THROMBOCYTOPENIA

• Decreased production• Increased destruction• 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 satellitism" - platelets stuck to WBC Abnormal platelet/leukocyte histograms Platelet count varies with different anticoagulants

PSEUDOTHROMBOCYTOPENIA

Platelet clumping in EDTA No clumping in heparin

PSEUDOTHROMBOCYTOPENIA

Platelet “satellitism”Blood 2012;119:4100

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

INHERITED THROMBOCYTOPENIA

• Congenital aplastic anemia/Fanconi's anemia• Congenital amegakaryocytic thrombocytopenia• Thrombocytopenia with absent radius syndrome (recessive)• Bernard-Soulier syndrome (recessive, giant platelets,

defective function, GPIb defect)• May-Hegglin anomaly and related disorders (dominant,

leukocyte inclusions, giant platelets, MYH-9 mutation)• Other autosomal dominant syndromes (platelets may be

normal or giant)• Wiskott-Aldrich syndrome (X-linked, immunodeficiency,

eczema)

May-Hegglin anomaly

Giant platelets (macrothrombocytopenia)

PMN inclusions

Bernard-Soulier syndrome

Wiskott-Aldrich syndrome

Macrothrombocyte Microthrombocytes

Drachman, Blood 2004:103:390

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)

INCREASED PLATELET CONSUMPTION

• Immune destruction• Intravascular coagulation (DIC or

localized)• Microangiopathy• Damage by bacterial enzymes, etc

IMMUNE PLATELET DESTRUCTION

• Autoimmune (ITP) Childhood Adult

• Drug-induced Heparin Quinine, others

• Immune complex (infection, etc)• Alloimmune

Post-transfusion purpura Neonatal purpura

POST-TRANSFUSION PURPURA

• Caused by re-exposure to foreign platelet antigen via blood product transfusion– Almost all cases in multiparous women– HPA-1a (formerly PLA1) antigen most commonly involved (present in 98% of

population)

• Antibodies cause destruction of patient’s own platelets by uncertain mechanism– Possibly due to coating of patient’s platelet by donor platelet

microparticles

• Typically presents as sudden onset of severe thrombocytopenia (<10K) 5-7 days after transfusion– Consider this diagnosis whenever there is sudden, severe, unexplained

drop in platelet count in hospitalized patient

• Diagnosis: clinical suspicion, demonstrate anti HPA-1a (or other) alloantibodies in serum

• Treatment: IVIG, avoid giving HPA-1a positive platelets; wash RBC to remove passenger platelets

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

DRUG-INDUCED IMMUNE THROMBOCYTOPENIA

• Quinine type: Drug binds to platelet membrane Antibody binds to drug Exposed Fc portion targets platelet for destruction Thrombocytopenia typically severe, with bleeding Some patients develop microangiopathy with renal failure

(HUS)

• Heparin type: Heparin-platelet factor 4 complex forms on platelet surface Antibody binds to complex Fc portion of antibody binds to platelet/monocyte Fc receptor Platelet and monocyte activation triggered Thrombocytopenia typically mild to moderate Associated with thrombosis in many patients

DRUGS MOST LIKELY TO CAUSE DRUGS MOST LIKELY TO CAUSE THROMBOCYTOPENIATHROMBOCYTOPENIA

Hematology 2009;153

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ITP

• 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%

Childhood (acute) ITP

Adult (chronic) ITP

ITP

• Prevalence: 1-10/100,000• Slightly more common in women• Peak incidence at age 60+• About 40% have an associated disorder

Epidemiology (adults)

ITP: associated disordersITP: 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

ITP IS A RELATIVELY BENIGN DISEASEITP IS A RELATIVELY BENIGN DISEASEA PROSPECTIVE STUDY OF ITP IN 245 ADULTSA PROSPECTIVE STUDY OF ITP IN 245 ADULTS

• Overall incidence 1.6/100,000/yr• Median age 56, F:M 1.2:1• 12% presented with bleeding, 28%

asymptomatic• 18% needed no treatment• Only 12% needed splenectomy• 63% in remission (plts > 100K) at end of

followup period (6-78 mo, median 60)• 87% had at least partial remission (plts

>30K) and freedom from symptoms• 1.6% died from complications of

disease or its treatmentAge-specific incidence

Brit J Haematol 2003;122:966Brit J Haematol 2003;122:966

ITP

• 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 (many?) patients

Intramedullary destruction? Enhanced TPO clearance?

