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Manajemen Perioperatif Penderita dengan Immune Thrombocytopenia (ITP): Pendekatan Berbasis Bukti Catharina Suharti Surabaya, 6 Oktober, 2019

Manajemen Perioperatif Penderita dengan Immune ... Catharina Suharti...Manajemen Perioperatif Penderita dengan Immune Thrombocytopenia (ITP): Pendekatan Berbasis Bukti Catharina Suharti

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Manajemen Perioperatif Penderita dengan Immune Thrombocytopenia

(ITP): Pendekatan Berbasis BuktiCatharina Suharti

Surabaya, 6 Oktober, 2019

Immune Thrombocytopenia (ITP)

ITP is an autoimmune disease in which antiplatelet antibodiesaccelerate the destruction of platelets.

In addition, platelet production can be impaired because the platelet antibodies can also damage megakaryocytes.

Although the thrombocytopenia of ITP can be severe, signs of bleeding are usually only minor.

Additional modifiers: comorbidities, age, activities, medicationsmay affect the risk of significant bleeding

Neunert CA. Hematology 2013

Immune Thrombocytopenia (ITP)

Phases of the disease: Newly diagnosed ITP: within 3 months of diagnosis Persistent ITP: 3-12 months from diagnosis Chronic ITP: >12 months

Diagnosis 12 months3 months

Newly diagnosed ITP

Persistent ITP Chronic ITPRodeghiero F, et al. Blood 2009; 113: 2386–93

Immune Thrombocytopenia (ITP)

Definitions

Primary ITP: Isolated thrombocytopenia, platelet count is repeatedly

<100x109/L, in the absence of other disorders associated with thrombocytopenia

Diagnosis of exclusion without a specific diagnostic test or clinical criteria

Secondary ITP: All forms of immune-mediated thrombocytopenia other than

primary ITP

Diagnosis of ITP

There is no specific test to rule in or rule out ITP

A diagnosis of exclusion: when history, PE, CBC and peripheral blood smear do not suggest an alternative etiology of thrombocytopenia

The detection of isolated thrombocytopenia in the presence of otherwise normal leukocyte and erythrocyte parameters is usually sufficient for an initial diagnosis.

A blood smears must always be examined

Matzdorff A, et al. Immune Thrombocytopenia. Current Diagnostics and Therapy: recommendations of a joint working group of DGHO, OGHO, SGH, GPOH and DGTI. Oncol Res Treat 2018;41 suppl5:1-30.PE, physical examination; CBC, complete blood count

Clinical Diagnosis of ITP

Medical history:• Review of systems: lupus• medication• bleeding history• family history

Physical examination:• bleeding manifestation: extent,

area, bleeding scores• splenomegaly (not consistent ITP)• Splenomegaly (not consistent ITP)• Hepatomegaly (not consistent ITP)

The extent of any further diagnostic workup depends on the severity and course of the disease

ISTH, 2016

Investigations in Persistent ITP

Infections:

HepatitisB

Hepatitis C

HIV

CMV

H. Pylory

ISTH, 2016

Controversial Investigations in

Persistent ITP

Testing for platelet autoantibodies is not recommended (not sensitive or specific enough to direct treatment)

Bone marrow examination: recommended only in thosewithabnormal features (signs and symptoms of systemic disease, CBC abnormalities), those >60 years, poor response to standard therapy, pre-splenectomy)

Matzdorff A, et al. Immune Thrombocytopenia. Current Diagnostics and Therapy: recommendations of a joint working group of DGHO, OGHO, SGH, GPOH and DGTI. Oncol Res Treat 2018;41 suppl5:1-30

Pathophysiology of ITP

The following pathomechanisms play a role in ITP:

1. Platelet autoantibodies• Antibody-coated platelets bind to Fc receptors on macrophages in

liver and spleen and subsequently degraded• Damaged platelets bind to Ashwell-Morell receptors in the liver and

are subsequently degraded• Autoantibodies damage platelet directly• Autoantibodies interfere with platelet function

Matzdorff A, et al. Immune Thrombocytopenia. Current Diagnostics and Therapy: recommendations of a joint working group of DGHO, OGHO, SGH, GPOH and DGTI. Oncol Res Treat 2018;41 suppl5:1-30

Pathophysiology of ITP

The following pathomechanisms play a role in ITP:

