THROMBOCYTOPENIA

Curs an IV - limba engleza2012-2013

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, Hemolytic-uremic 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 caused by

antiplatelet antibodies

• 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

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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 platelets cleared by tissue

macrophages 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

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• 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 antibody assay (poor sensitivity)

• 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

• 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 therapyDisadvantages: 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 ITPSplenectomy

• 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)

• 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 Relapsed ITP - Intravenous immunoglobulin therapy

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– 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

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Special aspects

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