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REVIEW ARTICLE

ADARSH A K, LAKSHMI KRISHNA

INTRODUCTION
ITP or immune thrombocytopenic purpura is
Immune
an autoimmune disorder characterized by increased Thrombocytopenic
platelet destruction & platelet count < 1 lakh . It is
seen in both children & adults. In children, it is usu- Purpura
ally acute and self limited whereas in adults it usu-
ally is insidious in onset and chronic .Pathogenesis
of the disease is complex
CLASSIFICATION
Primary Secondary Adarsh A. K
Not associated with Associated with other Junior resident
a secondary cause diseases like infections, Lakshmi Krishna
autoimmune diseases, Lecturer
malignancies, etc Dept of General Medicine
Childhood onset Adult onset Medical College, Calicut
Sudden onset Insidious in onset
Usually acute chronic
< 5 years Young adults
Equal incidence in
boys & girls Female preponderance
Preceding viral
infection No such history
Self limited indolent

The guidelines on ITP are published by the


American Society of Hematology ( ASH )-2011 &
International ITP Working Group (IWG )-2009 .

CLINICAL PROCEEDINGS 19
NEW IWG DEFINITIONS pression of cytotoxic genes like granzyme a, granzyme
Newly diagnosed- < 3 months b and perforin causing platelet destruction. T cells
are also involved in the release of cytokines which
Persistent - > 3 months
also interfere with megakaryocyte maturation and/or
Chronic - > 12 months platelet release
Severe- Bleeding symptoms at presentation 3-Fc Receptors and Role of Spleen- Platelets
needing remediation OR Occurrence of fresh bleed- coated with IgG autoantibodies undergo an acceler-
ing symptoms requiring increase in dose or new drug ated clearance through FC gamma receptors expressed
Refractory- Presence of severe ITP after sple- by tissue macrophages, predominantly in the spleen
nectomy and liver . The destruction of platelets by the mono-
Response -Platelet count > 1 lakh measured nuclear phagocyte system (MPS) leads to presentation
on 2 occasions 7 days apart OR Platelet count of additional platelet antigens to the immune system .
>30000 and a greater than twofold increase in plate- therefore, autoantibodies have specificity directed to
let count from baseline measured on 2 occasions multiple glycoproteins—anti-GP IIb/IIIa ,anti-GPIb/IX
7days apart and anti-GPIa/IIa
3-Impaired megakaryocytopoiesis –There is
EPIDEMIOLOGY compensatory increased platelet production in pa-
Multimodal incidence with one peak in child- tients with ITP but it is inadequate, indicating that
hood and second and third peaks in young adults antiplatelet glycoprotein antibodies & T cells have ef-
and the elderly. The incidence of primary ITP in adults fects not only on platelets but also on megakaryocytes
is 3.3/100000 adults per year .Prevalence is 9.5 per leading to impaired platelet release
100000 adults. There is predilection for female pa-
tients in younger adults but equal prevalence among Virus-associated ITP
elderly ( >65 years ) males & females Acute ITP often occurs following a viral illness.
PATHOGENESIS Viral infection is cleared normally but initiates ITP.
Mechanism is molecular mimicry or B-cell stimula-
1-Pathologic antiplatelet antibodies – tion. Commonly seen with HIV, HCV, EBV
Harrington et al in 1951 described a factor in the
plasma of ITP patients which when transfused into Bacteria-associated ITP: H. pylori
normal subjects induced thrombocytopenia in them.
Increased prevalence of H. Pylori is seen in pa-
It was later identified as antiplatelet autoantibody
tients with ITP with a response rate of between 38%
against glycoproteins in the platelet membrane. Dixon
and 73% in patients in whom H. pylori is eradicated.
and Ross in1975 quantified the platelet associated
Patients with newly diagnosed ITP and those with
IgG .These autoantibodies are produced by B cell,
milder thrombocytopenia are more likely to improve
driven by CD4+ helper T cells.
in their platelet counts following eradication of H.
2-T-cell–mediated destruction of platelets -In pylori
ITP, there is Th1 bias, compared with Th2
characterised by increased expression of genes in- Drug-associated ITP
volved in the Th1 cell response-INF gamma and IL-2
Drug induced development of immune
receptor-beta leading to autoimmunity. The direct
dysregulation & autoimmunity can be seen with
cytotoxic effect of T cells also leads to increased ex-