2. T lymphocytes• Reduced number of regulatory T lymphocytes (Tregs) lead to

immunodysregulation• T lymphocytes directly damage platelet

3. Impaired thrombopoiesis• Autoantibodies damage megakaryocytes• Relative deficiency of thrombopoietin• Impaired thrombopoietin production

Matzdorff A, et al. Immune Thrombocytopenia. Current Diagnostics and Therapy: recommendations of a joint working group of DGHO, OGHO, SGH, GPOH and DGTI. Oncol Res Treat 2018;41 suppl5:1-30

Treatment ITP

Grading the severity of bleeding

The severity bleeding in adults should be graded according to WHO bleeding scale or the National Cancer Institute Common Terminology Criteriafor Advanced Events (NCI-CTCAE)

Matzdorff A, et al. Immune Thrombocytopenia. Current Diagnostics and Therapy: recommendations of a joint working group of DGHO, OGHO, SGH, GPOH and DGTI. Oncol Res Treat 2018;41 suppl5:1-30

Bleeding grades according WHO and NCI-CTCAE

Bleeding grade Definition

0 • No sign of bleeding

I • Petechiae• Small hematoma, echymoses (<10cm)• Bleeding from mucous membrane (mouth, nose)• Epistaxis (<1 h duration, no medical intervention necessary)• Subconjunctival haemorrhage• Vaginal bleeding (independent of menstruation, no more than 2 bandages/d

necessary)

IINo transfusion

required

• Hematoma, echymoses (>10cm)• Epistaxis (>1 h duration, or tamponade necessary)• Retinal bleeding without visual impairment• Vaginal bleeding (independent of menstruation, more than 2 bandages/d

necessary)• Melena, hematemesis, hemoptysis, hematuria, hematochezia• Bleeding from puncture sites• Bleeding in muscle and joints

Matzdorff A, et al. Immune Thrombocytopenia. Current Diagnostics and Therapy: recommendations of a joint working group of DGHO, OGHO, SGH, GPOH and DGTI. Oncol Res Treat 2018;41 suppl5:1-30

Bleeding grades according WHO and NCI-CTCAE

Bleeding grade Definition

IIITransfusion

required

• Epistaxis• Bleeding from mucous membrane (mouth, nose)• Vaginal bleeding • Melena, hematemesis, hemoptysis, hematuria, hematochezia• Bleeding from puncture sites• Bleeding in muscle and joints

IVLife threatening,

potentially permanent functional

impairment

• Retinal bleeding with visual impairment• CNS bleeding• Hemorrhage in other organs with functional impairment (joints, muscles,

kidneys, lung, etc)• Fatal bleeding (NCI-CTCAE grade V)

Matzdorff A, et al. Immune Thrombocytopenia. Current Diagnostics and Therapy: recommendations of a joint working group of DGHO, OGHO, SGH, GPOH and DGTI. Oncol Res Treat 2018;41 suppl5:1-30

Indications for initiation of treatment: newly

diagnosed ITP

Platelet threshold: no evidence based

Platelet <30x109/L: the risk of bleeding and mortality ↑, but there are a large individual variations

Active bleeding OR platelet <10.000/µL: treatment is obligatory

No or mild bleeding AND platelet10-30.000/µL: consider to treat after evaluation of patient characteristics

No bleeding AND platelet >30.000/µL: no need for treatment unless special circumtances

Janssen A, et al, 2013; Matzdorff A, et al. 2018

Treatment

Before initiating treatment consideration must be given to:

Patient related factors: age, PS, comorbidities, life style (sedentary vs active), and patient wishes

Disease related factors: platelet count, previous major bleeding

Additional risk factors for bleeding: the use of antiplatelet and anticoagulant agents, uremia, poorly controlled hypertension, aneurysm, fever, chronic liver disease, history of peptic ulcer

Treatment related factors: contraindications and side-effects from particular treatment modalities

The need of medical intervention that may cause bleeding

Janssen A, et al, 2013; Matzdorff A, et al. 2018

Safe platelet count for medical interventions in

patient with platelet production problem

Dentistry ≥10-20.000/µL

Extractions (simple) ≥30.000/µL

Extractions (complex, molar) ≥50.000/µL

Lumbar puncture ≥50.000/µL

GI endoscopy with biopsy ≥20.000/µL

Bronchoscopy ≥20.000/µL (≥50.000/µL if also biopsy)

Organ biopsy ≥50.000/µL (< for bone marrow biopsy)

Minor surgery ≥50.000/µL

Major and neuro surgery ≥80.000/µL

Epidural anesthesia ≥80.000/µL

Janssen A, et al, 2013

Neuraxial analgesia and anesthesia

Neuraxial analgesia and anesthesia is the standard of care for management of the labouring parturient and cesarian delivery

Thrombocytopenia is considered a relative or even absolute contraindication in neuraxial techniques due to potential risk of epidural hematoma

There is no consensus on the acceptable platelet count required to safely perform neuraxial techniques

Lee LO, et al. Anesthesiology 2017; 126: 1053-64.

