DIAGNOSTIC APPROACH OF

THROMBOCYTOPENIA

Anna Mira Lubis

Hematology and Medical Oncology Division
Department of Internal Medicine
Universitas Indonesia- Cipto Mangunkusumo Hospital
Disclosure
• Nothing to disclose
Outline
• Thrombopoiesis
• Platelet life span
• Lab. test for thrombocytopenia
• Diagnosis algorithm of thrombocytopenia
• Cases of thrombocytopenia
• Summary
Hematopoiesis
 THROMBOPOIESIS (Megakaryocyte development)

Alan D.Michelson.Platelets.3rd ed.2013

 THROMBOPOIESIS (platelet production)

Alan D.Michelson.Platelets.3rd ed.2013

Platelet life span

• Human body produces approximately 100 billion platelets/day

• Majority are cleared by RES in the liver and spleen
• Time in circulation is up to 10 days
• Genetic or pharmacological manipulation of the apoptotic program,
can reduce or extend platelet life span in vivo
• Multiple-hit model (the rate at which plt endure hits; the number of
hits a plt can withstand)  platelet survival  platelet life span
Definition
• Platelet count < the lower limit of normal value ( 150 x 109/L).
• Mild (100.000-150,000/microL), moderate (50,000 – 99,000/microL)
and severe (< 50,000/microL)
• Associated with an increased risk of mortality in critically ill patients.
• As a marker of organ impairment and as a poor prognosis

Roberto S. ASH education book.2012

 Mechanism of thrombocytopenia
Megakaryocyte
development ⇩
Platelet
thrombocytophenia
production ⇩

Platelet survival ⇩

Less common mechanisms are platelet sequestration ( redistribution of platelet

from circulating pool to splenic pool) and hemodilution

Roberto S. ASH education book.2012

 Diagnostic approach

History taking and physical

examination : Laboratory Test
- Family history • Peripheral blood smear (blood lineage)
- Temporal profile • Liver and renal function
- Disease history (autoimmune, infection, • Hemostasis
malignancy) • LDH
- Pregnancy • BM aspiration and biopsy
- Recent medications and vaccinations • Reticulated platelet / immature platelet
- Recent travels fraction/MPV
- Recent transfusion • Plasma glycocalicin
- Recent organ transplantation • Thrombopoietin level
- Alcohol and quinine-containing drugs
- Risk factors for retroviral/hepatitis infection
- Location and bleeding severity
- Organomegaly
- Sceletal abnormalities
Common causes of thrombocytopenia

Roberto S. ASH education book.2012

 Mechanism of drug induced thrombocytopenia

How I evaluate and treat thrombocytopenia in the intensive care unit patient.Blood.2016
 Major mechanism of thrombocytopenia in ICU

pseudothrombo Hemodilution Platelet Platelet Decreased Platelet

cytopenia consumption sequestration platelet destruction
production
Platelet Infusion of - Blood loss hepatosplenomeg - Intoxication - Immune
aggregates in fluids/plasma - Massive aly - Viral infection thrombocytope
EDTA- trauma - BM infiltration nia
anticoagulated - DIC - Radiation - DITP
blood - Sepsis - chemotherapy - TTP-HUS
- Extracorporeal - PTP
circuit - Passive
alloiimune
thrombocytope
nia

How I evaluate and treat thrombocytopenia in the intensive care unit patient.Blood.2016
Clues for diagnosis of thrombocytopenia in critically-ill patients

Jacko Thachill. How do we approach thrombocytopenia in critically ill patients? British Journal oh Haematology.2016
 Novel test
Mean Platelet Immature Plasma glycocalicin Monoclonal Trombopoietin
Volume ( MPV ) Platelet Fraction ( Antibody-Specific Level
IPF ) of Immobilization
Platelet Antigens
(MAIPA)
- Discriminate - Newl platelet - Extracellulart - Sera containing - Key regulator of
over destruction contain NRA domain of platelet platelet-reactive megakaryocyte
>< under - RNA –staining Glycoprotein Ib Ɑ Abs (auto and development
production fluorescent dyes  platelet alloAb) against and platelet
- Peripheral - Discriminate destruction major plt production
destruction over destruction membrane production
BM production >< constituents - Treatment
 immature under/recovery (glycoproteins
platelet  MPV production and HLA class 1)
is higher - Acute and - Diagnostic tools
- Cut-off : 8,8 fL chronic immune
- Sen/spe - Active disease, mediated
77%/89% th/ response platelet
and disease destruction
relapse
Lalita, et al. The use of mean platelet volume for distinguishing the causes of thrombocytopenia in adults patients. Hematology reports.2019
Alan D.Michelson.Platelets.3rd ed.2013
 Diagnostic algorithm