Pathogenesis

Splenectomy specimen from a patient with chronic ITP. Left: (40x) Activated lymphoid follicles with expanded marginal zone (short arrow), a well-defined dark mantle zone (long arrow), and a germinal center containing activated lymphocytes (arrowhead). Right: (1000x) PAS stain showing histiocytes with phagocytized platelet polysachharides (arrows). Transfusion 2005;45:287

Infusion of ITP plasma into a normal person causes dose-dependent thrombocytopenia

ITP

• Petechiae, purpura, sometimes mucosal bleeding• Major internal/intracranial bleeding rare• Mortality rate < 5%• Absence of constitutional symptoms or

splenomegaly• Other blood counts and coagulation parameters

normal• No schistocytes or platelet clumps on blood smear• Marrow shows normal or increased megakaryocytes

(optional)• Rule out other causes of thrombocytopenia (HIV, etc)

Clinical features and diagnosis

ITP

• Serum antiplatelet antibody assay (poor sensitivity)

• Test for specific anti-platelet glycoprotein antibodies (more specific, negative in 10-30%)

Confirmatory laboratory testing

Confirmatory testing not necessary in typical cases

ITP IN CHILDREN

• Platelets > 20-30 K, no bleeding: no Rx 30-70% recover within 3 weeks

• Platelets < 10K, or < 20K with significant bleeding: IVIg or corticosteroids prednisone, 1-2 mg/kg/day single dose IVIg 0.8-1g/kg as effective as repeated dosing

• Splenectomy reserved for chronic ITP (> 12 mo) or refractory disease with life-threatening bleeding pre-immunize with pneumococcal, H. influenzae and

meningococcal vaccines

Management

ITP

Treatment of newly diagnosed adults

Indications:Platelets < 20-30KActive bleeding or high bleeding risk, platelets <50K

First line treatment options:GlucocorticoidsIVIGAnti-Rh globulin (WinRho)SplenectomyRituximab?

Hospitalization often not necessary

ITP

• 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

Glucocorticoid therapy

Prednisone attenuates the effect of ITP plasma infusion on platelet count

ITP

• Sustained remission in 2/3 of patients• Almost all responses occur within 7-10 days of splenectomy• Operative mortality < 1%• Severe intra- and postoperative hemorrhage rare (about 1% of

patients)• Laparoscopic splenectomy usually preferable technique

• Advantage: High sustained response/cure rate• Disadvantages: Operative risk (mainly older pts with comorbid

disease); post-splenectomy sepsis (fatality rate 1/1500 patient-yrs); increased risk of cardiovascular events

• Indication: Steroid failure or relapse after steroid Rx (persistent severe thrombocytopenia or significant bleeding)

Splenectomy

Splenectomy attenuates the effect of ITP plasma infusion on platelet count

LAPAROSCOPIC SPLENECTOMY IS THE LAPAROSCOPIC SPLENECTOMY IS THE PROCEDURE OF CHOICE IN ADULT ITPPROCEDURE OF CHOICE IN ADULT ITP

