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Idiopathic Thrombocytopenic Purpura


IDIOPATHIC?
idiopathic = cause not known
seems like most things called idiopathic in modern medicine are auto-immune
most pts have ABs against platelets
aka immune thrombocytopenic purpura or immune-mediated thrombocytopenic purpura

THROMBOCYTOPENIC
thrombocytopenic = low platelet count
normal platelet count: 150,000-400,000/mm3 of blood
mild thrombocytopenia: 100,000-150,000/mcL
moderate thrombocytopenia: 50,000-100,000/mcL
severe thrombocytopenia: less than 50,000/mcL

PURPURA
purpura = subcutaneous bleeding usudt a blood disorder, a hemorrhage in the skin greater than 3mm in diameter
early purpura: red, darkens to purple-->brown yellow as it fades
purpura does not blanch with pressure

SYMPTOMS
often asymptomatic
bruising (purpura)
petechiaea esp on extremities
bleeding from nose and gums
very heavy menstrual bleeding
blood in stool or urine
bleeding diathesis
very low count (under 10,000/mm3)-->hematomas in mouth & other mucous membranes
extremely low count (under 5,000)-->subarachnoid or intracerebral hemorrhage, lower GI bleeds, etc
danger with any abdominal trauma
this danger not so severe if PLT count is above 20,000

DIAGNOSIS
process of exclusion
DDX: liver disease (cirrhosis), thrombosis, autoimmune dz (lupus, nephritis, vasculitis, arthritis)
DDX: antiphospholipid syndrome, von Willebrand factor def
DDX: infection, esp HIV, hep C, sepsis, malignancy
DDX: Pseudothrombocytopenia (platelet clumping in the presence of ethylenediaminetetraacetic acid [EDTA])
DDX: Myelodysplasia, Lymphoproliferative, acute leukemia, megaloblastic anemia
DDX: Pregnancy, Isoimmune neonatal purpura
DDX: Drug-induced: alcohol, heparin, quinine/quinidine, sulfonamides, NSAIDS
DDX: Transfusion, Factitious
onset: acute in kids, gradual in adults
LABS: CBC with differential: isolated thrombocytopenia is key finding, WBCs and HGB usu normal unless bleeds
giant platelets on peripheral smear suggest congenital
no specific platelet count is attached to DX of ITP
LABS: coagulation studies usu normal, medscape doesn't think bleeding time is useful
CT: if suspect intracranial bleed, imaging urgent
PALP: spleen not usu enlarged
prevalence of palpable spleen is approx same as that in non-ITP population (3% in adults, 12% in children)
bleeding time mb prolonged but American Society of Hematology practice guidelines discourages using this
BIOPSY: bone marrow BX on pts over 60 or those not responding to TX may be necessary
ITP shows increase in megakaryocyte production (Wiki), otherwise normal marrow (Mayo)
most patients have either normal or diminished platelet production (Medscape)
LABS: test for anti-PLT ABs has 80% specificity and there is no consensus on its use

EPIDEMIOLOGY
incidence approx 50–100 new cases/million/year
in adults: ~66 cases/1,000,000/year
peak incidence in adults age 20-50
in children: 50 cases/1,000,000/year
peak incidence in kids age 2-4
40% of all patients are younger than 10 years
new cases of chronic refractory ITP: ~10 cases/1,000,000/year
US pop of chronic cases: approx 60,000
lower incidence in kids in Denmark and England (10-40)
higher incidence in Kuwait (125)
~half of new cases are in kids age 2-4, usu after a viral infection
1/3 of the chronic cases remit, and 1/3 end up with mild thrombocytopenia (PLTs over 50,000)
recurrence: 6% prevalence of recurrent ITP with most patients (69%) having one recurrence usu w/in 3mo
usu chronic in adults
probability of durable remission: 20-40%
median age of dx for adults: 56-60
slightly more females than males but in kids closer to equal genderwise, widening with age
2.6:1 female in adult chronic pop overall
72% of patients older than 10 years are female
ITP called "an orphan disease" = low prevalence such that busy GP might not see a case/year
ITP does not appear to be hereditary or familial
1% of cases have both AI hemolytic anemia and ITP: Evans syndrome

