1. THROMBOCYTOPENIA Decreased production Increased destruction
Sequestration
Pseudothrombocytopenia

2. 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

3. PSEUDOTHROMBOCYTOPENIA
Anticoagulant-dependent clumping of platelets in pseudothrombocytopenia.
Platelet clumping in EDTA
No clumping in heparin

4. PSEUDOTHROMBOCYTOPENIA
Anticoagulant-dependent clumping of platelets in pseudothrombocytopenia.
Platelet “satellitism”
Blood 2012;119:4100

5. 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

6. 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)

7. May-Hegglin anomaly PMN inclusions
Peripheral blood smear in a patient with May-Hegglin anomaly, a form of dominantly-inherited thrombocytopenia characterized by giant platelets and neutrophil inclusions.
Giant platelets (macrothrombocytopenia)

8. Bernard-Soulier syndrome Wiskott-Aldrich syndrome
Macrothrombocyte
Microthrombocytes
Drachman, Blood 2004:103:390

9. 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)

10. INCREASED PLATELET CONSUMPTION
Immune destruction
Intravascular coagulation (DIC or localized)
Microangiopathy
Damage by bacterial enzymes, etc

11. IMMUNE PLATELET DESTRUCTION
Autoimmune (ITP)
Childhood
Adult
Drug-induced
Heparin
Quinine, others
Immune complex (infection, etc)
Alloimmune
Post-transfusion purpura
Neonatal purpura

12. 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

13. 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

14. 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

15. DRUGS MOST LIKELY TO CAUSE THROMBOCYTOPENIA*
Hematology 2009;153

16. 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%

17. Childhood (acute) ITP
Adult (chronic) ITP

18. Epidemiology (adults)
ITP
Epidemiology (adults)
Prevalence: 1-10/100,000
Slightly more common in women
Peak incidence at age 60+
About 40% have an associated disorder

19. 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

20. ITP IS A RELATIVELY BENIGN DISEASE A 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 treatment
Age-specific incidence
This study challenges the notion of ITP as a chronic disease that preferentially affects women. The age of patients was also higher than in many other published series.
Brit J Haematol 2003;122:966

21. 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 (many?) patients
Intramedullary destruction?
Enhanced TPO clearance?

22. Splenectomy specimen from a patient with chronic ITP
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

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

24. Clinical features and diagnosis
ITP
Clinical features and diagnosis
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)

25. Confirmatory laboratory testing
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

26. ITP IN CHILDREN Management 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

27. Treatment of newly diagnosed adults
ITP
Treatment of newly diagnosed adults
Indications:
Platelets < 20-30K
Active bleeding or high bleeding risk, platelets <50K
First line treatment options:
Glucocorticoids
IVIG
Anti-Rh globulin (WinRho)
Splenectomy
Rituximab?
Hospitalization often not necessary

28. Glucocorticoid therapy
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 therapy
Disadvantages: steroid toxicity (increases with time and dose), high relapse rate

29. Prednisone attenuates the effect of ITP plasma infusion on platelet count
Prednisone blunts the decrease in platelet count caused by ITP plasma infusion.

30. ITP Splenectomy 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)

31. Splenectomy attenuates the effect of ITP plasma infusion on platelet count
More antibody needed to cause thrombocytopenia in asplenic subject.

32. LAPAROSCOPIC SPLENECTOMY IS THE PROCEDURE OF CHOICE IN ADULT ITP A 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

33. Intravenous immunoglobulin therapy
ITP
Intravenous immunoglobulin therapy
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

34. Treatment options for relapsed or refractory disease
ITP
Treatment options for relapsed or refractory disease
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)
Accessory spleen

35. Intervention: Rituximab, 375 mg/m2 weekly x 4 doses
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 K). 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
The most effective treatment for patients with ITP who relapse after corticosteroid treatment and/or splenectomy has not been established. This paper shows that Rituximab is effective in a majority of these patients, with minimal toxicity.
British Journal of Haematology 2004; 125: 232–239

36. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia
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
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
The most effective treatment for patients with ITP who relapse after corticosteroid treatment and/or splenectomy has not been established. This paper shows that Rituximab is effective in a majority of these patients, with minimal toxicity.
Blood 2012;119:5989

37. ROMIPLOSTIM 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

38. Lancet 2008;371:395

39. Responses to oral eltrombopag in ITP
Lancet 2010

40. LONG-TERM OUTCOMES IN ITP PATIENTS WHO FAIL SPLENECTOMY McMillan and Durette, Blood 2004;104:956-60
Most patients with “refractory” ITP eventually attain stable remission, but this takes a long time in many cases. There is a subpopulation with resistant disease that has significant morbidity and mortality.
11 deaths from ITP-related bleeding;
6 deaths from
complications of
Treatment (5%)
Median time to remission 46 mo

41. EMERGENCY TREATMENT OF ITP
Platelet transfusion + high dose steroids
Platelet transfusion + continuous IVIG
rVIIa (risk of thrombosis)
Antifibrinolytics
Emergent splenectomy

42. 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

43. 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