)
Table of contents :
(before and after transplantations)
(cancer chemotherapy and some immunosuppressive
drugs)ref1,
ref2,
ref3,
ref4,
ref5
in association with HHV-6
reactivationref1,
ref2,
ref3,
ref4,
ref5
and an increase in proinflammatory cytokines such as
TNF-a,
IL-6, and IL-5
(also transient lymphoid hyperplasia)ref
infectionref
pneumoniaref
deficiency => urticaria-necrotizing
vasculitis / angioitis;
e.g. Streptococcus
pneumoniae,
Haemophilus
influenzae)
deficiency => acquired
angioedema,
invasive
fungal infections,
intracellular bacteria (Salmonella
spp.,
Mycobacterium
spp.,
viruses
(reactivation of herpesviruses, expecially HHV-1
/
HSV-1,
HHV-3
/
VZV,
HHV-5
/
CMV)
: in the case of perinatal HIV-1
infection even AMI is compromised due to deficiency of memory
B cells.
;
e.g. Streptococcus
pneumoniae,
Haemophilus
influenzae)
as after splenectomy, gram positive bacteria (Staphylococcus
aureus),
rotavirus
and parvovirus
(due to decreased IgA on mucosal surfaces)
and Serratia spp.
or transfusions
(dwarfism, ..),
splenomegaly
that look for type
IV
hypersensitivities
after vaccinations or infection
and affect ~ 3-5% of the population with 2/3 of the patients being
women.
The site of attack is organ- or tissue-specific or more systemic :
as the
self-antigen(s) is usually expressed in more than one cell type,
from an
anatomical point of view autoimmune diseases should more properly
be enclosed
among the multi-organ failures
(MOF).
Anyway, due to common pathogenesis, I prefer to group them
globally among
the diseases affecting the immune system : a link to this page is
provided
in every page regarding involved organs. They can be classified as
follows
according to the main targeted organ(s) / apparatus(es) :
=> macrophages obstruct trabeculate, but no
lymphocyte infiltration occurs
or panuveitis,
vertigo, nausea
and vomiting,
very deep pain in the eyes => uveitis
(first one eye and in a couple of weeks the other eye may
become affected)
with preservation of the choriocapillaris (thanks to
anti-inflammatory
products secreted by the retinal pigment epithelium,
including TGF-b
and cystatin
C
/ retinal pigment epithelial protective protein that
is known to
suppress the phagocyte generation of superoxide) and
retina (despite extensive
inflammatory cell infiltration in the choroid) => retinal
detachment
=> rapid vision loss, drowsiness, alopecia areata,
autoimmune
vitiligo, poliosis, hearing
loss, facial
nerve
palsies,
rigidity, walking (gait) disturbance
and cataract.
or interphotoreceptor
retinoid-binding
protein (IRBP).
,
and even prostration, tinnitus (varying from a
whistle to a roar),
and deafness. The onset of symptoms is insidious,
usually with a
sensation of dullness or fullness in the ear, and an initial
fluctuation
in hearing of 10 to 30 dB, usually in the low tones. The
hearing improves
somewhat between attacks, but it continues to deteriorate as
time goes
on. There may be increased sensitivity to sound, or music
may sound distorted.
Any head movement aggravates the condition, with the vertigo
lasting several
hours. Some patients can have fleeting attacks lasting
several minutes,
and still others have attacks lasting a week or longer and
may take months
to regain normal equilibrium.
(isosorbide, an osmotic diuretic), regimen of bed rest,
no smoking, plus
inhalation of 5% CO2 + 95% O2 for
30' q.i.d. and
2.75 mg of histamine
diphosphate
in 250 cc of lactated Ringer's solution I.V. b.i.d.
Other drugs, given
individually, that are reported to be effective for an
acute attack are
1/150 grain atropine
I.V., diazepam
10 mgm I.V., and fentanyl
citrate
+ droperidol,
which must be administered in the hospital or by an
anesthesiologist. Vasodilators
are usually ineffective in Meniere's, as are the antivertiginous
drugs.ref1,
ref2
infectionmajor
core
protein lambda 1,
tinnitus, nausea
and vomiting,
and sudden hearing loss (SHL) which develop within several
months of each
other => bilateral deafness (67%),
and RPR
and/or CT
should be done primarily to rule out cerebellopontine
angle (CPA) tumors.
MRI may show enhancement of vestibular and cochlear
structures with gadolinium.
: topical for IK and oral for vestibuloauditory
involvement (prednisone
1 mg/kg for 2-4 weeks)
(?)
gene is mapped approximately at 200 kb telomeric to HLA-A on
chromosome
6. It has 11 SNPs : allele C is in linkage disequilibrium
with HLA-A11
(P<0.00001) and to a lesser extent with HLA-A1
(P<0.01).
,
molecular mimicry is presumed as trigger for this
disease.
/ Charcot's diseaseref
: positive RT-PCR on neuronal cell bodies within
the gray matter of the
spinal cord in 88.3% of patients vs. 3.4% of
controlsrefref
(OR: 3.2; p = 0.102)ref
(OR: 8.4; p = 0.064)ref,
and BDNF,
increased ROS and Glu. Immature (DEC205, CD1a) and
activated/mature (CD83,
CD40) DC transcripts are significantly elevated in ALS
ventral horn and
corticospinal tracts. Monocytic/macrophage/microglial
transcripts (CD14,
CD18, SR-A, CD68) are increased in ALS spinal cord, and
activated CD68+
cells were demonstrated in close proximity to motor neurons.
mRNA expressions
of MCP-1 by glial cells, which attracts monocytes and mDCs,
and of CSF-1
/ M-CSF
are increased in ALS tissues. Those patients who progressed
most rapidly
expressed significantly more dendritic transcripts than
patients who progressed
more slowlyref.
High
titer of IgM anti-GM1 antibodies are detected in
serum
of 46% LMND patients, 80% of MN patients, and 18% of the
classical ALS
casesref.
=> chronic encephalitis confined to one hemisphere and
contralateral cerebellar
hemi-atrophy. In the active phase, neuronophagia, activated
microglial
cells (rod cells), microglial nodules, and perivascular
lymphocytic infiltrates,
are present. In the more chronic phase neuronal loss and
gliosis predominate.
enteritis
),
stiff neck, and confusion; these are followed by
focal seizures, paralysis,
progressively deepening coma, and death.
(1 every 1,000 cases)
(1 every 4,000-10,000 cases)
(1-2 every 1,000,000 immunizations)ref,
meningismus, headache,
nausea
and
vomiting,
and drowsiness progressing to lethargy and coma;
disseminated neurological
disease => pyramidal signs, tremor, cerebellar
involvement (expecially
in ADEM due to HHV-3
/
VZV),
seizures, paralysis, ...
