PLATELET DISORDERS: ARE YOU PAYING ATTENTION? · obat, RPK jenis perdarahan dll . n Bleeding time panjang Jumlah trombosit normal PT normal APTT normal han Bleeding time panjang Jumlah

PLATELET DISORDERS:

ARE YOU PAYING

ATTENTION?

Usi SukoriniASM 2019

Kasus perdarahan

Pasien datang dengan keluhan bintik-bintik merah

Saran pemeriksaan hemostasis ?

Pasien 1

Kasus perdarahan

Pasien datang dengan keluhan perdarahan dari hidung

Saran pemeriksaan hemostasis ?

Pasien 2

Kasus perdarahan

Pasien datang dengan keluhan perdarahan:

Pasien 3

MUCOCUTANEOUS BLEEDING

Hemophiliac bleeding

Primary haemostasis

Anamnesis

Klinis

Pemeriksaan hemostasis

Jenis perdarahan

riwayat perdarahan

obat, RPK

jenis perdarahan dll

Perd

ara

han

Bleeding time panjang

Jumlah trombosit normal

PT normal

APTT normal

Perd

ara

han

Bleeding time panjang

Jumlah trombosit rendah

PT normal

APTT normal

Defek kualitatif Defek kuantitatif

PLATELET DISORDERS

QUANTITATIVE

PLATELET DISORDERS

THROMBOCYTOPENIA

THROMBOCYTOPENIA & ETIOLOGY

Thro

mbocy

top

eni

aA. Decrease production

B. Increase destruction

C. Sequestration

D. Dilution

E. Artifactual

• Aplastic

• Infection

• Drugs

• Malignancy (AML, ALL, MDS, solid tumour)

• nutritional

• Toxin: alcohol, cocaine

• Fanconi’s anaemia

• Bernard Soulier Syndrome

• May Hegglin Anomaly

• Wiskott-Aldrich Syndrome

• TAR syndrome

• Rubella

• Autosomal dominant

• B12/folate deficiency

A. Thrombocytopenia: decrease production

Decrease production:

bone marrow supressionThrombocytopenia:

aplastic

Thrombocytopenia:

infection

Thrombocytopenia in viral infections:

• as an almost universal feature of disseminated infection in the neonate or immunosuppressed patient

• as a rare complication of acute transient infection in previously healthy subjects

There are probably two main mechanisms of thrombocytopenia:

• immune mediated platelet destruction with or without immune mediated megakaryocyte damage

• or alternatively direct toxicity to megakaryocytes resulting from viral infection of these cells

Decrease production:

bone marrow supression

Thrombocytopenia:

drugs

Decrease production:

bone marrow supression

Thrombocytopenia:

malignancy

• Replacement normal hematopoetic cells by leukemic cells

Decrease production:

bone marrow supression

ToxinDecrease production:

bone marrow supression

• An essential nutrient, vitamin B-12 has a number of

physiological roles including a role in nerve function and cell

growth

• including platelets

• ineffective blood formation in the bone marrow

Thrombocytopenia:

B12/folate deficiencyDecrease production:

Ineffective production

• Immune thrombocytopenia (infections)

• Lupus

• Drugs

• Congenital thrombocyte syndromes

• HIT

• MAHA (TTP, HUS)

• DIC

• HELP

• Eclampsia (?)

• Chronic liver disease

• Collagen vascular d’s

• Primary splenic neoplasm

B. Thrombocytopenia: increase destruction

Thrombocytopenia:

ITPIncrease destruction:

Imune-mediated

There are probably two main mechanisms of

thrombocytopenia in viral infection:

• immune mediated platelet destruction with or without

immune mediated megakaryocyte damage

• or alternatively direct toxicity to megakaryocytes

resulting from viral infection of these cells

Thrombocytopenia:

Drugs

Increase destruction:

Imune-mediated

Drug induce thrombocytopenia

Heparin-induce

thrombocytopenia

(HIT)

Thrombocytopenia:

MAHAIncrease destruction:

Non-imune-mediated

HUS vs TTP

Thrombocytopenia:

DICIncrease destruction:

Non-imune-mediated

BT >

Thrombocytopenia

PT >, APTT >

Low fibrinogen

DD >>

DIC in Sepsis

Mechanisms of thrombocytopenia in liver

cirrhosis

• Hypersplenism:

• Infection

• Infammation

• Congestion

• Red cell disorder

• Storage disease

C. Thrombocytopenia: sequestration

Thrombocytopenia:

infectionsIncrease destruction:

sequestration

In bacterial infection thrombocytopenia is usually due

to peripheral causes consumptive coagulopathy and

peripheral sequestration in splenomegaly

D. Thrombocytopenia: dilution

• Massive transfusion

• Replacement of one entire blood volume within 24 h

• Transfusion of >10 units of packed red blood cells (PRBCs) in

24 h

• Transfusion of >20 units of PRBCs in 24 h

• Transfusion of >4 units of PRBCs in 1 h when on-going need is

foreseeable

• Replacement of 50% of total blood volume (TBV) within 3 h.

