THROMBOCYTOPENIA
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Transcript THROMBOCYTOPENIA
THROMBOCYTOPENIA
Curs an IV - limba engleza
2012-2013
Background
• 1/3 of all Hematology Consults in a General
Hospital are for thrombocytopenia
• 5 to 10% of all hospital patients are
thrombocytopenic in the ICU the number
increases to 35%
• Thrombocytopenic patients in the hospital
suffer a twofold greater mortality rate than
those who are not
Platelet Kinetics
• Normal circulating platelet count
– 150.000 to 450.000/mmc in Northern Europeans
– 90.000 to 300.000/mmc in people of
Mediterranean descent
• 1/3 of platelets are sequestered in the spleen
• Half life of a platelet is 9 to 10 days
• Platelet production is the function of the
multinucleated megakaryocyte
• 15.000 to 45.000 platelets are produced daily
to maintain steady state
Thrombopoietin (TPO)
• TPO is the primary regulatory protein in the
production of platelets
• TPO gene is on chromosome 3
• TPO is expressed in the liver, kidneys, and smooth
muscle cells
• Has a plasma half life of 30 hours
• The receptor for TPO is c-MPL which is present on
the megakaryocytes and platelets
• TPO rises with platelet fall and declines as the
megakaryocyte and platelet mass increase
Thrombocytopenia – risk of bleeding
• The primary reason for evaluating thrombocytopenia
is to assess the risk of bleeding and assess the
presence of underlying disorders (TTP, HIT etc.)
– < 20.000/mmc increased risk of bleeding
– 20.000 – 50.000/mmc rarely have increase risk of
spontaneous bleeding but increase risk of bleeding
from procedures
– 50.000 – 100.000/mmc no increased risk of
spontaneous bleeding and can undergo most
procedures
Thrombocytopenia mechanisms
• Decreased production
• Increased destruction
• Increased consuption
• Sequestration
• Pseudothrombocytopenia
Pseudothrombocytopenia
• Artifactually low platelet count due to in vitro
clumping of platelets
• Usually caused by antibodies that bind platelets only
in presence of chelating agent (EDTA)
• Seen in healthy individuals and in a variety of disease
states
• Diagnosis:
Marked fluctuations in platelet count without apparent
cause
Thrombocytopenia disproprotionate to symptoms
Clumped platelets on blood smear
Platelet count varies with different anticoagulants
Pseudothrombocytopenia
Platelet clumping in EDTA
No clumping in heparin
Decreased Platelet Production
• Marrow failure (pancytopenia)
aplastic anemia, chemotherapy, toxins
• B-12, folate or (rarely) iron deficiency
• Viral infection
• Drugs that can selectively reduce platelet production
Alcohol
Estrogens
Thiazides
Chlorpropamide
Interferon
• Amegakaryocytic thrombocytopenia
myelodysplasia (pre-leukemia)
immune? (related to aplastic anemia)
• Cyclic thrombocytopenia (rare)
• Inherited thrombocytopenia
Increased Platelet Consumption
• Intravascular coagulation (DIC or
localized)
• Microangiopathy – TTP, Hemolyticuremic sdr
• Damage by bacterial enzymes, etc
Thrombocytopenia and Infection
• Immune complex-mediated platelet destruction
Childhood ITP
Bacterial sepsis
Hepatitis C, other viral infections
• Activation of coagulation cascade
Sepsis with DIC
• Vascular/endothelial cell damage
Viral hemorrhagic fevers
Rocky Mountain Spotted Fever
• Damage to platelet membrane components by bacterial
enzymes (eg, S pneumoniae sialidase)
• Decreased platelet production
Viral infections (EBV, measles)
• Mixed production defect/immune consumption
HIV infection
Immune Platelet Destruction
• Autoimmune (ITP)
Childhood
Adult
• Drug-induced
Heparin
Quinine, others
• Immune complex (infection, etc)
• Alloimmune
Post-transfusion purpura
Neonatal purpura
Idiopathic (Immune)
Thrombocytopenic Purpura (ITP)
• Thrombocytopenia in the absence of
other blood cell abnormalities (normal
RBC & WBC, normal peripheral smear)
• No clinically apparent conditions or
medications that can account for
thrombocytopenia
ITP - Epidemiology
• ITP is a high prevalence disease 16 to 27 per
million per year
• Incidence increases with age
• Female predominance under the age of 60 but
not over the age of 60
• It can have an abrupt onset or insidious onset.