(protidorrachy = 50-150 mg/dL), lymphocytary
pleiocytosis (< 200 cell/mL;
sometimes
higher or with PMN in the first days of disease),
oligoclonal
bands
: diffuse symmetric contrast enhancement in white
matter of encephalon
and spinal cord,
ACTH,
and plasmapheresis
(more cycles if relapses occur)
or more are 40% less likely to develop MSref.
The link with sunshine may explain why MS is more
common in high latitudes
seropositivity is strongly associated with risk of
progressive MS (OR =
7.3)
(OR = 2.1) : the risk of MS increased
monotonically with serum titers of
IgG antibodies to VCA or EBNA complexref
after 15 years of age (OR = 2.3)
after 15 years of age (OR = 2.8)does
not increase the risk of developing multiple
sclerosis or cause exacerbationsref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8
polarization (but also Th2)
=> perivenular cuffing by inflammatory cells
(BBB is disrupted but,
unlike vasculitis, the vessel wall is preserved) and necrosis
of oligodendrocytes
(sometimes vascular demyelinization) =>
gray-to-pink plaques of
demyelination of various sizes (1-2 mm to many cm)
throughout the white
matter of the CNS, sometimes extending into the gray
matter, most commonly
in periventricular areas (lateral angles of lateral
ventricles) with a
net border between normal and affected areas =>
cicatricial gliosis.
Survived oligodendrocytes try to remyelinate some fibers (shadow
plaques)
but they are finally desroyed. Hyaluronan accumulates in
demyelinated lesions
and inhibits oligodendrocyte progenitor maturationref.
At least 4 fundamentally different neuropathological
patterns can be discerned.
Patterns I and II lesion pathologies are modeled in the
current virus-
and autoimmune-based animal models of encephalomyelitis
that have been
established in susceptible rodent strains or non-human
primates. MS is
characterized by periodic relapses correlated with
microbial infections,
most commonly URT infections (Influenzaviruses).
Several
possible mechanisms may explain this link :
that are quantitatively related to a reduction in
functional suppression
induced during suboptimal T-cell receptor (TCR) ligation.
Of importance,
this observation links a defect in functional peripheral
immunoregulation
to an established genetic marker that has been
unequivocally shown to be
involved in maintaining immune tolerance and preventing
autoimmune diseases.
Diminished FOXP3 levels thus indicate impaired
immunoregulation by Tregs
that may contribute to MS. Future studies will evaluate
the effects of
therapies known to influence Treg cell function and FOXP3
expression, including
TCR peptide vaccination and supplemental estrogenref.
CD4+CD25hi TReg cells
(not diluted by
recently activated cells involved in the ongoing
MS-associated immune response)
isolated from MS patients markedly fail to suppress CD4+CD25-
T-cell proliferation and IFN-g
production induced
by plate-bound CD3-specific antibodyref.
-W
encoded
viral envelope glycoprotein syncytin
is upregulated in glial cells within acute demyelinating
lesions of multiple
sclerosis patients. Syncytin expression in astrocytes
induced the release
of redox reactants, which were cytotoxic to
oligodendrocytes. Syncytin-mediated
neuroinflammation and death of oligodendrocytes, with the
ensuing neurobehavioral
deficits, were prevented by the antioxidant ferulic acid
in a mouse model
of multiple sclerosis. Thus, syncytin's proinflammatory
properties in the
nervous system demonstrate a novel role for an endogenous
retrovirus protein,
which may be a target for therapeutic interventionref.
Leptin
production was significantly increased in both serum and
CSF of naïve-to-therapy
relapsing-remitting multiple sclerosis (RRMS) patients and
correlated with
IFN-g secretion in the CSF. T
cell lines against
human myelin basic protein (hMBP) produced immunoreactive
leptin and up-regulated
the expression of the leptin receptor (ObR) after
activation with hMBP.
Treatment with either anti-leptin or anti-leptin-receptor
neutralizing
antibodies inhibited in vitro proliferation in response to
hMBP. Interestingly,
in the RRMS patients, an inverse correlation between serum
leptin and percentage
of circulating TRegs was also observed. To
better analyze the
finding, we enumerated TRegs in
leptin-deficient (ob/ob)
and leptin-receptor-deficient (db/db) mice
and observed the
significant increase in TRegs. Moreover,
treatment of WT mice
with soluble ObR fusion protein (ObR:Fc) increased the
percentage of TRegs
and ameliorated the clinical course and progression of
disease in proteolipid
protein peptide (PLP139-151)-induced
relapsing-experimental
autoimmune encephalomyelitis (R-EAE), an animal model of
RRMS. These findings
show an inverse relationship between leptin secretion and
the frequency
of TRegs in RRMS and may have implications for
the pathogenesis
of and therapy for multiple sclerosisref.
(35%) : weakness of the limbs may manifest as loss of
strength or dexterity,
fatigue, or a disturbance of gait. Exercise-induced
weakness is a characteristic
symptom of MS. The weakness is of the upper motor
neuron type and is frequently
accompanied by other pyramidal signs such as
spasticity, hyperreflexia
and Babinski signs. Occasionally, a tendon reflex may
be lost (simulating
a lower motor neuron lesion) if an MS lesion disrupts
the afferent reflex
fibers in the spinal cord..
However, unlike Bell's palsy, facial weakness in MS
is generally not associated
with ipsilateral loss of taste sensation or
retroauricular pain
(37%)
(24-32%)
(36%) => decreased visus (2-22.3%; higher in
youngs); it regress completely
thanks to resorption of the edema, which initially
is mild. At following
attacks regression is only partial as gliosis is
irreversible. It generally
presents as diminished visual acuity, dimness, or
decreased color perception
(desaturation) in the central field of vision. These
symptoms may be mild
or may progress to severe visual loss. Rarely, there
is complete loss of
light perception. Periorbital pain (aggravated by
eye movement) often precedes
or accompanies the visual loss. An afferent
pupillary defect may be found.
Funduscopic examination may be normal or reveal
optic disc swelling (papillitis).
Pallor of the optic disc (optic atrophy) commonly
follows ON. Uveitis
is rare and should raise the possibility of
alternative diagnoses. Visual
blurring in MS may result from ON or diplopia.