PROGNOSIS
~83% of children have a spontaneous remission, and 89% of children eventually recover
50%+ recover within 4-8 weeks
70+ percent of childhood cases will remit within six months (txed or not)
~2% die, 1% from hemorrhage
2% of adults have a spontaneous recovery
64% eventually recover
~30% have chronic disease
5% die from hemorrhage
older pts have worser prog than younger (5 year mort 48% over 60 and 2% under 40)

PATHOGENESIS
ABS vs PLTs detected in ~60% of pts
AB targets: platelet membrane glycoproteins IIb-IIIa or Ib-IX
mostly IgG
famous Harrington–Hollingsworth experiment established the immune pathogenesis of ITP
platelets get coated with IgG-->phagocytosis by splenic macrophages
IgG ABs thought to damage megakaryocytes (PLT precursor cells) but this seems to have relatively slight impact
trigger for AI rxn seems to be T cells influenced by drugs that target B cells, such as rituximab

RITUXIMAB
= a chimeric monoclonal antibody against the protein CD20
drug approved 1997 to Tx non-Hodgkin lymphoma that is resistant to other chemo
rituximab destroys any cell with CD20 marker, including both healthy and diseased B cells
now used to treat diffuse large B cell lymphoma and other B cell lymphomas
sold under the trade names Rituxan and MabThera
from IDEC Pharmaceuticals (formed in 1986 by biotech pioneers Ivor Royston and Howard Birndorf)
currently co-marketed by Biogen Idec and Genentech in the U.S. and by Roche in the European Union

PREGNANCY
mom w/ mild ITP usu can have a normal pregnancy and delivery
AB's to PLTs can cross placenta and affect baby's PLT count
newborn's PLT count in this case will probably increase after birth w/o TX
normal within 2 weeks
tx only needed if deficiency is severe
biggest concern is mom bleeds during delivery
~5% of women have low PLTs at the time of delivery, medscape says 7-8%
gestational thrombocytopenia and thrombocytopenia due to preeclampsia are more common than ITP in pregnancy

TREAT WHEN?
if PLTs below 20,000
if PLTs are 20-50,000, watch carefully, no TX
if count is very low (below 10,000) or pt has significant bleeding, hospitalize-->acute care

ACUTE TREATMENT
urgent care for bleeds, airway compromise
**PLT transfusions for emergency bleed
(6-8 U of PLT concentrate, or 1 U/10 kg)
(1 U of PLT to incr count 70-kg adult by 5-10,000/mm3 and an 18-kg child by 20,000/mm3)
**IV steroids (methylprednisolone or prednisone)
**IV immunoglobulin (IVIg) for rapid, temporary PLT increase
for more dosages see: http://emedicine.medscape.com/article/779545-treatment

LONG TERM TREATMENT
after stabilization with meds above, switch to oral steroid (prednisone 1-2 mg/kg/day)
most cases respond in 1st week of tx
after severel weeks on oral steroids the dose is tapered
60-90% of pts relapse if dose decreased below .25mg/kg per day or stopped
SEs of steroids longterm: osteoporosis, cataracts, loss of muscle mass, incr infection, high blood sugar
sometimes the spleen is surgically removed, successful in 60-65%, less in older pts
splenectomies are now laparoscopic, not a major procedure, risk is minimal except for bleeds in these pts

NEW TREATMENT: ANTI-D
"effective" but I can't find any numbers on its effectiveness
patient must be Rh-positive
products incl: WinRho, Rhophylac, RhoGAM
same products that are administered to Rh- women during preg and after birth of Rh+ child
expensive
short term improvement
not recommended if splenectomy already

IMMUNOSUPPRESSANT DRUGS
immunosuppresants (mycophenolate mofetil, azathioprine) also effective
IV immunoglobulin works for less than a month and is expensive, rarely used longterm
sometimes used in pre-splenectomy pts with dangerously low PLTs and poor response to other TX
strategy: prevent bleeds during splenectomy
**rituximab (Rituxan) — most used of this group
**cyclophosphamide (Cytoxan)
**azathioprine (Imuran)
all these unproven with significant side effects
EXTREME CASES
very rare esp in kids
tx with vincristine, chemo, to stop immune system from destroying PLTs
vincristine = vinca alkaloid
significant side-effects
caution!

