IDIOPATHIC/IMMUNE THROMBOCYTOPENIC

PURPURA

(ITP)

“Everybody bleeds sometimes,

I just bleed more………..”

Dr. Mohib Ali

• A 17 yr old adolescent is brought to the ER by her mother who is

concerned that she has bruised easily over the past few days and

has had a nose bleed this morning. There are no symptoms of other

illness and she is otherwise well. On examination there are

generalized petechiae and some bruising mainly affecting the

lower limbs. Blood testing reveals a platelet count of 35 * 109, but

the platelets are normal size. Hemoglobin is 11.1 g/dl and her white

blood cell count is normal. What diagnosis fits best with this clinical

picture ?

i. Immune thrombocytopenic purpura (ITP)

ii. Henoch Schonlein purpura

iii. Thrombotic thrombocytopenic purpura (TTP)

iv. Hemolytic Uremic Syndrome (HUS)

v. Generalized Bone Marrow Suppression

Platelets

• Platelets are released from the megakaryocyte.

• The normal blood platelet count is 150,000–450,000/L.

• The major regulator of platelet production is the hormone

thrombopoietin (TPO), which is synthesized in the liver.

• Synthesis is increased with inflammation and specifically

by interleukin 6.

• A reduction in platelet and megakaryocyte mass

increases the level of TPO, which then stimulates

platelet production.

• Platelets circulate with an average life span of 7 to 10

days.

• Thrombocytopenia can be broadly classified into five

categories based on the mechanism behind reduce

platelet count ;

– Pseudo or Spurious Thrombocytopenia

– Dilutional Thrombocytopenia

– Decreased Platelet Production

– Increased Platelet Destruction

– Altered Distribution of Platelets (Increased

Sequestraion)

Decreased

production of

platelets

Increased

destruction of

platelets

Increased

sequestration of

platelets

Other conditions

causing

thrombocytopenia

Congenital Bone

marrow failure(e.g.

fanconi anemia,

Wiskott-Aldrich

syndrome)

Immune

Thrombocytpenia

(including Hep C

& HIV related &

drug induced)

Hypersplenism

(e.g. related to

cirrhosis,

myeloproliferative

disorders,

lymphoma)

Gestational

thrombocytopenia

Acquired Bone

marrow failure (e.g.

Aplastic anemia,

myelodysplasia)

HIT , TMA , DIC ,

Post transfusion

purpura ,

Hemophagocytosi

s

Bernard-Soulier

syndrome , grey

platelet syndrome,

May-hegglin anomaly

Exposure to

chemotherapy,

irradiation

Neonatal

alloimmune

thrombocytopenia

Psudothrombocytope

nia

Marrow infiltration

(neoplastic,

infectious)

Von Willebrand

disease type2

Nutritional (def. of

vit.B12, folate, iron;

Mechanical (aortic

valvular

DRUGS THAT ARE STRONGLY ASSOCIATED

WITH THROMBOCYTOPENIA

ANTIBIOTICS AND

ANTIVIRALS

• Quinine/quinidine

• Penicillins

• Cephalosporins

• Vancomycin

• Trimethoprim/sulfamethoxazol

e

• Sulfonamides/sulfonylureas

• Linezolid

• Valacyclovir

• Ganciclovir

• Indinavir

CARDIOVASCULAR

MEDICATIONS

• Abciximab

• Tirofiban

• Eptifibatide

• Salicylates

• Digoxin

• Furosemide

MISCELLANEOUS

• Cimetidine

• Ranitidine

• Famotidine

• Valproate

• Interferon

Approach to the Thrombocytopenia Patient

• History

– Is the patient bleeding ?

– Do the sites of bleeding suggest a platelet defect ?

– Duration – Is thrombocytopenia acute or chronic ?

– Is there a history of medications, alcohol use, or recent

transfusion (post transfusion purpura) ?

– Are there any symptoms of a secondary illness ?

– (neoplasm , infection, autoimmune disease)

– Is there a family history of thrmobocytopenia ?

– Heparin exposure – recent or within past three months (HIT) ?