E. Thrombocytopenia: artifactual

• Platelet clumping & satellitosis Pseudothrombocytopenia

• EDTA-dependent autoantibody:

IgG antibodies formed are directed against the platelet GP

IIb/IIIa complex and the neutrophil FcγRIII

• malignancy, chronic liver disease, infection, pregnancy,

autoimmune diseases, and cardiovascular diseases have

an increased risk of EDTA-dependent

pseudothrombocytopenia

Artifactual thrombocytopenia

(pseudo-thrombocytopenia)

Resolusi:

• Pemeriksaan ulang darah lengkap menggunakan darah sirat (9:1)

• Jumlah trombosit terkoreksi = Hasil trombosit yang didapat x 1,1

Nagrebetsky A et al., Perioperative thrombocytopenia: evidence, evaluation, and emerging therapies, British Journal of Anaesthesia, 122 (1): 19e31 (2019)

Platelet clumping: blood EDTA vs citrated

THROMBOCYTOSIS

THROMBOCYTOSIS & ETIOLOGY

Thro

mbocy

tosi

sReactive

Malignancy

Inherited

Pseudo-thrombocytosis

Reactive thrombocytosis(secondary thrombocytosis)

• Platelets are acute-phase reactants

• due to the overproduction of pro-inflammatory cytokines IL-1,

IL-6, and IL-11, that occurs in chronic inflammatory, infective, and

malignant states

• Elevated of C-reactive protein (CRP), granulocyte colony-stimulating

factor (G-CSF), and granulocyte-macrophage colony-stimulating

factor (GM-CSF)

• Infection and inflammatory disorders

• Post splenectomy or hypo-splenism

• Malignancy

• Trauma

• Chronic inflammatory conditions

• Hemorrhage, blood loss, or both

• Iron-deficiency anemia

• Rebound thrombocytosis

• Asplenia (anatomic or functional)

• Idiopathic

Reactive thrombocytosis(secondary thrombocytosis)

Reactive thrombocytosis:

iron deficiency anaemia

IDA: expansion of megakaryocyte progenitors an increase

in megakaryocyte ploidy and accelerated megakaryocyte

differentiation

Megakaryocytic cell lines grown in iron-depleted conditions

exhibited reduced proliferation but increased ploidy and cell

size

without changes in TPO

Evstatiev et al., 2014

Reactive thrombocytosis:

Post splenectomy or hypo-splenism

2009

Thrombocytosis & Malignancy

• clonal thrombocytosis (primary or essential thrombocytosis) is

an unregulated abnormality of platelet production due to a

clonal expansion of bone marrow progenitor cells

• Chronic myeloid leukemia

• Polycythemia vera

• Primary myelofibrosis

• MDS with del (5q)

• MDS/MPN

• POEMS syndrome

• Familial thrombocytosis

Clonal vs Reactive Thrombocytosis

Inherited Thrombocytosis

• THPO mutation

• MPL mutation

Spurious Thrombocytosis

• Microspherocytes

• Cryoglobulinemia

• Neoplastic cell fragments

• Schistocytes

• Bacteria

Spurious thrombocytosis due to thermal injury

• microspherocytosis, spherocytes, fragmentation and blistering

(vesiculation) of RBCs

• extreme heat denaturation of RBC membrane proteins

hemolysis, RBC fragmentation, and vesiculation

• The loss of cell membrane causes the RBCs to lose their

biconcavity and assume the shape of spherocytes and

microspherocytes

• Troubleshooting:

• Peripheral blood smear platelet count

Microspherocytes:

pseudo-thrombocytosis

(Zahid & Alsammak, 2018)

Spurious thrombocytosis due to thermal injury

Widespread red blood cell fragmentation, budding, spherocytes, and

microspherocytes were revealed by microscopic examination (Zahid & Alsammak, 2018)

QUALITATIVE

PLATELET DISORDERS

DISORDERS OF PLATELET FUNCTION

ACQUIRED

DISORDERS

• Aspirin, thienopyridines and integrin αIIbβ3 antagonists, NSAIDs, antibotics, fish oil

• Renal failure, uremia

• Liver disease

• Anti-platelet antibodies

• Cardiopulmmonary bypass

• MPD, AML, ALL, MDS

• von Willebrand disease type 2B

• Platelet type von Willebrand disease

• Paraproteinemia

Caterina Casari, Wolfgang Bergmeier, Acquired platelet disorders, Thrombosis Research 141S2 (2016) S73–S75