It is generally abrupt in onset with children
ITP – Clinical forms
• Childhood form (most < 10 yrs old)
May follow viral infection, vaccination
Peak incidence in fall & winter
~50% receive some treatment
≥75% in remission within 6 mo
• Adult form
No prodrome
Chronic, recurrences common
Spontaneous remission rate about 5%
ITP - Pathogenesis
• Increased platelet destruction
antiplatelet antibodies
caused by
• Lack of compensatory response by
megakaryocytes due to suppressive effect of
antiplatelet antibodies
• Pathogenesis was proved by Harrington when
he infused himself with plasma from a women
with ITP
ITP - Pathogenesis
• ITP plasma induces thrombocytopenia in normal
subjects
• Platelet-reactive autoantibodies present in most cases
Often specific for a platelet membrane glycoprotein
• Antibody coated
macrophages
platelets
cleared
by
tissue
Most destruction in spleen (extravascular)
• Most subjects have compensatory increase in platelet
production
• Impaired production in some patients
Intramedullary destruction?
Enhanced TPO clearance?
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ITP - Clinic
• Abrupt onset (childhood ITP) / Gradual onset (adult ITP)
• Common signs, symptoms, and precipitating factors include the
following:
• Mucocutaneous bleeding
– Purpura – petechiae, echymosis
– Menorrhagia, metrorrhagia
– Epistaxis, gingival bleeding
– Recent live virus immunization, recent viral illness
(childhood ITP)
– Bruising tendency
– GI bleed, CNS bleed = RARE
• Absence of constitutional symptoms or splenomegaly
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ITP – Clinical manifestations
ITP – Clinical manifestations
ITP – Clinical manifestations
ITP - Diagnosis
• ITP is a Diagnosis of Exclusion
• No laboratory test can diagnose ITP
• Need to exclude other causes of
thrombocytopenia
ITP - Associated Disorders
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SLE
Antiphospholipid syndrome
CLL
Large granular lymphocyte syndrome
Autoimmune hemolytic anemia (Evans syndrome)
Common variable immune deficiency
Autoimmune lymphoproliferative disorder (ALPS)
Autoimmune thyroid disease
Sarcoidosis
Carcinomas
Lymphoma
H pylori infection
Following stem cell or organ transplantation
Following vaccination
HIV infection
Evaluation of Patient with Low
Platelets
• History
– Has the patient ever had a normal platelet count?
– Carefully review medications, including OTC meds.
• Antibiotics, quinine, anti-seizure medications
– Ask about other conditions which may be associated with low
platelets
• Liver Disease/hepatitis
• Thyroid Disease - both hypo- and hyper• Infections: viral, rickettsial
• Pregnancy
– Ask about other conditions which may be associated with ITP
• Lupus, CLL, lymphoma
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Evaluation of Patient with Low
Platelets
Physical
– Evaluate for lymphadenopathy and splenomegaly
– Look for stigmata of bleeding
– Blood blisters and oral petechiae, ie “Wet Purpura”
• best harbinger of intracranial hemorrhage
• Laboratory Data
– Other blood counts should be normal.
– Check B12 and folate levels.
– Look at peripheral smear to exclude pseudothrombocytopenia,
also exclude TTP (especially if anemia also present.)
– Send coagulation screens (PT/PTT) to exclude DIC
– Send HIV, hepatitis serologies and TSH
• Consider doing a bone marrow biopsy
– Megakaryocytes should be present.
ITP - Evaluation
• Features consistent with the diagnosis of ITP
– Thrombocytopenia with normal or slightly large platelets
– Normal RBC morphology and number (may have
associated iron def or thallasemia etc.)
– Normal white cell number and morphology
– Splenomegaly rare
• Features not consistent with the diagnosis of ITP
– Giant platelets
– RBC abnormalities ie schisotocytes
– Leukocytosis or Leukopenia
ITP - Laboratory evaluation
– Platelet associated immunoglobulin reflect plasma
concentration and alpha granule concentration
– Bone Marrow not very helpful as initial test
• May be helpful in patient over 50 years and concerned
about MDS
• If patient has failed initial treatment and diagnosis is in
question
– TSH and HIV test helpful, Peripheral Smear
helpful
ITP – Confirmatory Laboratory
Testing
• Serum antiplatelet
sensitivity)
antibody
assay
(poor
• Test for specific anti-platelet glycoprotein
antibodies (more specific, negative in 10-30%)
Confirmatory testing not necessary in
typical cases
ITP- Principles of Management
• Most patients with ITP do not have clinically
significant bleeding
– Risk of intracranial bleed 0.1 to 1% (This is an
overestimate)
– Wet Purpura ie epistaxis, gingival bleeding is a
risk factor for major bleeding
• In asymptomatic patients with platelets counts
greater then 20 K observation is reasonable
ITP - Pharmacologic Management
• Steroids
– Prednisone 1mg/kg/day with taper over 2 to 3
months
– Decadron 40 mg/day x 4 days
– Solumedrol 1 gram/day x 2 days
• Antibodies
– IVIG 1 gram/day x 2 days
– Anti-D 50 mcg/kg IV x1
ITP - Management
• Splenectomy
– Immunize with Pneumovax, Hib, Meningococcal
• Chronic Anti-D therapy
– Does not put the disease in remission
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Rituximab
Immunosuppressive treatment
AMG 531, Eltrombopag c-MPL agnonists
Observation
ITP – Glucocorticoid Therapy
• Mechanism of action: Slows platelet destruction, reduces
autoantibody production
• Prednisone, 1-2 mg/kg/day (single daily dose)
• Begin slow taper after 2-4 weeks (if patient responds)
• Consider alternative therapy if no response within 3-4 weeks
• About 2/3 of patients respond (plts > 50K) within 1 week
• Most patients relapse when steroids withdrawn
Advantages: high response rate, outpatient therapy
Disadvantages: steroid toxicity (increases with time and dose), high
relapse rate
ITP - Management of
Asymptomatic Adult
• If platelet count is >40.000-50.000/mmc, no
therapy is required. Check platelet counts at
designated intervals.