Visual blurring that resolves
when either eye is covered is due to diplopia.
or hyposthenia of extraocular muscles due to
involvement of brainstem nuclei
(expecially rectus lateralis > those innervated
by III or IV cranial nerves)
=> diplopia
(11-15%) and acquired pendular nystagmus
of abduced eye with a mild
oblique deviation (skew deviation)
(0.3%)
(1%), hemifacial spasm, and glossopharyngeal
neuralgia can occur when the
demyelinating lesion involves the root entry (or
exit) zone of the fifth,
seventh, and ninth cranial nerve, respectively.
Trigeminal neuralgia (tic
douloureux) is a very brief lancinating facial pain
often triggered by
an afferent input from the face or teeth. Most cases
of trigeminal neuralgia
are not MS-related. However, the occurrence of
atypical features such as
the onset before age 50 years, bilateral symptoms,
objective sensory loss,
or nonparoxysmal pain should raise concerns that a
symptomatic cause such
as MS is responsible.
(1-1.3%) due to involvement of brainstem nuclei---CD178
/ FasL
interaction-dependent manner. More common in elderlies
(5%)
(0.59%)
(3.6-6%) may appear suddenly and resemble acute
labyrinthitis. A brainstem
rather than end-organ origin is suggested by the
presence of coexisting
trigeminal or facial nerve involvement; vertical
nystagmus; or nystagmus
that has no latency to onset, no direction reversal,
and doesn't fatigue.
Hearing loss may also occur in MS but is uncommon.
(11%)
(3%)
(1.6%)
(2.6%)
(1.6%)
(1%) : men report impotence, less desire, impaired
genital sensation, impaired
ejaculation, and inability to achieve/maintain an
erection. Women report
genital numbness, diminished orgasmic response,
decreased libido, unpleasant
sensations during intercourse, and diminished
vaginal lubrication. Adductor
spasticity (in women) can also interfere with
intercourse, and urinary
incontinence (in either men or women) can be
problematic.
(> 90%) : urge incontinence in weekly or more
frequent episodes (33%),
urinary retention, or micturition exitation
(1%) consists of either persistent rapid flickering
contractions of the
facial musculature (especially the lower portion of
the orbicularis oculus)
or a contraction that slowly spreads across the
face. It results from lesions
of the corticobulbar tracts or brainstem course of
the facial nerve.
(0.3-1%)
(50%). Cognitive dysfunction sufficient to impair
activities of daily living
also occurs in 20%
can be reactive, endogenous, or part of the
illness itself and can contribute
to fatigue (50-60% along whole course; suicide has
RR = 7.5)
(3%) is the electric shock–like sensation (evoked by
neck flexion or other
movement) that radiates down the back into the legs.
Rarely, it radiates
into the arms. It is generally self-limited but may
persist for years.
Lhermitte's symptom can also occur with other
disorders of the cervical
spine (e.g., cervical spondylosis).has
demonstrated bursts of disease activity 7 to 10
times more frequently than
is clinically apparent. This finding indicates that
there is a large reservoir
of subclinical disease activity in MS, especially
during the early stages
of the disease. The triggers causing these bursts
are unknown, although
the fact that patients may experience relapses after
nonspecific upper
respiratory infections suggests that either
molecular mimicry between viruses
and myelin antigens or viral superantigens
activating pathogenic T cells
may play a role in MS pathogenesis. Within 15
years from onset,
50% (the great majority of RRMS ultimately) develop
...
(plaques don't captate : differential diagnosis with
cerebral vasculitides);
impaired BBB is seen by extravasation of Gd-DPTA
(sensitivity > 95%); Gd-enhancement
persists for up to 3 months, and the residual MS
plaque remains visible
indefinitely as a focal area of hyperintensity (a
lesion) on spin-echo
(T2-weighted) and proton-density images. Lesions are
frequently oriented
perpendicular to the ventricular surface,
corresponding to the pathologic
pattern of perivenous demyelination (Dawson's
fingers). Lesions
are multifocal within the brain, brainstem, and spinal
cord. Lesions in
the anterior corpus callosum are helpful
diagnostically because this site
is usually spared in cerebrovascular disease.
Different criteria for the
use of MRI in the diagnosis of MS have been proposed.
The total volume
of T2-weighted signal abnormality (the "burden of
disease") shows a significant
(albeit weak) correlation with clinical disability.
Approximately one-third
of T2-weighted lesions appear as hypointense lesions
(black holes) on T1-weighted
imaging. Black holes may be a better marker of
irreversible demyelination
and axonal loss than T2 hyperintensities, although
even this measure depends
upon the timing of the image acquisition (e.g., most
acute Gd-enhancing
T2 lesions are T1 dark). Newer MRI measures such as
brain atrophy, magnetization
transfer ratio (MTR) imaging and proton magnetic
resonance spectroscopic
imaging (MRSI) may ultimately serve as surrogate
markers of clinical disability.
For example, MRSI can quantitate molecules such as
N-acetyl aspartate (NAA),
which is a marker of axonal integrity, and MTR may be
able to distinguish
demyelination from edema.
: intratechal IgG synthesis (> 2 oligoclonal bands
in 75-90%), mononucleated
pleiocytosis > 5 cell/mL
(usually < 20/mL,
> 50/mL in myelopathies;
improbable when > 75/mL)
(> 25%), and protidorrachy < 100 mg/dL
(differential diagnosis with
infections and tumors if higher)
(at least 1 in 80-90%) provide the most information
when the pathways studied
are clinically uninvolved. For example, in a patient
with a remitting and
relapsing spinal cord syndrome with sensory deficits
in the legs, an abnormal
somatosensory EP following posterior tibial nerve
stimulation provides
little new information. By contrast, an abnormal
visual EP in this circumstance
would permit a diagnosis of clinically definite MS.
Abnormalities on one
or more EP modalities occur in 80 to 90% of MS
patients. EP abnormalities
are not specific to MS, although a marked delay in the
latency of a specific
EP component (as opposed to a reduced amplitude) is
suggestive of demyelination.,
IFN-b1band
IFN-t)
decrease BBB permeability (once the BBB breaks,
massive infiltration of
T cells, augmented expression of adhesion
molecules on endothelial cell
surface, and leakage of inflammatory cytokines
and antibodies will aggravate
the MS lesions))
(mitoxantrone) : 12 mg/m2 in 100 mL
(60 gtt/min) every 3 months
up to 120 mg/m2 (8-10 doses)
in SPMS
agonists (methylprednisolone
1 g in 500 mL of slow-drop physiological solution
for 5 consecutive mornings)
+ gastric protectants since day before or same day
if i.v. => then decreasing
dose (125 mg in p.o. vials q.d. for 7 days =>
a.d. for 15 days)ref1,
ref2, ref3,
rituximab
?)
prevents expression of CIITA in all cell types
that need IFN-g
to express MHC class II molecules, including
neurons. Further atorvastatin,
but not pravastatin, stabilizes LFA-1 interactions
for 6 months decreases the number and size of
cerebral lesions by around
40% in a 30-patient clinical trial : it is not
clear if the drug also eased
the symptoms of MS, which commonly include
fatigue, tremor and paralysis,
as the study was not designed to assess this, but
prolonged use will help
users live a more normal life.