THROMBOPOEITIN RECEPTOR AGONISTS
strategy: stimulate PLT production
**romiplostim (trade name Nplate)
orphan drug in 2003 under USA law
= thrombopoiesis stimulating Fc-peptide fusion protein (peptibody)
administered by subcutaneous injection
effective in treating chronic ITP
esp post-splenectomy pts
approved by FDA for adult chronic ITP on August 22, 2008
**Eltrombopag (trade name Promacta)
orally-administered
increases PLTS and decreases bleeding in dose dependent manner
developed by GlaxoSmithKline
also designated an orphan drug by the FDA
Promacta was approved by the FDA on November 20, 2008
**AMG 531 and eltrombopag are in clinical trials now, well tolerated, long term SE's unknown

EVEN MORE EXPERIMENTAL
**Dapsone (also called Diphenylsulfone, DDS, or Avlosulfon)
anti-infective sulfone drug
used to tx lupus, RA, and 2nd line tx for ITP
mechanism unclear
limited studies
PLTs increase in 40-50% of pts
**off-label use of rituximab
INTERESTINGLY THIS IS THE DRUG IMPLICATED IN CAUSING ITP
shown in preliminary studies to be an effective alternative to splenectomy in some patients
many pts had significant SEs
small risk of fatality dt progressive multifocal leukoencephalopathy dt reactivated JC virus
randomized controlled trials are lacking
**tamatinib fosdium (R788)
experimental kinase inhibitor
promising results in small phase II study
n = 14 pts, 10 of whom relapsed after splenectomy
9 responded, 6 achieved PLT couns over 100,000
PLATELET TRANSUFIONS
only used in emergencies
does not increase PLTs longterm

HELICOBACTER PYLORI ERADICATION
researchers in Japan and Italy have found a connection between H. pylori and ITP
ABX for H. pylori infx has led to dramatic PLT count increases in some pts
Mayo clinic says results inconsistent, need studies

NAMES
idiopathic or immune thrombocytopenic purpura (most used)
eponym: Werlhof's disease (rarely used)
AKA: essential thrombocytopenia, haemogenia, haemogenic syndrome, haemorrhagic purpura, idiopathic thrombopenic purpura, morbus haemorrhagicus maculosus, morbus maculosis haemorrhagicus, morbus maculosus werlhofii, peliosis werlhofi, primary splenic thrombocytopenia, primary thrombocytopenia, primary thrombocytopenic purpura, purpura haemorrhagica, purpura thrombocytopenica, purpura werlhofii, splenic thrombocytopenic purpura, thrombocytolytic purpura

NATUROPATHIC TX
(just getting started here, suggestions welcome)
if acute/severe, traumatic bleeding, life of limb threat-->hospital for steroids, Ig, PLT transfusion
avoid traumatic injuries from any source! only low-impact sports for this pt
don't fly if PLTs under 60,000 dt risk of intracranial hemorrhage
also no scuba diving, etc
blood support herbs
treating the case: autoimmune
fish oil to reduce inflam, thus reduce overall immune reactivity
avoid NSAIDS which impair PLT fx
limit alcohol intake
watch for infx, esp if post-splenectomy
winter season: elderberry juice to prevent viral transmission, colds, flu
avoid dairy to keep resp system mucus thin
keep emunctories open esp: skin, GI
treatments for chronic viral infection?
treat for H.pylori? 10/28/09: SSL says 48% of ITP pts have underlying H Pylori infx
(ITP resolves when H Pylori is txd, do breath test to eval H pylori load)

*****************************************************************************************
TREATMENT: THERAPEUTIC AMENORRHEA

Obstet Gynecol Surv. 2008 Jun;63(6):395-402; quiz 405.
Therapeutic amenorrhea in patients at risk for thrombocytopenia.
Martin-Johnston MK, Okoji OY, Armstrong A.