– Are there any risk factors for HIV infection ?

– History of liver disease ?

Algorithm for Thrombocytopenia

Evaluation

Platelet count < 150,000/mcl

Hb & WBC count

Normal Abnormal

Peripheral

Smear

Bone Marrow

Examination

Normal RBC

morphology;

platelets

normal or

increased in

size

Fragmented

red blood cells

Microangiopathic

hemolytic anemias

(e.g. DIC, TTP)

Consider:

Drug induced thrombocytopenia

Infection induced thrombocytopenia

Idiopathic immune thrombocytopenia

Congenital thrombocytopenia

Platelets clumped: Redraw in

Sodium citrate or Heparin

ITP

• Immune thrombocytopenic purpura (ITP; also

termed idiopathic thrombocytopenic purpura) is

an acquired disorder in which there is immune-

mediated destruction of platelets and possibly

inhibition of platelet release from the

megakaryocyte.

Clinical Presentation

• Excessive bleeding with minor injuries

• Spontaneous bleeding from mouth & nose

• Unexplainable or spontaneous bruising

• Ecchymoses and Petechiae

• Hematuria

• Menorrhagia

• Intracranial bleed

• Purpura

• Thrombocytopenia

• Which of the following conditions is not associated with

ITP ?

i. SLE

ii. HIV

iii. Tuberculosis

iv. CLL

v. Hep B & C

Classification

• Primary

• Secondary;

– Post-Infectious : HIV, HCV, CMV, H.Pylori

– Antiphospholipid syndrome

– SLE

– Autoimmune thrombocytopenia (e.g. Evan’s

syndrome)

– Lymphoproliferative Disorders : CLL , NHL , HD

– Common Variable Immune Deficiency

– Drug Induced ITP

Types of ITP

ITP can be divided into acute and chronic forms:

Acute ITP

• More commonly seen in children

• May follow an infection or vaccination

• Usually runs a self-limiting course over 1-2 weeks

Chronic ITP

• More common in young/middle-aged women

• Tends to run a relapsing-remitting course

Features Acute ITP Chronic ITP

1 Age Usually 2 to 6 years 20 to 30 years

2 Sex Any Predominant in

female

3 Onset Acute Chronic

4 Previous Infection Common Unusual

5 Platelet Count <20,000/mm3 >20,000/mm3

6 Spontaneous Remission Common Less, <20%

7 Duration 2 to 4 weeks Chronic, months to

years

• In ITP , the autoantibodies are most commonly directed

at ?

A. Platelet activating factor

B. Glycoprotein IIb/IIIa complex

C. ATP receptor

D. Anti-thrombin III receptor

E. ADP Receptor

Pathophysiology

• Increased platelet destruction caused by antiplatelet

antibodies Antibodies directed against platelet

membrane antigens such as glycoprotein IIb/IIIa

The platelets coated with immune complexes bind to Fc

portion of macrophages in spleen and other RES and

are removed

• Lack of compensatory response by megakaryocytes due

to suppressive effect of antiplatelet antibodies

• So a combination of increased platelet destruction +

ineffective megakaryopoiesis

Diagnosis

• Careful and detailed history, clinical examination

• CBC

• Peripheral Smear

• PT , apTT

• LFTs , RFTs

• Hep B & C Serology

• ANA

• Antiphospholipid antibodies

• IgG levels to rule out CVID

• HIV , EBV , CMV Serology

• Bone Marrow Examination

• Nutrient workup (Iron, B12, folate )

When to do Bone Marrow Examination

• Bone marrow examination can be reserved for older

adults (usually >60 years) or

• those who have other signs or laboratory abnormalities

not explained by ITP, or

• in patients who do not respond to initial therapy.

• Megakaryocyte abnormalities and hypocellularity or

hypercellularity are not characteristic of ITP.