20 CLINICAL PROCEEDINGS
Alemtuzumab & purine analogs Petechiae, purpura, and easy bruising are the
most common manifestations. Epistaxis, gingival
Genetics factors in ITP bleeding, and menorrhagia are common. Overt
ITP has been diagnosed in monozygotic twins gastrointestinal bleeding and gross hematuria are rare.
and in several families indicating propensity for au- Intracranial hemorrhage is very uncommon. Wet pur-
toantibody production in family members. However, pura & retinal haemorrhages herald life threatening
no consistent association between ITP and specific bleeds. Younger patients tolerate low platelet levels
MHC class I or class II polymorphisms have been better than the elderly. Bleeding can be aggravated
identified by antiplatelet drugs like aspirin, viral infections or
Secondary Itp trauma
Seen with Antiphospholipid syndrome, Anemia in ITP
Systemic lupus erythematosus , Evans syndrome, Post- ITP per se, does not cause anemia. Chronic
hematopoietic cell transplantation ITP, Sarcoidosis , blood loss can lead to iron deficiency anemia con-
Chronic lymphocytic leukemia, Autoimmune tributed by nutritional anemia . Evan’s syndrome can
lymphoproliferative syndrome , etc… cause ITP with associated autoimmune hemolytic
anemia
CLINICAL FEATURES Correlation between bleeding and the platelet
Childhood ITP-Typically develops in a healthy count
child with a preceding history of viral infection Bleeding in ITP is less severe at equivalent plate-
presenting with petechiae or mucosal bleeding. It is let counts than in thrombocytopenia due to marrow
a self-limited with spontaneous recovery in the aplasia or chemotherapy-induced marrow suppres-
majority sion. Bleeding tendency generally occurs with plate-
Adult ITP-Insidious in onset with no preced- let counts < 30,000/cu mm. Major severe bleeding
ing viral or other illness. Sometimes it may be occurs with platelet counts < 20,000/cu mm, usu-
incidentally detected in an asymptomatic patient ally < 10,000/cu mm

Figure 2-petechiae & wet purpura

CLINICAL PROCEEDINGS 21
APPROACH
Features consistent Features not consistent
` History :Drugs, herbal medication, systemic with diagnosis of ITP with diagnosis of ITP
diseases
Thrombocytopenia:
` Physical examination: normal except bleeding
Platelet size normal
manifestation and anemia, No splenomegaly or larger. Predominant
` Determine the type of bleeding and distinguish giant platelets
‘platelet-type’ from ‘coagulation-type’ (approaching the size
` Assess the severity, extent and duration of of erythrocytes) should Predominant giant
bleeding be absent platelets
` Determine the presence of medical conditions, Normal red cell Red blood cell
which may be associated with autoimmune morphology poikilocytosis,
thrombocytopenia schistocytosis,
` Identify conditions, which may aggravate risk of macrocytes, nucleated
bleeding: peptic ulcer, renal stones, and severe red cells,
hypertension polychromatophilia
(unless as a response
ITP is a diagnosis of exclusion. Only two crite-
to bleeding)
ria need to be satisfied
Normal white blood cell Leukocytosis or leuko-
1. Isolated thrombocytopenia is present( except for
penia, morphology
other coincidental abnormalities such as iron
immature or abnormal
deficiency)
leucocytes(In child-
2. Clinically apparent associated conditions (eg, hood ITP atypical
systemic lupus erythematosus, antiphospholipid lymphocytes oreosino-
syndrome, chronic lymphocytic leukemia) are not philia may be seen)
present
INVESTIGATIONS 2 .Autoimmune screening
1.Peripheral Smear- For evidence for other causes of 3. LFT,USG abdomen to exclude CLD
thrombocytopenia & to exclude “pseudothrombo- 4. HIV, HCV
cytopenia”-due to EDTA dependent platelet 5. Coomb’s test
agglutinins
6. Antiplatelet Antibodies— neither sensitive nor spe-
Artifacts affecting platelet counting cific for ITP & not recommended in the diagnostic
• Cold-dependent platelet agglutinins and autoanti- work-up
bodies causing “rosetting” of platelets around 7.Helicobacter pylori—IWG recommends H pylori
neutrophils or monocytes stool antigen testing in all patients with ITP
• Giant platelets 8. Bone Marrow Examination
• Cryoglobulin particles may be counted as IWG guidelines suggest to do bone marrow
platelets examinations in patients 60 years old or more with
newly diagnosed ITP. However, ASH guidelines 2011

