selective inhibitor of B and T cell proliferation during S phase of cell cycle.
May also inhibit growth- factor induced smooth muscle and fibroblast proliferation.
Mycophenolate toxicity
GI hemorrhage, anorexia, diarrhea.
Leflunomide
synthetic organic isoxazole that the intestinal mucosa metabolizes to A77-1726.
The active drug works at the S phase of the cell cycle to inhibit de novo pyrimidine biosynthesis via dihydrorotate dehydrogenase
It’s also an inhibitor of tyrosine kinases associated with growth factor receptors
Has effects on B and T lymphocytes, and also has an anti proliferative effect on smooth muscle cells and fibroblasts.
Toxicity of leflunomide?
GI toxicity via actions of trimethylfluoroanaline (metabolite)
One odd use of leflunomide
It may be useful in the treatment of reactivation of latent feline herpesvirus 1 infection that occurs secondary to the stress of injury, illness, surgery, or immunosuppression.
It has cytostatic, antioxidant, and apoptotic effects in humans and may play a role in cancer chemoprevention
What are the major diagnostic criteria for IMHA
spherocytosis, autoagglutination and strongly regenerative anemia
What are other abnormalities in dogs with IMHA
hyperbilirubinemia, leukocytosis, thrombocytopenia, elevated liver enzymes
What is the mechanism of RBC destruction in IMHA
Extravascular hemolysis: destruction by macrophages in the spleen caused by antibodies coating surface of RBC
Intravascular hemolysis: complement-mediated lysis, mediated by IgM antibodies activating complement.
No matter what mechanism of RBC destruction, from the standpoint of therapy, IMHA is primarily a CD4 T cell driven disorder.
Triggers for development of IMHA
few proven- vaccination, infection, tissue injury, drug therapy
may be genetic susceptibility.
spring and early summer more common.
Can you detect circulating anti-erythrocyte antibodies in the serum of affected dogs w IMHA?
NOT usually. But easy to find Ig on surface of RBC with flow cytometry.
Usually antibodies involved are IgG or IgG AND IgM.
IgM alone is really are.
Which antibodies bind surface of RBC in IMHA
IgG or IgG and IgM. IgM alone is super rare
What percent of dogs with IMHA have platelet activation?
75% have activated platelets, as assessed by up-regulation of P-selectin expression
What is one mechanism of development of Evan’s syndrome possibly?
Anti-RBC antibodies are commonly detected in dogs with thrombocytopenia, suggesting that cross-reactive antigens may be present in dogs with immune-mediated platelet destruction.
What is the prevalence of thromboembolic disease with IMHA?
30-50%, but probably higher.
What are some negative prognostic factors for survival with IMHA
hyperbilirubinemia, thrombocytopenia, leukocytosis, esp with increased bands
Other ones identified (but not as commonly) are azotemia, petechiation, hypoalbuminemia
Degree of anemia, magnitude of retic response, and degree of spherocytosis was not associated with outcome.
Which acute phase proteins are high with IMHA?
alpha-1-acid glycoprotein, and C-reactive protein.
Which serum cytokines are high in dogs with IMHA?
IL-15, IL-18, GM-CSF, MCP-1. And MCP-1 found to be increased and associated with higher risk of death in dogs.
What is mechanism of action of unfractionated heparin?
Binds to AT which enhances its activity and leads to inhibition of factors II and Xa. Pharmacokinetics of this drug are super variable.
Monitor response to therapy with PTT measurement- should be 1.5-2.5x baseline.
How does low-molecular-weight heparin work?
Inhibits function of factor Xa but does not block the activity of thrombin. Thus, the likelihood of inducing unintended hemorrhage with LMWH is much lower than with unfractionated heparin.
How does plavix work?
Irreversible inactivation of a subtype of the adenosine diphosphate receptor on the membrane of platelets- the result is decreased platelet aggregation
How does IVIG work?
Unknown. But it has immunosuppressive effects that involve signaling through immunosuppressive receptors on macrophages.