Acquired Disorders of Platelet Function

Konkle 2011

Medications: Aspirin

Acquired Disorders of Platelet Function

Laboratory test:

• Platelet aggregation

Mechanism of Antiplatelets

clopidogrel

ticagretol

aspirin

abciximab

eptifibatide

tirofiban

Konkle BA, 2011

Herbs & foods

Konkle BA, 2011

Renal failure, uremia

• Bleeding disorder caused by renal dysfunction and azotemia

• Pathogenesis

• abnormal platelet-endothelium interaction

• intrinsic defect of platelets

• dysfunction of GpIIb/IIIa

• defect of adhesion and aggregation

• uremic toxins

• uremic plasma factors that produce NO (endothelium-derived relaxing factor) inhibits platelet aggregation

Uremic toxin

Lau et al., 2018

Addi et al., Tryptophan-Derived Uremic Toxins and Thrombosis in Chronic Kidney Disease Toxins 2018, 10(10), 412;

https://doi.org/10.3390/toxins10100412

Tryptophan-derived uremic toxin (Addi et al., 2018)

tryptophan metabolization in the gut through the indolic and the kynurenine

pathways uremic toxin

Platelet dysfunction: uremic (Lutz et al., 2017)

Bleeding &

thrombosis

Liver diseaseAcquired Disorders of Platelet Function

von Willebrand disease type 2B

Acquired Disorders of Platelet Function

Ware J., Thrombocytopathy and type 2B von Willebrand disease, The Journal of Clinical Investigation Volume 123 Number 12 December 2013

DISORDERS OF PLATELET FUNCTION

INHERITED

DISORDERS

von Willebrand disease

• is a genetic disorder caused by missing or defective von

Willebrand factor (VWF)

• Role of VWF:

• F. VIII carrier (bind F.VIII)

• Platelet adhesion

• Platelet aggregation

Classification of vWD

Bernard-Soulier syndrome (BSS)

• autosomal recessive inheritance

• is characterised by missing or functional abnormal platelet GPIb/V/IX complexes

• absent or markedly reduced adhesion and agglutination/aggregation inresponse to ristocetin or low concentrations of thrombin

• characterized by a prolonged bleeding time, large platelets and thrombocytopenia (varied)

Glanzmann thrombasthenia

• Disorders of platelet

aggregation

• autosomal recessive

disorder

• is caused by an abnormality

in the genes for

glycoproteins IIb/IIIa

• Deficiency of Gp IIB/IIIa

Von Willebrand

disease

Glanzman

thrombasteniaBernard Soulier

syndrome

• Easy bruising

• Nose bleeds

• Bleeding gums

• Heavy menstrual periods

• Gastrointestinal bleding

GIT bleeding

Von Willebrand

disease

Glanzman

thrombastenia

Bernard Soulier

syndrome

Diagnosis of Inherited Platelet function

disorders

• Platelet count normal

• BT >

• Closure time >

• PT & APTT normal

• LTA: RIPA decreased

• vWF Ag: decreased

• Platelet aggregation (ADP): normal

• APTT > type 2N

• F. VIII < type 2N

• Platelet count normal

• BT >

• closure time >

• PT & APTT normal

• LTA: platelet aggregation fails to occur with any agonist, except ristocetin

• GpIIb/IIIa not detectable (flowcytometry)

• Platelet count normal/decrease

• BT >

• Closure time >

• PT & APTT normal

• LTA: RIPA decreased

• Platelet aggregation (ADP): normal

• Giant platelets

Von Willebrand

diseaseGlanzman

thrombastenia

Bernard Soulier

syndrome

Platelet aggregation of inherited platelet

function disorders

Evaluation of patients with bleeding

Algorithm for management of thrombocytopenia

Erkurt et al., Thrombocytopenia in Adults: Review Article, J Hematol • 2012;1(2-3):44-53

Pemeriksaan laboratorium hemostasis

Jenis perdarahan

Riwayat perdarahan

Skrining hemostasis

Bleeding time (BT)

Clotting time (CT) tidak direkomendasi !

PT

APTT

Fibrinogen

D-dime

Pemeriksaan khusus

Kesimpulan

Penyakit perdarahan terkait abnormalitas trombosit

diwaspadai pasien dengan perdarahan mukokutaneus

Platelet disorders kualitatif & kuantitatif, didapat &

herediter, imun & non imun

Perlu dilakukan pemeriksaan skrining hemostasis BT

memanjang, jumlah trombosit N/rendah/tinggi, dengan

PT dan APTT N/panjang

Perlu pemeriksaan lanjutan