A Systematic ReviewA Systematic Review

• 66% complete response rate (2632 patients)• No preoperative characteristic consistently

predicted response

Type of procedure

Mortality Complication rate

Open 1% 12.9%

Laparoscopic 0.2% 9.6%

Blood 2004;104:2623

ITP

• 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 toxicityDisadvantages: high cost, short duration of benefit, high relapse rateIndications: Lifethreatening bleeding; pre-operative correction of

platelet count, steroids contraindicated or ineffective

Intravenous immunoglobulin therapy

ITP

• No treatment (platelets > 10-20K, no major bleeding or bleeding risk)• Corticosteroids (low-dose, or pulse high dose)• I.V. Ig (frequent Rx, very expensive)• Accessory splenectomy• Vinca alkaloids• Danazol• Colchicine• Eradication of H. pylori, if present Rituximab Thrombopoiesis-stimuating drugs

Romiplostim (Nplate)Eltrombopag (Promacta)

Treatment options for relapsed or refractory disease

Accessory spleen

British Journal of Haematology 2004; 125: 232–239

• Background: Most patients treated for ITP with corticosteroids relapse when steroids are withdrawn. Many patients can be cured by splenectomy, but some are not. Treatments for relapsed and chronic ITP and adults have variable efficacy.

• Subjects: 57 adults with chronic ITP, with platelet counts <30K. All had at least 2 prior ITP treatments and 31 had been splenectomized.

• Intervention: Rituximab, 375 mg/m2 weekly x 4 doses• Outcome: Overall 54% response rate (32% with plts >150K, 22% with plts

50-150K). 89% of complete responders remained in remission a median of 72.5 weeks after treatment. Toxicity was minimal.

• Conclusion: Rituximab is a promising treatment for chronic/refractory ITP

Blood 2012;119:5989

Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia

• 26% of children and 21% of adults with ITP who had an intial response (CR or PR) to rituximab remained in remission without further treatment after 5 years

• No major toxicity observed• Children did not relapse after 2 years, but adults did

Vivek L. Patel, Matthieu Mahévas, Soo Y. Lee, Roberto Stasi, Susanna Cunningham-Rundles, Bertrand Godeau, Julie Kanter, Ellis Neufeld, Tillmann Taube, Ugo Ramenghi, Shalini Shenoy, Mary J. Ward, Nino Mihatov, Vinay L. Patel, Philippe Bierling, Martin Lesser, Nichola Cooper, and James B. Bussel

ROMIPLOSTIM FOR CHRONIC ITPROMIPLOSTIM FOR CHRONIC ITP

• Patients: 125 patients with chronic ITP (about half had been splenectomized)

• Intervention: Random assignment to treatment with romiplostim (AMG 531) or placebo

• Endpoint: Durable platelet response (platelets at least 50K during at least 6 of last 8 wks of treatment)

• Outcome: 16/42 splenectomized patients had durable response with romiplostim, vs 0/21 with placebo. 25/41 non-splenectomized pts had durable response with romiplostim vs 1/21 with placebo. 20/23 pts on romiplostim stopped or reduced concurrent treatment for ITP, vs 6/16 on placebo.

• No significant toxicity from romiplostim

Lancet 2008;371:395

Lancet 2008;371:395

Lancet 2010

Responses to oral eltrombopag in ITP

LONG-TERM OUTCOMES IN ITP PATIENTS WHO LONG-TERM OUTCOMES IN ITP PATIENTS WHO FAIL SPLENECTOMYFAIL SPLENECTOMY

McMillan and Durette, Blood 2004;104:956-60McMillan and Durette, Blood 2004;104:956-60

Median time to remission 46 mo

11 deaths from ITP-related bleeding;6 deaths fromcomplications of Treatment (5%)

EMERGENCY TREATMENT OF ITP

• Platelet transfusion + high dose steroids• Platelet transfusion + continuous IVIG• rVIIa (risk of thrombosis)• Antifibrinolytics• Emergent splenectomy

ITP AND H PYLORI

• 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

ITP IN PREGNANCY

• Mild cases indistinguishable from gestational thrombocytopenia• Rule out eclampsia, HIV etc• Indications for treatment

platelets < 10K platelets < 30K 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 < 20K