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
syndrome

Macrothrombocyte
Drachman, Blood 2004:103:390

Wiskott-Aldrich
syndrome

Microthrombocytes

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 patients own platelets by uncertain

mechanism
Possibly due to coating of patients 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

Age-specific incidence

Brit J Haematol 2003;122:966

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

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 patientyrs); 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
procedure
Open
Laparoscopic
Blood 2004;104:2623

Mortality Complication
rate
1%

12.9%

0.2%

9.6%

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: 232239

Outcomes 5 years after response to rituximab therapy in

children and adults with immune thrombocytopenia
Vivek L. Patel, Matthieu Mahvas, 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 ITPrelated bleeding;

6 deaths from
complications of
Treatment (5%)

Median time to remission 46 mo

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