Desired Platelet Count Ranges

Clinical Scenario Platelet Count (/mcL)

Prevention of spontaneous

mucocutaneous bleeding

>10,000-20,000

Insertion of Central Venous

Catheters

>20,000-50,000

Administration of

therapeutic anticoagulation

>30,000-50,000

Minor Surgery and selected

invasive procedures

>50,000-80,000

Major Surgery >80,000-100,000

Some Facts

• ITP was originally described in 1735 by a German

physician, Paul Gottlieb Werlhof, and was therefore

known as Werlhof’s disease.

• In 1916, Paul Kaznelson reported the first successful

treatment for ITP after a patient showed a response to

splenectomy

• Splenectomy was then used as the first-line therapy for

ITP until 1950.

Management

Initial Treatment

Prednisone 1 mg/kg/d for 7-10

days followed by rapid taper

Or

Dexamethasone 40mg/d orally

for 4 days monthly for 6 months

IVIG, 1g/kg/d i/v for 2 days

Or

Anti-D, 75mcg/kg i/v for 1 dose

Platelets, if bleeding

+/-

+/-

Relapsed or Persistent ITP

Prednisone 1 mg/kg/d for 7-10 days followed by rapid taper

Or

Dexamethasone 40mg/d orally for 4 days monthly for 6

months

Rituximab

375mg/m2 i/v

weekly for 4

weeks

Anti-D

75mcg/kg i/v

serially as

needed for

platelets <

30,000/mcl

IVIG, 1g/kg/d

i/v for 2 days

serially as

needed for

platelets <

30,000/mcl

Thrombopoeiti

n Receptor

Agonist

Romiplostim

(s/c)

Eltrombopag

(orally)

Splenectomy

(Laparoscopic)

or or or

and

Persistent or Worsening ITP

Mycophenolate mofetil – Azathioprine/Danazol – Cyclosporine -

Chemotherapy

Enrollment in Clinical trial – Autologous transplantation

Splenectomy

(Laparoscopic)

Trial of additional agent(s) above

THERAPY FOR THE INITIAL

MANAGEMENT OF

IMMUNE THROMBOCYTOPENIC

PURPURA

ORAL PREDNISONE

• Effect is dose dependent—approximately 80% of

patients respond to 1 mg/kg/day.

• Toxicity also increases with dose and duration of

treatment and includes glucose intolerance,

immunosuppression, osteoporosis, and cataracts.

Relapse is typical once therapy is discontinued.

• Steroids are presumed to reduce the risk of symptoms in

ITP patients by:

– Reducing antibody production

– Reducing reticuloendothelial system phagocytosis of

antibody-coated platelets

– Improving vascular integrity

– Improving platelet production

INTRAVENOUS IMMUNOGLOBULIN (IVIG)

• More rapid than daily prednisone. Administered at a

dose of 1 g/kg/day for 2 consecutive days or 0.4g/kg/day

for 5 consecutive days.

• Response rates are approximately 80%, and effects

typically last 2-4 wk.

• Toxicity includes headache, allergic reactions, and,

rarely, thrombosis.

ANTI-D IMMUNOGLOBULIN

• Administered at a dose of 50-75 μg/kg IV.

• Response rates are dose dependent but can approach

75-80%.

• Hemolysis is a common toxicity. Rarely, hemolysis can

be life threatening and can be associated with

disseminated intravascular coagulation, renal failure, and

end-organ infarction.

THERAPY FOR THE MANAGEMENT

OF REFRACTORY IMMUNE

THROMBOCYTOPENIC PURPURA

ORAL PREDNISONE

• Effect is dose dependent and rapidly dissipates after

discontinuation of the medication. Some patients can be

maintained on a very low and tolerable daily dose (e.g.,

5 mg).

• Long-term use is associated with infections, diabetes,

osteoporosis, avascular necrosis, weight gain, and

cataracts.

ORAL DEXAMETHASONE

• Administered at a dose of 40 mg/day for 4 consecutive

days. Repeated every 2-4 wk for several months.

• Sustained response rates of 29-42% are possible.

• Toxicity is similar to that of oral prednisone.

SPLENECTOMY

• Durable (often lifelong), significant responses are seen in

65-70% of patients who undergo this procedure.