: paralysed mice became increasingly active just 10
days after receiving
the intravenous injection of 1 million cultured
brain stem cells. Over
40% of them turn into cells that make myelinref
and 4-aminopyridine to improve conduction blocks)
stings along the backref1,
ref2,
ref3,
ref4,
ref5,
ref6,
polyosol and bee pollen
provided relief from some of the painful symptoms of
MS, but independent
physiotherapists failed to find hard evidence of
reduced muscle stiffness
and disability. However, new data presented at the
annual meeting of the
British Association for the Advancement of Science
in Exeter, UK, indicates
that this assessment might have been premature. Of
the patients in the
initial trial, 80% opted to continue cannabinoid
treatment for up to 1
year. In the longer term, there is a suggestion of a
more useful beneficial
effect, which was not clear at the initial stage.
Animal studies have indicated
that cannabinoids slow nerve-cell death-mediated
inflammatory demyelinating disorder of the CNS induced
by immunization
of mice and rats with Freund's
complete adjuvant together with ...
heals EAE and worsens MS, while TNF-a
heals MS and worsens EAE. Just before the onset of
disease, the animals'
leptin levels double : but in mice that ate nothing for
48 hours - the
equivalent of 7 to 10 days for humans - the leptin surge
was smaller. Neurons
in the brain lesions of diseased mice produce leptin.
Mice with a condition akin to MS that were deprived of
food for 48 hours
still developed the disease but had fewer brain lesions
and performed better
on tests of walking, balance, weakness and paralysis. IL-23
produced by CNS-resident cells controls Th1-cell
encephalitogenicity
during the effector phase of EAEref.
SJL mice that express a transgenic TcR specific for PLP
(5B6 TcR-transgenic
mice) readily develop spontaneous EAE, unless on the
B10.S background,
in which APCs express lower levels of MHC class II and
co-stimulatory molecules
(reversed by TLR9 but not TLR4 agonists)ref.
mediated disease
and molecules on caudatus and subthalamic nuclei.
(4-8 weeks after < 10% of infections) and molecules on
caudatus and
subthalamic nuclei.
)
or bilateral involuntary movements that gradually become
severe, affecting
all motor activities including gait, arm movements, and
speech, disappearing
during sleep. A mild psychic component is usually present (obsessive-compulsive
disorder
(OCD)).
The disorder may take the form of muscular rigidity (paralytic
chorea).
Westphal's
sign : the patellar reflex evokes a transient
maintenance of hyperextension
of leg before falling down (a sign of dystonia).
,
neuroleptics or benzodiazepines
can be used for treatment
(some cases)and
bulimia
nervosa,
ACTH
and LHRH
are found
in
75% of affected patients compared to just 16% of those
without eating
disorders.
(insect repellent) increases DEET absorption 5-fold
(belief in a threat from biological or chemical weapons)
: b-adrenergic
load potentiates the toxicity of PB. While similar types
of chemical and
physiological stressors are present in the general
population, the veteran
population received these stressors in a short time,
with greater intensity,
and at a higher percentage exposure than normal for the
general population.
Vietnam veterans who experienced PTSD were 3 times more
likely to have
an autoimmune illness (arthritis, psoriasis
or hypothyroidism) or coronary
artery
disease
than veterans not having experienced PTSD.
: veterans with the neurologic symptom complexes were
more likely to have
the R allele (heterozygous QR or homozygous R) than to
be homozygous Q
for the paraoxonase
/
arylesterase 1 (PON1) gene. Moreover, low activity
of the PON1 type
Q (Gln192, formerly designated type A)
arylesterase allozyme
distinguished ill veterans from controls better than
just the PON1 genotype
or the activity levels of the type R (Arg192,
formerly designated
type B) arylesterase allozyme, total arylesterase, total
paraoxonase, or
butyrylcholinesterase. A history of advanced acute
toxicity after taking
pyridostigmine was also correlated with low PON1 type Q
arylesterase activity.
Type Q is the allozyme of paraoxonase/arylesterase that
most efficiently
hydrolyzes several organophosphates including sarin,
soman, and diazinon.
Moreover, sarin suppresses T cell responses via the
autonomic nervous system
and independently of the HPA axis.
contained in some lots of the absorbed anthrax
vaccine
used on military personnel immunized for service in
Desert Shield/Desert
Storm during 1990-1991. Squalene is a common
component of "over the counter"
performance food supplements like "Power Bar" and
others, usually abused
by special forces. Anti-squalene antibodies
(ASA) have a 100%
sensitivity
and specificity for patients with GWS and
adverse reactions
in vaccinated personnel were similar to symptoms of
GWS.
: Lieutenant Colonel Graham Howe, clinical director of
psychiatry with
the British forces health service in Germany describes
the case of Lance-Corporal
Alex Izett, who received vaccines, anthrax, botulism,
plague and other
unspecified biological agents in anticipation of war. As
the subject was
not involved in fighting, the report states that the
common factor linking
the osteoporosis with which he suffers to the high
incidence of osteoporosis
in Gulf-war veterans is the vaccines he received.
autoantibody
ref
)
(20-40%; expecially O types 19 and 41, which have
class A, B, or C locusref
able to biosynthetize specific types of the
lipo-oligosaccharides (LOS)
mimicking gangliosides in nervous tissueref
: cross-reactive antibodies between Campylobacter
LOS and gangliosides
have been demonstrated in serum from GBS patientsref.
Ganglioside-mimicking structures are found more
frequently in neuropathy-associated
C.
jejuni strains than in strains isolated
from patients with diarrhearef.
An important feature in ganglioside mimicry is the
presence of sialic acid
(N-acetylneuraminic acid) in both LOS and
gangliosidesref)
(1 case per about 2,000 infections) (20-50%)
(Buzby JC, Allos BM, Roberts T. 1997. The
economic burden of Campylobacter-associated
Guillain-Barre
syndrome. J Infect Dis 176 Suppl 2:S192-7),
bulbar palsy, absent or lessened tendon reflexes, and an
increase in the
protein of the cerebrospinal fluid without corresponding
increase in cells.
The disease can progress to involve the respiratory
muscles, resulting
in dyspnea (=> respiratory failure).