• If platelet count is < 20.000-30.000/mmc, begin
therapy with corticosteroids.
• Stop all NSAIDS and ASA to improve platelet
function.
ITP - Initial Management of
Adult with Symptomatic Purpura
• If platelet count is >10.000/mmc, treat with
prednisone alone - use 1 mg/kg.
• If platelet count <10.000/mmc, treat with
prednisone, but also add IVIg 1g/kg/d x 2d. may require admission
• Along with prednisone, add Calcium and
Vitamin D to prevent bone loss.
• If patient has severe bleeding, may need platelet
transfusions.
ITP - Subsequent Management of
Adult with Symptomatic Purpura
• Follow platelet counts daily until >20, then can d/c
patient with close follow-up
• Once platelet count normalizes, commence a slow
steroid taper over 6-8 weeks.
• 1/3 of adults will have gone into remission.
• 2/3 of patients will relapse during or after steroid
taper.
Management of Relapsed ITP
Splenectomy
• Splenectomy is effective in 2/3 of patients, leading to
normal platelet counts.
• Almost all responses occur within 7-10 days of
splenectomy
• Can be performed via open method or laparoscopically.
• Need to vaccinate against encapsulated bacteria 2 weeks
before procedure.
• May need steroids and/or IVIg before procedure to boost
platelet counts preoperatively.
• Operative mortality < 1%
• Indication: Steroid failure or relapse after steroid Rx (persistent
severe thrombocytopenia or significant bleeding)
Management of Relapsed ITP Intravenous immunoglobulin therapy
• Possible mechanisms of action:
Slowed platelet consumption by Fc receptor blockade
Accelerated autoantibody catabolism
Reduced autoantibody production
• Dose: 0.4 g/kg/d x 5 days (alternative: 1 g/kg/d x 2 days)
• About 75% response rate, usually within a few days to a week
• Over 75% of responders return to pre-treatment levels within a
month
• Advantages: rapid acting, low toxicity
• Disadvantages: high cost, short duration of benefit, high relapse
rate
• Indications: Lifethreatening bleeding; pre-operative correction of
platelet count, steroids contraindicated or ineffective
Management of Refractory ITP
• One third of patients will have an inadequate
response to splenectomy.
• Management of these patients involves accepting that
they have a chronic, incurable condition.
• Target platelet counts should be lower--aim for about
30.000/mmc or absence of bleeding.
Treatment of Refractory ITP
• Immunosuppressive agents
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Rituximab (anti-CD20)
Mycophenolate mofetil
Cyclophosphamide
Vinca alkaloids
Accessory splenectomy
Danazol
Colchicine
Eradication of H. pylori, if present
Adjunct agents
– Thrombopoietin Receptor Agonists
• Romiplostim
• Eltrombopag
Special aspects
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ITP and H Pylory
• Up to 50% of patients with ITP and
concomitant H pylori infection improve after
eradication of infection
• Confirm infection via breath test, stool antigen
test or endoscopy
• Higher response rates in:
• Patients from countries with high
background rates of infection
• Patients with less severe thrombocytopenia
Thrombocytopenia and Pregnancy
• Benign thrombocytopenia of pregnancy
Occurs in up to 5% of term pregnancies
Accounts for about 75% of cases of
thrombocytopenia
Asymptomatic, mild, occurs late in gestation
• Microangiopathy (Preeclampsia/eclampsia,
HELLP)
• ITP (? increased incidence in pregnancy)
ITP In Pregnancy
• Mild cases indistinguishable from gestational thrombocytopenia
• Rule out eclampsia, HIV etc
• Indications for treatment
platelets < 10.000/mmc
platelets < 30.000/mmc in 2nd/3rd trimester, or with bleeding
• Treatment of choice is IVIg
corticosteroids may cause gestational diabetes, fetal toxicity
• Splenectomy for severe, refractory disease
some increased risk of preterm labor; technically difficult in 3rd
trimester
• Potential for neonatal thrombocytopenia (approx 15% incidence)
consider fetal blood sampling in selected cases
consider Cesarian delivery if fetal platelets < 20.000/mmc