• Produces lifelong immunosuppression to encapsulated

and gram-positive organisms.

• American Society of Hematology guidelines recommend

waiting until at least 12 months after diagnosis, if

possible.

• When possible, surgery should be performed using

laparoscopic techniques.

When to vaccinate the patient before & after

splenectomy ?

• Patients should receive pneumococcal, Haemophilus

influenza type b, and meningococcal vaccination at least

2 weeks before the procedure.

• Post Splenectomy;

– Pneumococcal 5 yearly

– Meningococcal 3 yearly

– Hemophilus Influenza type b 1 yearly

• RITUXIMAB

• Given at a dose of 375 mg/m2/wk IV for a total of 4 wk.

Significant responses are seen in 28-44% of patients

and typically last for months.

• Toxicity includes reactivation of hepatitis B,

immunosuppression, and, rarely, progressive multifocal

leukoencephalopathy.

• For selected refractory patients, other

immunosuppressives, such as cyclophosphamide,

azathioprine, cyclosporine A, mycophenolate mofetil,

dapsone, interferon, and etanercept, can be used.

• THROMBOPOIETIN RECEPTOR AGONISTS

• Administered daily (eltrombopag) or weekly

(romiplostim).

• An effect is typically seen in 2-3 weeks and disappears

a few weeks after discontinuation of the medication.

• Toxicity from long-term use is not well known but may

include excessive thrombosis and bone marrow fibrosis.

ITP in Pregnancy

• The goal of management of pregnancy-associated ITP is

a platelet count of 10,000–30,000/mcL in the first

trimester,

• > 30,000/mcL during the second or third trimester, and

• > 50,000/mcL prior to cesarean section or vaginal

delivery.

• Moderate-dose oral prednisone or intermittent infusions

of IVIG

are standard.

• Splenectomy is reserved for failure to respond to these

ITP with HIV & HCV

• For thrombocytopenia associated with HIV or hepatitis C

virus, treatment of either infection leads to an

amelioration in the platelet count in most cases;

• Refractory thrombocytopenia may be treated with

infusion of IVIG or anti-D (HIV and hepatitis C virus),

splenectomy (HIV), or interferon-alpha or eltrombopag

(hepatitis C virus, including eradication).

• Treatment with corticosteroids is not recommended in

hepatitis C virus infection.

Response after Initial Treatment

(Steroids)

• Complete Responders

– Platelet count > 100,000

• Partial Responders

– Platelet count 50,000-100,000

• Non Responders

– Platelet count < 50,000

New Terminologies in ITP

i. Complete Response

ii. Partial response

iii. No response

iv. Loss of complete response

v. Loss of response

• Complete response

– A platelet count of >/= 100 * 109/L measured on two occasions

more than 7 days apart and the absence of bleeding.

• Partial response

– A platelet count of >/= 30 * 109/L and a > 2fold increase in

platelet count from baseline measured on two occasions more

than 7 days apart and the absence of bleeding.

• No response

– A platelet count of < 30 * 109/L or a < 2 fold increase in platelet

count from baseline or the presence of bleeding. Platelet count

must be measured on two occasions more than a day apart.

• Loss of complete response

– A platelet count of < 100 * 109/L measured on two occasions

more than a day apart and/or the presence of bleeding.

• Loss of response

– A platelet count of < 30 * 109/L or < 2 fold increase in platelet

count from baseline or the presence of bleeding. Platelet count

must be measured on two occasions more than a day apart.

• A 40-year old lady , 3 years post splenectomy for chronic ITP

presents with a petechial rash and gum bleeding . Her blood count

shows;

– WBC of 6.3 *109 /L

– Hb of 11.5 g/dL

– platlet count of 3*109 /L

• What would be the most appropriate next treatment modality

provided ?

A. Thrombopoietin agonist ( eltrombopag or romiplostim)

B. Rituximab

C. Cyclosporine

D. Mycophenolate mofetil

E. All of the above are acceptable, treatment should be patient-

centered as regard to choice of the immunosuppressive agent

Thank You