,
ataxia,
and ophthalmoplegia.
These antiganglioside antibodies have been shown to
produce neuromuscular
block, and may in part explain the clinical signs of
that disorder.Reports
on cerebellar ataxia and supranuclear oculomotor
derangement in MFS suggested
an additional involvement of the CNS, resembling Bickerstaff's
brainstem
encephalitis (BBE).,
which removes plasma and nerve-damaging antibodies
from the blood, is used
during the first few weeks after a severe attack and
may improve the chance
of a full recovery => IVIg
are not recommended as they chronicize the
viral infection. Steroid-pulse
therapy should be considered in GBS patients
associated with CMV infection
when other conventional treatments are ineffectiveref
is of great interest because both melanocytes and Schwann
cells derive
from neural crest tissue and share common antigens
(gangliosides GM3,
GM2, GD3, and GD2, myelin-associated
glycoprotein
(MAG), other myelin glycoproteins, and
sulfoglucuronyl
glycolipids). After some patients with melanoma receive a
therapeutic vaccination
with melanoma lysates, they develop a subacute
demyelinating neuropathy.
detect slowed conduction velocities < 80% of the
lower limits of normal
(LLN) if the compound muscle action potential (CMAP)
amplitude is greater
than 80% of LLN, and < 70% of LLN if the CMAP
amplitude is less than
80% of LLN (in axon degeneration nerve conduction
velocities rarely fall
to less than 80% of the lower limit of normal, and
distal latencies of
F-waves rarely exceed 1.25 times the upper limit of
normal). In patients
with demyelination limited to proximal nerve segments
(66%), with or without
dropout of large myelinated axons, routine
electrophysiologic studies might
be normal but F-wave latencies are prolonged unless a
sufficient number
of large myelinated fibers remain unaffected. The
slowing in sensory
nerves is less than that in motor nerves.Only 11.7% of
patients exhibit
temporal dispersion and 13.3% have conduction block.
Demyelination in proximal
regions can result in distal axon degeneration.ref,
glucocorticoidsref,
tacrolimusref
,
whose genome cross-reacts with histidyl-tRNA
synthetase
/ Jo-1
(the target of autoantibodies in some patients)
=> CHF,
dilated cardiomyopathy,
soft tissues and fasciae, articular contractures,
tuberculosis, pyogenic
infections.
(positive sharp waves from splitted fibers)
>
(azathioprine
and methotrexate)
> IVIg
> cyclosporine
A,
chlorambucil,
cyclophosphamide
or mycophenolate
mofetil,
plasma
exchange.
Bisphosphonates,
aluminum hydroxide, probenecid, colchicine, warfarin and calcium
channel blockers (CCB)
to treat calcinosis
cutis.
,
AV block, tachyarrhythmias, myocarditis
=> CHF,
dilated cardiomyopathy
(10%, in 80% of patients with anti-Jo-1 autoantibodies
and 69% of patients
without anti-Jo-1 autoantibodies),
LDH, aldolase, SGOT, and Mb (related to muscle mass and
circadian rhythm),
up to 50-fold increase in CK (CPKMB > 12% CPKTOT
indicates heart involvement), myopathic (short and mild)
potentials at
needle EMG
(positive sharp waves from splitted fibers). Myoglobinuria
in severe conditions.
> azathioprine
and methotrexate
> IVIg
> cyclosporine
A,
chlorambucil,cyclophosphamide
or mycophenolate
mofetil
, plasma exchange
(positive sharp waves from splitted fibers)
,
plasma
exchange.
(100% of patients with HLA-DR3 / HLA-DRw6; RR = 20)
in vaccines
incretion => decreased muscle repair after efforts and
increase of [SP]CSF
=> pain; alteration of hypothalamus-hypophysis-adrenal axis
=> decrease
of [cortisol]plasma. focal oedema,
mitochondriopathy,
=>
lowering
of pain threshold
(10%), no alterations in biohumoral parameters
,
neuropathies.
,
anorexia => weight loss, GCA
(> 50%; however, only a minority of patients with the
disease, who have
no evidence of arteritis, ever develop giant cell arteritis).
,
sideropenic anemia, leukocytosis,
gGT, AlkP, biopsy, angiography, and echocolordoppler
(ECD)of
temporal arteries, ophthalmologic visit, high levels of
circulating
ICAM-1.
incretion => decreased cortisol
and increased ACTH.
High levels of 2',5'-oligoadenylate (2-5A)-dependent
37-kDa form
of antiviral RNase
L has been reported in extracts of peripheral blood
mononuclear cells
(PBMC), present as a catalytically inactive heterodimer
complex with the
RNase L inhibitor (RLI).
(90%)
(75%),
... (65%)
(40%),
neuromyasthenia, hypoglicemia, multiple chemicals
hypersensitivity syndrome,
chronic candidosis, chronic HHV-4
/ EBV
infection, postviral fatigue syndrome.
(anna 1 antibodies) (85%) that interfere with the
release of acetylcholine
at the motor nerve terminal
(oat-cell carcinoma of the lung; trigger ?). Autonomic
dysfunction (> 50%)
ref
(primarily the a-chain) at the
postsynaptic
membrane of the neuromuscular junction => neuromuscular
exhaustiveness
,
diplopia),
50% has positive autoAb
(10-20%%)
(0-2)
(double-step nerve stimulation => sensitization of
postactivation exhaustion
by ischemia => 5 Hz activity with decrease > 12% in
DV registered at deltoid
or fifth finger abductor muscles). It is necessary to test
the repetitive
nerve stimulation (PRNS) and intercostal repetitive nerve
stimulation (IRNS)
in type II MG patients regularly
chloride), the patient's eye signs (ptosis and
extraocular muscle abnormalities)
markedly decrease within 2 minutes in cases of
myasthenia gravis.
(Prostigmine) test : used in children, and in
adults suspected of having
myasthenia gravis but with a negative Tensilon test;
neostigmine methylsulfate
mixed with atropine sulfate is injected intramuscularly;
lessening of myasthenic
symptoms is indicative of the disease
to assess thymic diseases
(p.o. pyridostigmine
2mg/kg/die = 60 mg 3-4 times a day : t1/2 = 10
hr)
0.4 g/kg/die for 5 days
is an important treatment option in MG, especially if a
thymoma is present.