Roberto S. ASH education book.2012

 Case 1
• Tn. PH, 44 thn , 16/10/1973, 23/8/2018
• Keluhan hematuria sejak 1 minnggu SMRS.
• Hematuria sejak 2013,hilang timbul. Berulang kembali di 2015 dan 2017,
terakhir 1 minggu yang lalu. Riwayat trombositopenia sejak 2013, dengan
hematuria beberapa kali,bercampur klot darah, hilang timbul, tidak nyeri.
Perdarahan ditempat lain tidak ada. Nyeri perut -, demam -, komorbid -.
Konsumsi obat-obatan ketosteril. Riwayat transfusi -, nyeri sendi-.
• Dikonsulkan karena trombositopenia pro tindakan sistoskopi dan
pemasangan DJ Stent.
• Pemeriksaan fisik : dalam batas normal
• 28/6/2013 : Hb 14,5, Ht 40, Leu 6550,Tr 45.000, UL : darah +3,
eritrosit penuh
• 20/3/2015 : Hb 15,8, leu 6030, Tr 61.000
• 10/4/2015 : Hb 15, leu 6950 (0/2/1/56/34/7), Tr 77.000, ANA IF
1/100
• 20/8/2019 : Hb 15,1, Ht 42, leu 11.820 (0/1/0/64/28/7), tr 87.000, ur
cr 26/0,8, PSA 0,74
• CT urografi : HN dan HU kanan sampai distal, VU dinding menebal,
additional shadow di dinding posterolateral kanan buli, lesi idodens
kecil yang sebagian menempel dengan dinding buli sisi kiri bag.
Posterior, curiga bekuan darah DD/massa
• Masalah :
1. Isolated trombositopenia
2. Hematuria (ca buli? ) pro sistoskopi dan pemasangan DJ stent kanan

DPL, GDT, IPF, SGOT/SGPT, Alb/glob, elektroforesa protein,

imunofiksasi HBsAg, Anti HCV, Anti HIV, TSHs, FT4, PT/APTT
• Hb 14,4, Ht 41, Leu 14200 • SPEP : peningkatan fraksi alfa1 dan
(0/1/0/78/12/9), Tr 150.000, IPF beta2 globulin, peningkatan fraksi
3,9, GDT : neutrofilia dan gamma globulin dengan gambaran
monositosis, trombosist morfologi poliklonal
normal • Imfix : tidak tampak gamopati
• Alb/glob 4,8/3,3 monoclonal
• SGOT/PT 20/18 • CD4 %/abs : 13/223
• Ur/cr 37/1 • HIV RNA Konvensional : 1,23x104,
• HBs Ag NR (SI 2,05 x 104 )
• Anti HCV NR • IGRA +
• Anti HIV reaktif
• FT4/TSHs 0,56/11,65
• Hasil Histopatologi buli (25/8/18) : sediaan terdiri atas jaringan otot
dan jaringan ikat longgar, dengan sebukan ringan sampai sedang sel
radang menahun dan PMN. Setempat-setempat tampak proliferasi sel
histiosit/makrofag disertai sel datia jenis langhans --> sesuai dengan
radang granulomatosa, kemungkinan ec tuberculosis
 Case 2
• NY. MM, NMR 439-69-93, 27/7/1949
• MRS 1/8/2019
• Keluhan sulit komunikasi sejak 2 bulan yl, bicara melantur dan sering
lupa. 2 mg terakhir tangan dan tungkai kanan lemah. Dari MRI brain,
dikatakan terdapat tumor di basal ganglia kiri, dan direncanakan utk
radiasi. Komorbiditas -
• Selama pengobatan riw kejang 1x, dan saat ini dalam WBRT
• Terapi : dexametason, ondansentron, omeprazole, depakene (3/8)
loading 3x500 mg, ceftriaxone
• Tgl 2/9/2019 : pasien dikonsulkan karena trombositopenia
• 2/8/2019 :
• Hb 12,6, Ht 36, leuko 21270 (0,1/0,5/78,5/14,3/6,6/0), tr 313.000
• SGOT/PT : 13/35, Cr 0,5

Drug induced thrombocytopenia?

DPL, IPF, GDT, LDH, stop asam valproate

 6/8 11/8 17/8 22/8 24/8 28/8 30/8 31/8 2/9 3/9 5/9 6/9 8/9 10/9 16/9 26/9
Hb 14,7 12,3 10,3 10,6 10,4 10,5 10,3 11,8 11,5 11,2 10 9,8 10,3 9,6 10,3 12
Ht 41,6 36,1 29 28,6 28,9 30,1 28,4 32,8 32,3 30,9 27,8 27,6 28,6 25,9 28,3 32,5
Leu 21320 2333 2389 1768 1419 7370 7920 1214 1138 1161 1103 1429 1539 1545 1043 8140
0 0 0 0 0 0 0 0 0 0 0 0
TR 275.00 235.0 264.0 206.0 159.0 79.00 70.00 65.00 79.00 97.00 92.00 100.0 147.0 154.0 172.0 180.0
0 00 00 00 00 0 0 0 0 0 0 00 00 00 00 00
IPF 1,5
GD
T

