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

PMN inclusions

Giant platelets
(macrothrombocytopenia)
 Bernard-Soulier Wiskott-Aldrich
syndrome 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
THROMBOCYTOPENIA

*
*

*
*

Hematology 2009;153
 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

Epidemiology (adults)

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

Brit J Haematol 2003;122:966

 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?
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
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)
 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 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
 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
 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
Prednisone attenuates the effect of ITP
plasma infusion on platelet count
 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)
Splenectomy attenuates the effect of ITP
plasma infusion on platelet count
 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 Mortality Complication

procedure rate
Open 1% 12.9%
Laparoscopic 0.2% 9.6%

Blood 2004;104:2623
 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
 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
• 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

British Journal of Haematology 2004; 125: 232–239

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

Blood 2012;119:5989
 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
Lancet 2008;371:395
Responses to oral eltrombopag in ITP

Lancet 2010
LONG-TERM OUTCOMES IN ITP PATIENTS WHO
FAIL SPLENECTOMY
McMillan and Durette, Blood 2004;104:956-60

11 deaths from ITP-

related bleeding;
6 deaths from Median time to remission 46 mo
complications 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