Dr. med. Jeroen Goede

FMH Innere Medizin, Medizinische Onkologie, Hämatologie

FAMH Hämatologie

Chefarzt Hämatologie

Kantonsspital Winterthur

Thrombocytopenia: a practial approach

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Outline

• Introduction and Definitions

• Diagnostic steps differential diagnosis

• Thrombocytopenia during pregnancy

• Immune thrombocytopenia

• Conclusions

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Introduction

Thrombocytes are formed by fragmentation of the cytoplasm of

megakaryocytes

Under physiological circumstances thrombocytes then circulate in

the blood for 7-10 days and play a critical role in haemostasis

In case of significant quantitative or qualitative platelet

dysfunction:

Patients present typically with mucocutaneous bleeding

Typically no soft tissue or joint bleeding

Presence should raise suspicion of additional plasmatic

coagulation problems

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Introduction

In most laboratories: normal platelet count between 150-450 G/l

(+/- 2 standard deviations)

By definition 2.5% of the “normal” range will be below 150 G/l

NCI-definition of grading for thrombocytopenia (for cancer

patients receiving treatment):

Grade 1 : 75-150 G/l

Grade 2 : 50-75 G/l

Grade 3 : 25-50 G/l

Grade 4 : <25 G/l

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Introduction

In otherwise healthy conditions

Bleeding time is generally not prolonged until platelet count is

below 100 G/l

As long as platelet counts are above 20 G/l clinical

manifestations are mild

Below 10 G/l the risk for spontaneous bleeding increases

rapidly

Several factors such as functional defects modify the bleeding

risk

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Diagnostic steps

Main laboratory questions in newly diagnosed thrombocytopenia:

Exclude pre-analytic reasons for thrombocytopenia

Concomitant anemia and/or neutropenia?

Degree of thrombocytopenia?

Tc 75-150 G/l vs. 50-75 G/l vs. 25-50 G/l vs. <25 G/l

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Diagnostic steps

Main clinical questions in newly diagnosed thrombocytopenia:

Recent and actual medication?

History of previous thrombocytopenia?

Family history?

Pregnancy?

Diagnostic steps

Mr. S.O. 1971

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Diagnostic steps

Diagnostic steps

Mr. M.O. 1968

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Diagnostic steps

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Diagnostic steps

Diagnosis:

Bernhard-Soulier-Syndrome

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Diagnostic steps

Initial laboratory evaluation:

Peripheral blood smear with reticulocytes

Serum creatinine

DIC panel

LDH

Total and direct bilirubin

AST and ALT

Ev. pregnancy testing

This allows as initial determination whether thrombocytopenia is

an isolated abnormality or part of a constellation of abnormalities

Diagnostic steps

If thrombocytopenia is confirmed:

Stepwise evaluation to assess the causes and the urgency of

treatment

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Diagnostic steps

If thrombocytopenia is confirmed:

Stepwise evaluation to assess the causes and the urgency of

treatment:

Thrombotic thrombocytopenic purpura (TTP)

Heparin-induced thrombocytopenia (HIT)

Immediate Intervention is required

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Diagnostic steps

Isolated thrombocytopenia without specific clues on the

peripheral blood smear:

Diagnosis of immune-thrombocytopenia (ITP) is probable

Drug induced thrombocytopenia can’t be excluded

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Diagnostic steps

The role of bone marrow exam:

Differentiation between inadequate production versus

excessive destruction/consumption as predominant cause of

thrombocytopenia

With age the incidence of primary marrow disorders is rising

(lymphoma as condition that causes ITP)

Differential diagnosis

Decreased production:

Hematologic malignancies

Aplastic anaemia

Myelodysplasia

Chemotherapy and alcohol

Radiation

HIV

Vitamin D deficiencies

Hereditary thrombocytopenia

Metastatic cancer to bone marrow

Increased destruction:

Immune:

ITP

HIT

Drug-induced antibodies

HIV

Post transfusion purpura

Connective tissue diseases

Nonimmune:

DIC

Sepsis

Cardiac valves

TTP-HUS

Splenic sequestration

Sudhir S. et al. SMJ, 2006

Thrombocytopenia during pregnancy:

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Thrombocytopenia during pregnancy

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Immune thrombocytopenia (ITP)

Immune thrombocytopenia of the adult:

• Outcome 5 years after diagnosis (Sailer, Haematologica 2006, McMillan,

Blood 2004):

• 40% of the patients have a platelet count lower than 100 G/l

• 15% of the patients have a platelet count lower than 30 G/l

• 60% of the patients are in remission

• ITP is becoming more and more a disease of elderly people

(median of age around 50 years)

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Schoonen, BJH 2009

Immune thrombocytopenia (ITP)

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Therapeutic options:

• 1915 Splenectomy

• 1951 Steroids

(Wintrobe)

• 1960ies Azathioprin

• 1970ies Vincristin

Cyclophosphamid

• 1980ies Danazol

IVIG

anti-D

• 1990ies Cyclosporin A

Mycophenolat

• 1998 Rituximab

• 2009 Eltrombopag

Romiplostim

Immune thrombocytopenia (ITP)

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Definition of response to treatment

• Complete response:

• increase in platelet count above 100 G/l

• Clinically relevant response:

• platelet increase above 30 G/l with at least a twofold

increase of the baseline count and the absence of bleeding

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Marc Michel: Immune Thrombocytopenia Nomenclature, Consensus Reports, and Guidelines: What Are the Consequences for Daily

Practice and Clinical Research? Seminars in Hematology Volume 50, Supplement 1 2013 S50 - S54

Phases of Immune thrombocytopenia

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TPO agonists

Very good clinical data with a high proporiton of responders

Good tollerability

Chronic treatment

Chronic costs

Splenectomy

• Splenectomy is an option with a high rate of durable and

complete remissions

• Mortality of the intervention: 0.5-1%

• Gonzalez-Porras JR et al. Eur J Haematol. 2013 Sep;91:

• Comparison of 57 patients ≥65 years of age with 162

patients below the age of 65 years with splenectomy due

to ITP:

• Favorable response in 72% of elderly patients and 92% of younger patients (P=0.005)

• Probability of maintaining response for 14 years after

splenectomy was 56%

• In elderly patients mortality is higher (1.8% vs. 0.6%)

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Splenectomy

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Rituximab

• First report at ASH 1998:

Perotta, ASH Annual Meeting 1998

• Since then many case reports and phase II studies, but only

two phase III studies in first line treatment:

Zaja, Blood 2010

Gudbrandsdottir, Blood 2013

• With rituximab we can expect 21% of adult patients to be

without ITP-treatment after 5 years

Patel VL et al., Blood 2012 Jun 21

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Rituximab

Patel VL et al., Blood 2012 Jun 21

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Marc Michel: Immune Thrombocytopenia Nomenclature, Consensus Reports, and Guidelines: What Are the Consequences for Daily

Practice and Clinical Research? Seminars in Hematology Volume 50, Supplement 1 2013 S50 - S54

Which treatment in which phase of the disease?

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• Newly diagnosed ITP (during the first 3 months):

• Be sure that steroids don’t work

• Personally I prefer dexamethason (4 days every 14-28 days)

• In clinically severe cases I give IVIg and wait for the action of

steroids (I don’t give up to early)

• In general: I avoid second line treatment

• Persistent and chronic ITP (3 – 12 months and later)

• Now I know that steroids did not work !

• I start with a TPO receptor agonist the patient gets stabilized.

• After stabilization I discuss the option of rituximab

• Splenectomy can be discussed in chronic phase

My approach in ITP

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Conclusion

• At first diagnosis of thrombocytopenia:

• Combined evaluation of laboratory and clinical data

• Laboratory and clinical data determine further investigations

• Diagnostic algorithms can be helpful

• Thrombocytopenia during pregnancy

• In most cases not therapy is indicated or very low doses of

prednisone resolve the problem

• Immune thrombocytopenia

• Despite the number of treatment options: some cases still

stay very challenging!

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