Neuraxial analgesia and anesthesia

The multicentre perioperative outcomes group database and a systematic literature review were combined to estimate the relationship between platelet count and the risk of epidural hematoma requiring surgical decompression after neuraxial

techniques:

The upper bound for 95% CI for epidural hematoma risk (n=573)

Platelet count/mm3 Epidural hematoma(%)

0-49.000 11

50.000-69.000 3

70.000-100.000 0.2

Lee LO, et al. Anesthesiology 2017; 126: 1053-64.

Frequently used drugs and dosages for ITP

Corticosteroids

Predniso(lo)n 1-2mg/kg/d/p.o. or i.v. for 1-2 weeksAfter response, weekly dose reductions in 10mg steps until a dose of 0.5mg/kg/d is reached, then dose reduction by 5mg/weekResponse: Initial rates 70%-80%; 1wk; 10%-30% have durable remission

Methylprednisolone 125-1.000mg i.v. for 1-5 days (followed by prednisone 1mg/kg/d p.o. and subsequent dose reduction as above

Dexamethasone 40mg p.0. dailyx4d, 4-6 cycles every 14-28 d

Matzdorff A, et al. Immune Thrombocytopenia. Current Diagnostics and Therapy: recommendations of a joint working group of DGHO, OGHO, SGH, GPOH and DGTI. Oncol Res Treat 2018;41 suppl5:1-30Neunert CA, 2013

Frequently used drugs and dosages for ITP

Other treatments

I.V. Immunoglobulins

0.4-1g/kg/d, if no response this dose can be repeated once after 3 daysResponse: initial rates 80%; 24-48 hours; durability: 3-4 wk

Elthrombopag 25-75 p.o. daily, continuous therapy

Azathioprine 2mg/kg p.o. daily, response may take several months

Matzdorff A, et al. Immune Thrombocytopenia. Current Diagnostics and Therapy: recommendations of a joint working group of DGHO, OGHO, SGH, GPOH and DGTI. Oncol Res Treat 2018;41 suppl5:1-30Neunert CA, 2013

Frequently used drugs and dosages for ITP

Other treatments (no regulatory approval for the treatment of ITP)

Rituximab 375mg/m2 1x per week i.v. for 4 weeks

Cyclosporine Dosage by blood level, target 100-400ng/ml

Danazol 400-800 mg p.o. daily

Dapsone 75-100mg p.o. daily

Mycophenolate 2x250 bis 2x1000 mg p.o. daily

Anti D The only anti-D product approved for ITP (WinRho SDF) was withdrawn from the European market in 2009, but is still available in US and other non-European countries

Matzdorff A, et al. Immune Thrombocytopenia. Current Diagnostics and Therapy: recommendations of a joint working group of DGHO, OGHO, SGH, GPOH and DGTI. Oncol Res Treat 2018;41 suppl5:1-30

Side effects of corticosteroids and preventive

measures

Side effects:

Acne Hypertension

Cushingoid appearance (moon face) Thinning, fragile skin, stretch marks (striae)

Blood glucose elevation Weight gain

Infection Stomach pain

Muscular atrophy Osteoporosis

Sleeplessness Loss of emotional control

Matzdorff A, et al. Immune Thrombocytopenia. Current Diagnostics and Therapy: recommendations of a joint working group of DGHO, OGHO, SGH, GPOH and DGTI. Oncol Res Treat 2018;41 suppl5:1-30

Side effects of corticosteroids and preventive

measures

Preventive measures:

Inform the patient about the above-listed side-effects and provide a time table as to how long this therapy should be taken

Osteoporosis prophylaxis: 600-1.000units vitamin D3/d and 1.000 mg calcium/day

Protect stomach with proton pump inhibitor

Antibiotics as infection prophylxis usually not indicated

Matzdorff A, et al. Immune Thrombocytopenia. Current Diagnostics and Therapy: recommendations of a joint working group of DGHO, OGHO, SGH, GPOH and DGTI. Oncol Res Treat 2018;41 suppl5:1-30