It has been proposed as a first-line therapy in most
patients with generalized
myasthenia. The beneficial effect of thymectomy was
reported as early as
the 1930s and 1940s in a variety of case reports and small
series. Even
though no controlled trial to assess the efficacy of
thymectomy in MG has
been reported, thymectomy has become the standard of care
and should be
done in all patients with thymoma and in patients aged
10-55 years without
thymoma but with generalized MG. Thymectomy may induce
remission. This
occurs more frequently in young patients with a short
duration of disease,
hyperplastic thymus, and high antibody titer. Remission
rate increases
with time: at 7-10 years after surgery, it reaches 40-60%
in all categories
of patients except those with thymoma.
(usually remits when the drug is stopped)
,
show sequence homology with some intracellular proteins, and
may persist
in connective tissue diseases such as dermatomyositis.
Autoantigens :
(97%)
autoantibodies
,
estradiol
and relaxin
.
with fever,
leukocytosis,
pleuritis,
and pneumonia
ref
(AIHA) : the antibodies that cause AIHA can be
classified by isotype
(IgG, IgM, or IgA) and by the temperature at which they
react maximally
with the antigen on the red cell: warm reacting if that
temperature is
37º, cold reacting if that temperature is less. Much of
the pathophysiology
and many of the clinical manifestations are determined by
these characteristics.
For the most part, the isotype and the temperature of
reaction coincide:
most
frequently, cold-reacting antibodies are IgM and
warm-reacting antibodies
are IgG, but important exceptions exist.|
|
|
|
|
| isotype | IgG | IgM | IgG |
| temperature | 37°C | 4°C | 4°C and 37°C |
| complement fixation | variable | yes | yes |
(e.g. CVID)
antibodies, including IgAref.
It is an ion transporter found in erythrocyte membranes
also shown to be
involved in erythrocyte senescence. The major target of
the pathogenic
red blood cell (RBC) autoantibodies in New Zealand black
(NZB) mice (which
spontaneously develop AIHAref
: RBC-bound IgG autoantibodies can be detected by direct
antiglobulin test
(DAT) from 3 months of age, and the mice develop signs
of anemia from about
6 months of age onwardref)
is the anion channel protein band 3, and CD4+
T cells from NZB
mice respond to band 3 peptide 861-875ref1,
ref2
: nasal administration of different peptides containing
the dominant T-cell
epitope can have potentially detrimental or beneficial
effects on the diseaseref
antibodies
or non-neoplastic clones activated during chronic
lymphocytic leukemia
antibodies),
that binds to RBCs at 0÷-20°C and induces
complement-mediated
lysis on warming at 37°C; it is responsible for
hemolysis in a
frigore paroxismal hemoglobinuria
(with anti-i specificity)
(with anti-I specificity) infections
and it should be used only when the simultaneous presence
of IgG antibodies
is found. Antibody production can sometimes be suppressed
by chemotherapy,
but the rate of proliferation of benign clones is so small
that this is
often ineffective; obviously, if malignancy is present,
its treatment will
treat the cold agglutinin problem. More recently, the use
of anti-CD20
(rituximab)
has found some successref
as has the use of fludarabineref.
Some patients appear to benefit by small to moderate doses
of erythropoietin.
Plasmapheresis
can be used to remove antibody temporarily but is
difficult to maintain
for chronic treatment; great caution is required to be
sure that the blood
does not get cold during the procedureref.
(or so it is thought) and was frequently seen in secondary
and tertiary
syphilis; this is now rare. It is most commonly
encountered in children
as a response to viral illness
or immunization,
much like immune
thrombocytopenia in this group; in these cases, it
does not persist,
but the clinical syndrome it produces may be severe enough
to cause death.
In adults, it is usually an autoimmune antibody and may be
associated with
other evidences of autoimmunityref.
has no place in the regimen as the spleen is not involved
in hemolysis.
Prednisone,
chemotherapy, and anti-CD20
(rituximab)
treatment have all been used.
,
expressed primarily on adult RBCs,
expressed primarily on RBCs of fetuses and infants. They
are highly unusual
in being encoded by a single VH gene segment,
VH4-34.
Although VH4-34 is mandatory, a variety of
different D and JH
gene segments, as well as L chains from different
families and isotypes,
are used. The I/i Ag is composed of repetitive N-acetyllactosamine
units
(Galb1->4GlcNAc) which are
linear in the
i structure and branched in I. The strong association of
a single VH
gene segment with specificity for the I/i Ag indicated
that the particular
structure formed by the VH4-34-encoded
portion of the Ab is
required for I/i binding. The structural interaction is
of an unconventional
nature involving FR1 and therefore independent of the
conventional Ag binding
site. These IgM autoantibodies characteristically will
not react with cells
at 37°C but only at lower temperatures. Since the
blood temperature
(even in the most peripheral parts of the body) rarely
goes lower than
20°C, only antibodies active at higher temperatures
than this will
produce clinical effects. In the cooler parts of the
body (fingers, nose,
ears), agglutination of RBCs by the IgM antibodies will
transiently occur.
Hemolysis results indirectly from attachment of IgM,
which in the cooler
parts of the circulation binds and fixes complement.
When the RBC returns
to a cooler temperature, the IgM antibody dissociates,
leaving complement
on the cell. Lysis, or destruction, of cells rarely
occurs. Rather, C3b
present on the RBCs is recognized by Kupffer cells
(which have receptors
for C3b); and red blood cell formation follows.,
which, unlike I and i antigens, are protease sensitive.
IgAkref|
|
|
|
|
|
| autoimmune | a-methyl-DOPA,
L-DOPA,
and mefenamic
acid
induce IgG cross-reacting against Rh Ags |
standard therapeutic dose for 3-6 months | gradual onset of hemolysis, progressive if drug is not discontinued | IgG |
| high-affinity hapten | penicillins,
cephalosporins,
tetracyclines
and tolbutamide firmly adhere to RBC plasma
membrane creating non
self epitopes and inducing drug specific IgGs |
high dosage for days of weeks | subacute extravascular hemolysis for 7-10 days, progressive if drug is not discontinued | IgG |
| low-affinity hapten | quinidine
unstably adheres to RBC plasma membrane inducing Abs
that stabilize such
a binding |
standard or low dose for days | rapid onset, sometimes hyperacute with extravascular hemolysis | IgG or IgM |
| nonimmunological proein adsorption | cephalotin
damages RBC plasma membrane allowing many proteins
to adhere it and creating
many new non-self epitopes. |
high dosage for days or weeks | clinically not releant | IgG |
interacts with both an IgG antibody and a RBC membrane
epitope probably
located on the Band 3 anion channelref
(AIN)
with replacement of 1.0 to 1.5 times the predicted
plasma volume of the
patientref
that should be continued until the platelet count is
normalref1,
ref2
or for a minimum of 2 days after the platelet count
returns to normal (>150,000/ml)ref.
