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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
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
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
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
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
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