22 CLINICAL PROCEEDINGS
do not suggest bone marrow examination in any pa- definitive treatment is made. Long-term glucocorticoid
tient population if diagnosis of ITP is sure treatment is not appropriate in view of its side effects.
But, a marrow examination is mandatory in Patients treated with prednisone for more than three
patients with lassitude , protracted fever, bone or joint months require calcium and vitamin D supplementa-
pain & unexplained macrocytosis or neutropenia tion with monitoring of bone mineral density
In children, bone marrow examination is not b.High dose dexamethasone
necessary if management involves observation or in- 40 mg per day (either orally or intravenously)
travenous immune globulin. Aspiration should be for four consecutive days can produce an early re-
performed before starting corticosteroids to rule out sponse compared to prednisone
acute leukemia . The British guidelines for ITP in chil-
c.High dose methylprednisolone
dren recommend bone marrow to be examined be-
fore steroid therapy is given 30 mg/kg intravenously over the course of one
hour for 1-3 days
9.Immunoglobulin levels-IgA deficiency
2.Intravenous immunoglobulin and anti-D
TREATMENT Increase the platelet count in most patients with
Treatment needs an individualised approach. It ITP, including patients who have not responded to
is to treat the patient & not the platelet count & to corticosteroids.
provide a safe platelet count to prevent major bleed- Dose—IVIg — 1 g/kg per day, given for one to
ing, rather than returning the platelet count to normal. two days ; Anti-D — 50 to 75 mcg/kg per day, given
Platelet < 30,000 needs treatment whether symptom- once
atic or not whereas asymptomatic & platelet > 30,000 Anti-D is effective only in Rh-positive patients
needs no treatment & only observation & in patients who have not had splenectomy . Anti-D
First line drugs causes immune-mediated clearance of the sensitized
1.Glucocorticoids erythrocytes which occupy the Fc gamma receptors
a.Prednisone in splenic macrophages ,minimizing removal of anti-
body-coated platelets. Hence, a modest amount of
Oral prednisone , 1 mg/kg as a single daily dose hemolysis is expected
for 2-4 weeks.Most adults respond within two weeks.
Duration of initial prednisone treatment is determined No long-term remission is seen with both. They
by the platelet count response .If the platelet count are valuable in a patient with life-threatening bleed-
recovers promptly to normal, the prednisone dose is ing, or in preparing for splenectomy or other surgical
tapered and discontinued. There is no standard regi- procedures. Either IVIg or anti-D may be used as a
men for tapering the prednisone dose. It is ideal to first-line treatment if corticosteroids are contraindi-
taper and discontinue prednisone over four to six cated.
weeks after achieving a normal platelet count. Persis- Second-line management after failure of initial
tent symptomatic and severe thrombocytopenia (plate- therapy
let count <10,000/microL) after two weeks of pred- 1.Splenectomy
nisolone needs additional treatment. Similarly, severe Splenectomy removes the major site where an-
bleeding also require additional treatment immediately tibody-coated platelets are trapped and destroyed by
. If thrombocytopenia recurs after stopping prednisone, the reticuloendothelial system & also leads to decrease
it is temporarily resumed until a decision for more

CLINICAL PROCEEDINGS 23
in the B-lymphocytes responsible for anti-platelet an- Thrombopoiesis-stimulating agents
tibody production. It is the most effective treatment Are used in ITP in adults with insufficient
for ITP with the highest rate of complete and durable response to corticosteroids, immunoglobulins, or sple-
remissions ,ie,60-70 %. Complications include risks nectomy ; who have a contraindication to splenec-
of surgical procedure, increased susceptibility to seri- tomy and who have failed at least one other therapy;
ous infection, thrombosis risk & pulmonary hyperten- who have failed one line of therapy such as corticos-
sion. Immunization at least two weeks prior to sple- teroids or IVIg and who are not willing for splenec-
nectomy for Streptococcus pneumoniae, Haemophilus tomy .TPO-RA (romiplostim and eltrombopag) are US
influenzae B, and Neisseria meningitidis & penicillin FDA approved for adults with chronic ITP.
prophylaxis daily for atleast 1 year after splenectomy Eltrombopag is approved for use in children as well.
are recommended Side effects include headache, nasopharyngitis,
2.Rituximab upper respiratory infection, fatigue, transaminitis,
Rituximab, the anti CD 20 monoclonal antibody thromboembolism, reticulin deposition in bone
is used when glucocorticoids have been ineffective marrow & rebound thrombocytopenia after
and who are not candidates for splenectomy or who discontinuation
have failed to achieve a response to splenectomy. It is Immunosuppressives
typically administered as a single agent at a dose of 1.6-mercaptopurine 50-75 mg/m2 orally once
375 mg/m 2 /week for four weeks. Rituximab after sple- per day ; side effects-Hepatotoxicity, neutropenia, in-
nectomy is effective in both adults and children with fection, pancreatitis
refractory ITP (ie, ITP for which splenectomy was in- 2.Azathioprine 1-2 mg/kg orally once per day
effective). Complications include infusion reactions, (maximum 150 mg/d) ; side effects-Hepatotoxicity,
prolonged immunosuppression, reactivation of hepa- neutropenia, infection, pancreatitis
titis B & very rarely progressive multifocal leukoen-
cephalopathy . Initial response rates are 40% to 60% 3.Cyclosporin A 5-6 mg/kg/d orally divided into
& long-term response rate is 20% at 5years post 2 doses per day (titrate to blood levels of 100-200 ng/
initial rituximab treatment mL) ; side effects-Nephrotoxicity, hypertension, tremor,
parathesias, gingival hyperplasia
CHRONIC REFRACTORY ITP 4.Cyclophosphamide 0.3-1.0 g/m2 IV repeated
Defined as ITP with plt < 50000 lasting > 3 once every 2 to 4 weeks 1 to 3 doses; 50-200 mg
months & failed response to splenectomy & rituximab orally once per day; after response has been achieved,
dose can be tapered to 50 mg ; side effects-Neutrope-
Management of refractory ITP
nia, nausea/vomiting, infertility, secondary malignancy
• No bleeding & plt > 30000 - observation
5.Danazol 50-800 mg/d orally divided into 2 to
• Persistent symptomatic thrombocytopenia 4 doses per day ; side effects-Hepatotoxicity, viriliza-
between 20000-30000 - thrombopoiesis stimulating tion, amenorrhea
agents
6.Dapsone 75-100 mg orally once per day ; side
• Lack of response with thrombopoiesis stimu- effects-Hemolysis (in patients with G6PD deficiency),
lators - observation with supportive care with IVIg or rash, nausea, methemoglobinuria
steroid pulse at time of major bleeding
7.Mycophenolate mofetil 250-1000 mg orally
• Persistent symptomatic thrombocytopenia < twice per day; side effects-Headache, diarrhea,
20000 - immunosuppressive agents