This combines plasmapheresis (which may remove circulating
ULVWF multimer-platelet
strings, agents that stimulate endothelial cells to
secrete ULVWF multimers,
and autoantibodies against ADAMTS13) and the infusion of
fresh-frozen plasma
or cryosupernatant (containing uninhibited ADAMTS13). Both
solvent-detergent–treated
plasmaref1,
ref2
and methylene blue/light-treated plasma (for inactivation
of lipid envelope
viruses) also contain active ADAMTS13; however, protein S
activity is below
normal in solvent-detergent plasma. Plasma exchange allows
about 80–90%
of acquired TTP patients to survive an episode, usually
without persistent
overt organ damage. Lower titers of ADAMTS13
autoantibodies are associated
with better responses to plasma exchange procedures.
Plasma exchange normalizes
pattern of vWF polymers and allows complete remission for
1 weekref.
LDH levels, which reflect tissue ischemia as well as
hemolysisref,
are also a marker of response to treatment. Risks of
plasma exchange should
be recognizedref.
In a 9-year cohort study of 206 consecutive patients
treated for thrombotic
thrombocytopenic purpura, 5 (2%) died of complications
attributed to the
plasma-exchange treatment (3 from hemorrhage related to
the insertion of
a central venous catheter and 2 from catheter-related
sepsis)ref.
53 other patients (26%) had major complications attributed
to plasma-exchange
treatment, including systemic infection, venous
thrombosis, and hypotension
requiring dopamineref.
However, given the poor prognosis of untreated TTP, the
benefits of therapy
outweigh the risks.
(e.g., 1 to 2 mg/kg of prednisone daily until remission
is achieved; or
1 g of methylprednisolone per day for 3 daysref
administered intravenously)ref1,
ref2
if plasma exchange doesn't work, chronic relapsing TTPref,
plasma-exchange dependence, or relapsing cerebral
ischemia despite normal
peripheral blood analysis. Rituximab is also used for
prophylaxis in patients
who experienced at least 2 episodes (at least 1 with
extrahematological
symptoms & signs), in complete remission, failure of
at least one first-line
therapy, and ADAMTS < 5%ref1,
ref2.
In 30-40% of patients with chronic relapsing TTP autoAb
persist during
clinical remissionref.,
vincristineref,
or cyclosporineref1,
ref2,
ref3-induced
thrombocytopenia (HIT)|
|
|
|
|
|
|
| heparin (new or remote [> 100 days] exposure) | high | patients undergoing orthopedic surgery | 14 | 3-5 | at baseline and at least every other day from days 4 to 14 of heparin therapy or until heparin discontinued |
| intermediate | adults undergoing cardiac surgery. Children undergoing cardiac surgery | 25-50 | 1-2 | ||
| intermediate | general medical patients, patients with neurological conditions, patients undergoing percutaneous coronary intervention for acute coronary syndrome, patients undergoing acute hemodialysis | 8-20 | 0.8-3.0 | ||
| low to rare | general pediatric patients, pregnant women, patients undergoing chronnic hemodialysis | 0-2.3 | 0-0.1 | not essential | |
| LMWH | intermediate | medical patients
patients with neurologic conditions patients undergoing surgical or orthopedic procedures |
2-8 | 0-0.9 | at baseline and every 2 to 4 days after days 4 through 14 of LMWH therapy or until therapy discontinued |
| rare | pregnant women
general pediatric population |
unknown | 0-0.1 | routine monitoring not recommended | |
| heparin or LMWH (exposure within 100 days) | unknown | all clinical populations | unknown | unknown | at baseline, within 24 hr, and every other days from days 4 through 14 until heparin is discontinued |
complexes in their plasma at the time the
disease develops. PF4 is
a platelet-specific C-X-C chemokine that is released
in high concentrations
at sites of platelet activation. Recent evidence in a
transgenic mouse
model suggests a role for PF4 in thrombus formationref.
Heparin-PF4 complexes form though an interaction
between the highly sulfated
anionic heparin and a circumferential band of lysine
and arginine residues
on PF4. Binding of PF4 to polyanions appears to expose
new antigenic epitopes
that lead to antibody formation. This phenomenon is
not heparin-specific;
other negatively charged polyanions can also induce
antigenic sites. Although
all major classes of antibodies have been detected, it
appears that patients
with high titer IgG responses are at greatest
risk to develop clinical
diseaseref1,
ref2.
Anti-heparin-PF4 antibodies also appear to be more
prevalent among individuals
undergoing cardiac surgery with bypass, where high
doses of heparin are
used in the setting of intense platelet activation. Up
to 50% of individuals
who undergo cardiac surgery with bypass will become
seropositive. However,
at present, there are no reliable means to predict
which seropositive individuals
will develop thrombocytopenia or the even smaller
fraction who will manifest
thrombotic complications. IgG/heparin-PF4
complexes activate platelets
through the platelet FcR, resulting in further PF4
release and amplification
of this process. In addition, this process results in
thrombin activation,
thereby eventuating in a systemic hypercoagulable
state. For reasons that
are not clear, only a minority of heparin-treated
patients who form anti–PF4
(PF4)/heparin antibodies develop thrombocytopenia,
thrombosis, or other
sequelae of HIT. To date, investigators have focused
on explaining this
clinical heterogeneity through serologic
differences, such as antibody
class, titer, and platelet-activating propertiesref1,
ref2.
But there are still patients with otherwise typical
"HIT antibodies" who
do not develop HIT. A HIT-mimicking anti-PF4/heparin
monoclonal antibody
(named KKO) exhibited greatly increased binding to
human platelets in the
presence of added PF4 (maximal binding at 50
µg/mL), even when heparin
was not present. Similar findings were observed using
purified IgG obtained
from patients with HIT. Moreover, treatment of
platelets with chondroitinase,
but not heparanase, greatly reduced antibody binding.
Thus, HIT antigens
are formed by stoichiometrically optimal
concentrations of PF4 and platelet
surface chondroitin sulfate. These observations
help explain certain
features of HIT, such as thrombocytopenia that
persists for several weeks
or that begins a few days after stopping heparin ("delayed-onset
HIT")ref.
These data might also help account for why thrombotic
risk remains high
for a time despite stopping heparinref
(if no alternative anticoagulant is given), perhaps
because of continuing
platelet activation. The results could also
explain the common serologic
finding of heparin-independent platelet activationref1,
ref2.