Illinois Masonic Medical Center, Chicago, Illinois, USA.
Abstract
To examine the need for and evaluate the method of menses suppression in women at risk for thrombocytopenia. A systematic review of the published literature in MEDLINE using the search terms thrombocytopenia, menorrhagia, therapeutic amenorrhea, progestin intrauterine device, combination oral contraceptive--extended and cyclic, gonadotropin releasing hormone agonist, danazol, and progestins. There are an increased number of reproductive age women at risk for thrombocytopenia who would benefit from menses suppression. A number of effective medical regimens are available. In patients who fail medical therapy, endometrial ablation appears to be effective in women with thrombocytopenia. As a result of the increased number of women at risk for thrombocytopenia, there is a need for therapeutic amenorrhea. The type of regimen selected depends upon the patients need for contraception and the ability to tolerate estrogen-containing medications. For women who fail medical therapy, there are surgical options, which are associated with less morbidity than hysterectomy.

PMID: 18492296 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/18492296
*********************************
NOTES FROM 2010 DR THOM NOTES
suspect if unexplained thrombocytopenia when other disorders have been ruled out
low plt count with otherwise normal CBC
ai dz with incr plt destruction
acute and self limited in children, mb triggered by viral illness
chronic in adults
sx: petechiae, mucosal bleeding, pssible splenomegalyl
dx: bone marrow exam if other abn present in peripheral smear
etio: mbdt splenic sequestrtaion (the larger the spleen the more plts it can hold, will not have bleeding issues b/c epinephrine will cause the spleen to dump the plts into circ during a stress, so low plts on screening but they are hiding in storage.
plt count usu under 30,000
disorders that produce splenomegaly: advanced cirrhosis, myelofibrosis or myeloid metaplasia

other causes of thrombocytopenia:
immune: blood transufsion, CT and lymphoproliferative disorders, drugs, HIV
non-immune: ARDS, gram negative sepsis

THROMBOTIC THROMBOCYTOPENIC PURPURA
etio: def in plasma enzyme ADAMTS13, hemorrhagic colitis dt E Coli 0157:H7 or some shigella strains
pregnancy, drugs (quinine, cyclosporine, mitomycin C), idiopathic
plts destroyed by deposited fibrin strands in small vessels-->thrombi form in multiple organs
high mortality untxd
sx: fever, organ ischemia, confusion, coma, abd pain, arrhythmia, chest pain
dx: us, peripheral blood smear, retic count, serum LDH, renal fx, bili (direct and indirect), Coomb's test (neg)
dx suggested by anemia, thrombocytopenia, RBC framents on blood smear, evidence of hemolysis (falling hgb, polychromasia, elevated retics, neg coumbs), renal abnormalities

HEMOLYTIC UREMIC SYNDROME
HUS = TTP in kids with enterohemorrhagic infx (E Coli 0157:H7 or some shigella
usu spontaneously remits
untxd cases dt other causes oft fatal
most pts have only one incidence of TTP-HUS

**********************************************************************

SOURCES
http://www.mayoclinic.com/health/idiopathic-thrombocytopenic-purpura/DS00844
http://www.nhlbi.nih.gov/health/dci/Diseases/Itp/ITP_WhatIs.html
http://en.wikipedia.org/wiki/Idiopathic_thrombocytopenic_purpura
http://familydoctor.org/online/famdocen/home/common/blood/113.html
http://emedicine.medscape.com/article/779545-overview

http://www.ncbi.nlm.nih.gov/pubmed/18492296

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