Drug Drug Plt recovery

exposure withdrawal
 Platelet count
300000

250000

200000

150000
Trombosit

100000

50000

0
3-Aug 13-Aug 23-Aug 2-Sep 12-Sep 22-Sep 2-Oct

val acid withdrawal

 Case 3
• Tn. NE, 433-83-85, 5/5/1957
• Kunjungan I : 5/12/2018
• Keluhan tidak enak badan sejak 2 mg SMRS, riwayat demam, batuk
dan cenderung tidur/lemas, penurunan BB +, demam lama -, ke
daerah malaria-
• Komorbid DM : th/ diamicron 1x60 tab dan metformin 3x500 mg
Pemeriksaan Fisik Pemeriksaan penunjang
• TV normal • 19/11/2018 : Hb 12,4, Leuko 8700,
Trombosit 135.000
• Splenomegali S1
• 5/12/2018 : Hb 9,8, Leuko 4080
• Extremitas udem+/+ (0/3/0/78/17/2), Tr 32.000, IPF 10.1%,
retikulosit 0,75%
• GDT : pansitopenia, blast -
• HBsAg/Anti HCV/Anti HIV -/-/-
• Alb/glob 2,7/2,6
• LDH 2553
• As urat 6,3
• IgM/IgG dengue -/-
1. Pansitopenia dengan splenomegaly  BM problem : leukemia,
limfoma, MDS?
2. DM II

Aspirasi dan biopsy sumsum tulang

• 28/12/2018 readmisi dengan keluhan lemas yg memberat sejak 1
mg SMRS, mual dan muntah. Bicara pelo/hemiparese-, demam sejak
1 bulan (BB 64 kg, TB 170 cm)
• Lab tgl 27/12/2018 : Hb 7,2 gr/dl, Ht 21,8, Leuko 7600 (0/0/89/9/2),
Tr 44.000
• DPL : Hb 8, Ht 21,7, MCV/H 77,8/28,7, Leuko 8240, Trombo 38.000
• Na/K/Cl 119/4,2/95
• Sitomorfologi ss tlg : hiperseluler, blast 3%, M:E Ratio 1,5 :1,
eritropoiesis meningkat, granulopoiesis dan trombopoiesis menurun

• Imunotyping : blast 22%, morfologi : ALL-L3 Burkitt, gating pada blast

: CD20 +, CD 19+  B lineage

• Histopatologi : hiperseluler, M:E ratio normal, seri myeloid maturasi

hingga segmen, megakariosit ditemukan. Tampak sel-sel berukuran
besar, berinti pleomorfik, vesikuler, anak inti nyata, sitoplasma
eosinofilik  sesuai dengan Leukemia akut DD/ infiltrasi limfoma
malignum non Hodgkin, sel besar

• Imunohistokimia : CD 20 + difus, CD3 -, CD 10 -, Ki67 + pada sekitar

80%, MUM-1, PAX-5 +, TdT -, bcl6, CD34 tidak dapat diperiksa
infiltrasi LNH, sel B, jenis sel besar, difus, subtype non GCB
• PET-CT Scan :
Multipel pembesaran KGB di upper dan lower diafragmatika disertai splenomegaly
hipermetabolik (SUV max 10,3). Dijumpai keterlibatan extranodal lymphoma intra
BM dan kecurigaan extranodal lainnya di daerah hepar (SUV max 6,1). Asites
intraperitoneal, efusi pleura bilateral terutama sisi kiri disertai dislektasis jaringan
paru kiri normal diatasnya.

DLBCL, Non-GCB B-cell-like subtype stad 4

R-CHOP + CNS profilaksis (MTX IT)

 4/1/19 6/1 8/1 10/1 14/1 21/1 25/1 13/2 13/9

Hb 9,2 8,3 6 7,1 9,3 9,7 9,8 9,4 12,3

Ht 25,8 23,4 17 20,8 26,7 29 29 38
leukosit 8739 5160 11640 3980 540 4600 5610 3100 8200

trombosit 20.000 7000 43.000 64.000 85.000 281.000 321.000 168.000 400.000

TC, R-miniCHOP TC TC R-CHOP II R-CHOP III

 Summary
• Thrombocytopenia is a common hematologic finding with variable clinical
appearance
• Can result from a wide range of conditions and determined by multiple
mechanism
• A prompt and correct identification of the causes is crucial for the
appropriate management
• Different approach between outpatients and acute thrombocytopenia in
ED/ICU
• Thrombocytopenia in pregnancy deserves special consideration because of
the possible consequences on the fetus
• Integration of clinical findings and laboratory support
THANK YOU