—a
small
positively charged molecule familiar to clinicians for
its heparin-neutralizing
properties—prevented thrombocytopenia in both FcgRIIA/hPF4low
and FcgRIIA/hPF4high
double-transgenic
mice, presumably because protamine competes with PF4
for binding to platelet
surface chondroitin sulfate. These intriguing results
suggest that protamine
should be evaluated in clinical studies for its
potential to reduce HIT
antibody–induced platelet activation
due to the high incidence of crossreactivity (although
compared
with unfractionated heparin, LMWH therapy is less
likely to result in HIT)
appears not to crossreact with HIT antibodies, but
this remains to be tested,
such as lepirudin,
bivalirudin
or argatroban
: 2 DTIs are approved for treatment of HIT in the
USA : argatroban and
lepirudin. Argatroban is also approved for
prevention of thrombosis in
HIT patients and for coronary interventions. Danaparoid
has been used extensively for HIT therapy but is
not currently available
in the US. Hirsh and colleagues recently published
a critical review on
HIT treatmentref.
They examined 4 issues: risk of thrombosis in
patients with HIT where heparin
was discontinued in the absence of an alternative
anticoagulant; the efficacy
of DTIs in a patients with HIT (with or without
thrombosis); the use of
DTIs in patients with a history of HIT requiring a
coronary intervention;
and bleeding risk associated with this therapy.
The criteria for inclusion
were a study design of randomized controlled
trial, prospective cohort
study or retrospective observational study
enrolling patients consecutively;
treatment with lepirudin, argatroban or
danaparoid; and a minimum of 30
patients. Of 999 potentially relevant citations
identified, only 9 met
these criteria; no studies using danaparoid met
the criteria. There were
no randomized controlled trials comparing
treatments. The incidence of
new thromboembolic events in patients with HIT
treated by discontinuing
heparin alone or by heparin withdrawal and
initiation of warfarin in the
absence of a DTI ranged from 19% to 52%. The use
of historical controls
in the lepirudin and argatroban trials, together
with differences in trial
design, made it difficult to compare the efficacy
of the two drugs directly.
For example, patients in the lepirudin trials were
treated twice as long
on average as those in the argatoban trial. All
patients in the lepirudin
trial had a positive test for HIT antibodies,
compared with 65% of those
in the argatoban trial. Even with treatment,
mortality ranged from 9% to
22%; 6–18% of patients required amputation or
experienced a new thrombotic
event. Neither outcome was statistically
significantly different from historical
controls. However, as Warkentin and others have
pointed outref,
using a single endpoint of new thrombosis (rather
than the composite endpoint
of all cause mortality, new thrombosis and limb
amputation) may be a better
measure of DTI efficacy. Amputation of a limb with
severe ischemic injury,
for example, might well be required despite the
use of an effective anticoagulant
following the injury. Both drugs significantly
reduced the incidence of
new thromboembolic events. Bleeding rates of 6–18%
were reported for both
drugs. The bleeding rate in coronary inventions
was approximately 1%. In
the absence of properly designed drug comparison
trials, the choice of
drug is generally based on differences in their
mode of elimination; lepirudin
is renally cleared whereas argatroban is cleared
by the liver. There is
no antidote for either drug. Therefore, in
patients with renal insufficiency,
argatroban would be preferred; in those with liver
disease lepirudin would
be a better initial choice. Lepirudin is a
recombinant form of the leech
anticoagulant hirudin. Up to 40% of individuals
receiving the drug will
develop antihirudin antibodies, which sometimes
prolongs the drug half-life.
There have been a few cases of fatal anaphylactic
reactions in patients
re-exposed to lepirudinref.
Either drug should be used cautiously in
critically ill and elderly patients.
For example, because the serum creatinine does not
correlate with the creatinine
clearance as well in the elderly population as it
does in younger individuals,
lepirudin may be cleared more slowly than
expected. Argatroban clearance
may be prolonged in ICU patients with normal liver
function tests (LFTs)
but compromised hepatic blood flow due to
congestive heart failure or hemodynamic
instability. Bivalirudin
has been used in HIT patients during angioplasty
and clinical trials in
other settings are underway.
: almost all patients require oral anticoagulation
either because of the
underlying indication for heparin or the risk of
new thromboembolic events
due to HIT, which persists for about a month.
Conversion to warfarin may
be accomplished while on the DTI, after there is
evidence of clinical stability
and platelet recovery. Prolongation of the PT is
rarely an issue with lepirudin.
This conversion is more complicated in patients
treated with argatroban,
which generally prolongs the INR. Thus, the
observed INR in a patient on
argatroban is a reflection of the effect of both
warfarin and argatroban.
A nomogram has been developed by the manufacturer
to assist in this conversion;
however, the effect on the INR depends on both the
argatroban infusion
rate and thromboplastin used. A validation of this
nomogram in HIT patients
on concurrent argatroban and warfarin is in
progress.
: whenever possible, such surgery should be
postponed in patients with
clinical or serologic evidence of HIT. HIT
antibodies are relatively
short-lived, and not all patients develop HIT
upon re-exposure to heparinref.
Thus, the generally preferred strategy is to wait
for several weeks and
perform the surgery using unfractionated heparin
(UFH) when serologic tests
are negative. Postoperatively, it is prudent to
monitor patients for the
development of HIT antibodies and to have a low
threshold for prophylactic
use of a DTI; a DTI or other non-heparin
anticoagulant should be used for
acute coronary syndromes or interventions
requiring anticoagulation. Argatroban
is approved for use in HIT patients requiring percutaneous
coronary
intervention (PCI).
The hirudin analog bivalirudin has also been
studied in HIT patients requiring
PCI, and while not FDA-approved, appears to be a
safe and effective alternativeref.
If surgery cannot be delayed, then the approach
will depend on the experience
of the institution. Surgery should be performed
"off-pump," if possible,
to decrease the anticoagulant requirement.
Alternative approaches are not
FDA-approved, involve off-label use of available
anticoagulants, are based
primarily on anecdotal evidence and involve a
significant risk of bleeding.
Lepirudin
and bivalirudin
have been used successfully in this setting.
However, there is no neutralizing
agent and monitoring drug levels on the pump
optimally requires use of
the ecarin clotting time or chromogenic substrate
thrombin assayref.
The use of these drugs for cardiac bypass has
recently been reviewed in
detailref.
Another alternative is to use UFH along with prostacyclin
to inhibit platelet activationref.
Norepinephrine
or similar agents must be used concurrently to
counteract the vasodilatory
effects of prostacyclins.
are not elevated in patients with ITP, as they are in patients
with thrombocytopenia
due to chemotherapy or aplastic anemiaref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8;
the mechanism underlying this phenomenon is thought to be
related to clearance
of endogenous thrombopoietin by the megakaryocyte and platelet
poolsref1,
ref2.