Volume 10, Issue 1
April 2006
GAG Mimetics
Amyloid deposits are complex structures
where the amyloid fibrils are
intertwined with other amyloid proteins
called proteoglycans that are
always present in the deposits regardless
of the type of amyloid fibril
present. Proteoglycans, especially
the sulfated glycosaminoglycan
(PSGAG) molecule portion of specific
proteoglycans, have been shown
to interact with the amyloidogenic
amyloid proteins. These GAGs promote
fibril formation. Glycosaminoglycans
may affect precursor processing,
folding of the amyloidogenic
proteins to form a beta-pleated sheet
conformation or polymerization
and deposition of amyloid fibrils.
An increase in the rate of synthesis
of glycosaminoglycans in tissues in
which amyloidosis developed would
argue for a local response and
against nonspecific binding of
GAGs.
Small, organic molecules known as
GAG mimetics have a similar structure
to the sulfated GAG molecules
but inhibit the fibrillogenesis process.
These GAG mimetics compete
with the natural GAGs for the same
binding sites on the amyloid proteins
preventing the association of the
natural GAGs with the protein. By
preventing the natural GAGs from
binding to the amyloid proteins, the
GAG mimetics can prevent fibril formation.
The first GAG mimetic tobe commercially available for the treatment of amyloidosis is a
drug called Fibrillex™. Unfortunately these drugs are very expensive
and not readily available so I don’t foresee their wide application
in the very near future.
Thromboemboliism and Splenic Infarction
Thromboembolism is the process of blood clots forming in the cardiovascular
system. These can remain stationary or can break loose and travel
throughout the blood vessels eventually lodging in smaller capillary beds
located in the lungs, liver, spleen, and kidneys. Worse case scenarios involve
clots ending up in the brain and heart which can rapidly lead to life
threatening consequences. I have seen a syndrome of thromboembolism
in Chinese Shar-Pei especially leading to splenic infarction or thromboembolism.
In fact, the only breed I’ve seen this in during the last 26 years
have been in Shar-Pei and only those suffering with Familial Shar-Pei Fever.
Predisposing factors for splenic infarction can be categorized:
- Coagulopathies
- Splenic enlargement
- Cardiac disease
- Liver disease
- Renal disease
- Neoplasia
- Hyperadrenocorticism (Cushing’s disease)
- Sepsis
- Splenic hematoma
- Vasculitis
I believe there are several reasons that splenic infarction is often associated
with Familial Shar-Pei Fever. It is well known that protein-losing kidney
disease often accompanies FSF. Renal amyloidosis can result in protein-
losing kidney disease as well as immune-mediated glomerulonephritis.
This results in urinary loss of antithrombin III and other coagulation
proteins leading to a hypercoagulable state which can result in thromboembolism.
It is also known that FSF results in vasculitis or inflammation
of blood vessels. This leads to damage of the lining of the blood vessels
and potential activation of the coagulation cascade as well as platelet
activation. FSF also causes release of acute phase proteins from the
liver such as tumor necrosis factor, C-reactive protein, cytokines and
other products which can activate the platelets and the coagulation
system. Systemic Inflammatory Response Syndrome (SIRS) leading to disseminated
intravascular coagulation (DIC) often leads to thromboembolism.
Hepatic amyloidosis involving the liver can result in deficiencies of
coagulation factors as well. Clinical signs include acute collapse, anorexia,
lethargy, vomiting, polyuria/polydipsia, pale mucous membranes, abdominal
pain and sometimes a palpable abdominal mass. I would include
this syndrome in my “ain’t doing right” (ADR) dog category. Laboratory findings
may include anemia, higher white cell count, increased platelet
counts, increased liver and kidney enzymes, low serum albumin levels and
abnormal coagulation tests. Radiology may reveal a lack of definition in
the anterior abdomen where the spleen is usually seen in the lateral view
as a distinct triangular shadow. Ultrasound is a very useful diagnostic tool
as well. Treatment involves exploratory surgery and removal of the spleen.
Mortality is high due to the underlying causes, coagulation problems such
as DIC and other organ involvement.
What is the spleen and what does it do?
The spleen is important in the primary immune response – probably as important as the lymph
nodes in that regard. It has several functions including acting as a blood filter removing old red
blood cells and filtering out antigenic particles (such as bacteria, viruses, protozoa, rickettsial
organisms, etc.), acting as a storage organ for red blood cells and platelets and serving as a primary
organ participating in immune responses.
Histologically the spleen consists of two components: the red pulp and the white pulp. The red
pulp functions in red blood cell storage and antigen trapping due to its large population of
macrophages or antigen presenting cells. The white pulp contains lymphocytes and here is
where the immune response occurs. Antigens trapped in the spleen are taken up by macrophages
in the white pulp which eventually results in a proliferation of antibody-producing cells
known as B-lymphocytes. The antigens processed in the spleen also result in “lymphocyte trapping”
phenomena which causes the lymphocytes to stay in the spleen increasing the efficacy of
the immune response.
(1/31/06)
Hardie EM, Vaden SL, Spaulding K, Malarkey DE. Splenic Infarction in 16 Dogs: A Retrospective
Study. J Vet Intern Med 1995; 9: 141-148
Homemade Kidney Diets
- Restricted Protein/Phosphorus Diet for Dogs
1/4 lb. ground beef (regular) – not lean ground beef or chuck. Braise the
meat, retaining fat.
1 large egg, hard-cooked
2 cups cooked white rice without salt
3 slices white bread, crumbled
1 tsp. calcium carbonate
Combine all ingredients and mix well. This mixture is somewhat dry and the palatability can be
improved by adding some water (not milk). Yield: 1 1/4 lb.
Analysis:
Moisture % .........................................65.5
Protein % .............................................6.9
Fat % ....................................................5.5
Carbohydrate .......................................21.0
Ash % ....................................................1.0
Phosphorus %.........................................0.1
Sodium %...............................................0.1
ME (kcal) ............................................750/lb
This diet supplies 17% protein calories, 30% fat calories and 53% carbohydrate calories.
- Restricted Protein/Phosphorus Ultra Low Protein Diet for Dogs
2 1/2 cups cooked rice
1 oz. (2 T.) vegetable oil
1 large hard-cooked egg
1/4 tsp. calcium carbonate
1/4 tsp. salt
Cook rice as per package instructions except use only 1/4 tsp. salt. Add other ingredients and mix
well. Refrigerate between feedings. Yield: 1.1 lbs.
Analysis:
Moisture % .......................................69.2
Protein % ............................................3.0
Fat % ...................................................6.7
Carbohydrate % .................................20.5
Ash % .................................................. 0.6
Calcium % ............................................0.12
Phosphorus % .......................................0.07
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