thrombocytopenia decreased production increased destruction sequestration pseudothrombocytopenia
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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