THROMBOCYTOPENIA

Report
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
•
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

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