Treatment algorithm

Diagnosis ITP

Predni (so)lon, methylprednisolone, dexamethasone

For life threatening bleeding + platelet concentrates

Consider rituximab and TRA

For severe bleeding + IVIg

1st Line

2nd LineWith minimal bleeding consider

‘watch and wait’

Thrombopoietin receptor agonists, for emergency splenectomy

3rd Line

With minimal bleeding consider ‘watch and wait’, even when platelet

are very low, respect patient preference

Azathioprine, ciclosporin (OL), cyclophosphamide, danazol (OL),

hydroxychloroquine (OL), mycophenolate (OL), rituximab (OL),

vinca alkaloids, splenectomy (not before 12 months

Matzdorff A, et al. Immune Thrombocytopenia. Current Diagnostics and Therapy: recommendations of a joint working group of DGHO, OGHO, SGH, GPOH and DGTI. Oncol Res Treat 2018;41 suppl5:1-30. OL, off label

Recombinant Human TPO

Platelets: fragments of megakaryocyte cytoplasma

Megakaryocytes: located in the bone marrow

Thrombopoietin: is the dominant hormone for megakaryocytopoiesis

Platelet life span: about 10 days

Spleen sequesters ± 1/3 of the circulating platelet.

Rebozet mechanism of action

TPO-R inactive

Rebozet

Cell membrane

Cytoplasm

Signal transduction

STAT

JAK

SHCSOS

Increased platelet production

RAS/RAF

TPO-R active

GRB2

MAPKK

P42/44

p p

Kuter D. Blood 2007;

109: 4607–16.

©

Eltrombopag (Rebozet)

FDA and EMA approval for:

ITP insufficient response to corticosteroids, IVIg (second line)

LOR:A, LOE:2

Others: Chronic HCV infection to allow initiation and maintenance IFN-

based therapy Severe aplastic anemia, insufficient response to

immunosuppressive therapy

FDA, Food Drug Administration; EMA, European Medicines Agency

Matzdorff A, et al. Oncol Res Treat 2018;41 suppl5:1-30

Emergency treatment

Emergency treatment

An urgent increase in platelet count may be required for some ITP patients: Needing surgical procedures At high risk of bleeding With active central nervous system, Gastrointestinal, or genitourinary

bleeding (life-threatening)

Provan D, et al. Blood 2010; 115: 168–86; 2. Neunert C, et al. Blood 2011; 117: 4190–207

Matzdorff A, et al. Oncol Res Treat 2018;41 suppl5:1-30

Emergency treatment

Guidelines recommend emergency treatment of severe bleeding in adults with ITP:

High-dose parenteral corticosteroid (e.g. methylprednisolone)1

IVIg alone or in combination with corticosteroids (e.g. prednisone)1,2

Platelet transfusions, possibly in combination with IVIg1,2

In life-threatening bleeding and if the above measures do not achieve hemostasis, consider rituximab and TPORAs

LOR A; LOE3

Provan D, et al. Blood 2010; 115: 168–86; 2. Neunert C, et al. Blood 2011; 117: 4190–207Matzdorff A, et al. Oncol Res Treat 2018;41 suppl5:1-30

Splenectomy

Splenectomy

Indication: persistent or chronic thrombocytopenia and severe bleeding (WHO III,IV) who have no, or only an insufficient respons to all other treatment modalities

There is no compelling indication for splenectomy in patients with chronic, therapy resistant ITP who have no, mild, or only moderate bleeding (WHO 0,I,II)

Splenectomy should not be performed before the 12th month

LOR C, LOE3

Matzdorff A, et al. Oncol Res Treat 2018;41 suppl5:1-30

Laparascopic Splenectomy (LS)vs Open

Splenectomy (OS) for ITP

A retrospective analysis of 73 patients with refractory ITP, 32 (LS) and 41 (OS) (2003-2012)

Laparascopic Splenectomy:

shorter hospital stay less blood loss and blood transfusion, quicker resumption of

oral diet earlier drain removal operation time longer

p=0.01 p<0.0001

p<0.01 P<0.0001

No difference in relapse free survival rate between 2 groups (p=0.777)Conclusion: long-term outcome of LS is not different from that OS for patients

with ITP

Qu Y, etal. Int Surg 2014;99:286-290

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