24 CLINICAL PROCEEDINGS
nausea, anorexia, infection fetus lacks enzyme for converting azathioprine to its
8.Vinca alkaloids -Vincristine: 1 to 2 mg IV once active form. Use of anti-RhD immune globulin,
per week for 3 weeks ; Vinblastine: 10 mg IV once cyclosporine, and rituximab are reported with good
per week for 3 weeks; side effects-peripheral outcomes but cannot be routinely recommended.
neuropathy, constipation There are a few reports of successful romiplostim
therapy & recombinant human thrombopoietin in se-
Role of platelet transfusion- Provide critical tem-
vere refractory thrombocytopenia in pregnancy
porary hemostatic support
ITP IN SLE REFERENCES
HARRISON’S PRINCIPLES OF INTERNAL MEDICINE-
Is due to immunologic platelet injury & similar
19th edition
to ITP. 5-15 % of ITP patients satisfy diagnostic crite-
UPTODATE MEDICINE 2013
ria for SLE at presentation. Others may have positive
ANA at presentation; A few progress to SLE in several API TEXT BOOK OF MEDICINE-10th edition
years . High ANA titre & speckled pattern have a high ASH ITP pocket guide-2011
risk of progression to SLE. Thrombocytopenia corre- REVIW ARTICLE – ITP-NEJM MEDICAL PROGRESS 2002
lates with SLE disease activity. ITP in SLE to be treated How I treat refractory immune thrombocytopenia; Adam
on same grounds as ITP, but role of splenectomy con- Cuker -Department of Medicine and Department of
troversial Pathology and Laboratory Medicine, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, PA;
ITP IN PREGNANCY and Cindy E. Neunert-Department of Pediatrics, Columbia
ITP is the most common cause of thrombocy- University, New York, NY
topenia in the ûrst trimester. There are no fertility is- Clinical updates in adult immune thrombocytopenia;
sues for ITP patients. But pregnancy is contraindicated Michele P. Lambert-Gernsheimer Division of
for patients on immunosuppressives except azathio- Hematology, The Children’s Hospital of Philadelphia,
Philadelphia, PA; and Terry B- Division of Hematology,
prine. Therapy however does not appear to affect the
University of Washington School of Medicine, Seattle,
neonatal risk of thrombocytopenia. Treatment is di-
WA
rected towards maintaining a safe platelet count in
High-dose dexamethasone vs prednisone for treatment
the mother, generally considered 30,000 throughout
of adult immune thrombocytopenia: a prospective
pregnancy & 50,000 towards delivery. Pregnancy multicenter randomized trial-BLOOD article
needs to be managed like a normal pregnancy .
Role of Helicobacter pylori eradication therapy on platelet
Caesarean is done only for obstetric indications.
recovery in chronic ITP; Sheema K, et al. Gastroenterol
Epidural anaesthesia requires a platelet count 75000- Res Pract 2017.
80000.
First-line therapy include intravenous
immunoglobulin(IVIg) or corticosteroids. Prednisolone
is the preferred steroid. Both are similarly eficacious
in increasing platelet counts. Patients
refractory to first-line treatment can be treated with
combination of IVIg and corticosteroids. Options for
second-line therapy are limited by fetal risk. Azathio-
prine may be used as a steroid sparing agent as the

CLINICAL PROCEEDINGS 25