VON WILLEBRAND DISEASE

 Kelainan perdarahan bawaan yang diwariskan secara autosomal, atau didapat, dimana ada
kekurangan atau disfungsi von Willebrand factor (vWF).
 vWF adalah glikoprotein multimerik yang dibuat di hepatosit, dan juga dibuat dalam sel
endotel dan megakariosit dan diekskresikan ke dalam plasma, vWF juga terdapat dalam
trombosit.
 Protein vW terdiri dari banyak monomer, masing-masing mengandung sejumlah domain
spesifik dengan fungsi spesifik yang bertanggung jawab untuk pengikatan FVIII atau adhesi
dan agregasi trombosit.
 vWF memiliki dua fungsi, sebagai berikut:
o vWF menempel pada kolagen suendotelial dan trombosit, mempromosikan
pembentukan sumbat platelet di tempat cedera pembuluh darah kecil dan
o vWF mengikat dan mengangkut FVIII yang dibuat dalam sel-sel endotel
 Masalah klinis utamanya adalah mimisan: perdarahan dari luka kulit kecil dan dari lesi di
mukosa atau saluran GIT: menorrhagia dan perdarahan yang berlebihan setelah trauma,
operasi bedah atau persalinan.
 Pasien dengan defisiensi vWF yang parah dapat mengalami perdarahan pada … otot.
Variasi Normal Kadar vWF :

 Variasi kadar vWF dan FVIII dipengaruhi oleh lingkungan, sebagai berikut:
o ↑ pada pelepasan adrenalin seperti dalam latihan berat atau stress,
o ↑ pada kondisi inflamasi/peradangan
o ↓pada penyakit hati yang parah
o ↑ pada kadar hormone tiroid yang tinggi seperti pada hipertiroidisme dan
o ↑ pada kadar estrogen dan progesterone yang tinggi seperti pada kehamilan
 Kadar juga terkait dengan penanda genetik tertentu, khususnya golongan darah dan ras
o Kadar lebih ringgi pada golongan darah A dan B dibandingkan dengan golongan O 
Golongan O dikaitkan dengan tingkat glikosilasi protein yang relative rendah, vWF
kurang glikosilasi pada gologan O. tingakat protease ADAMTS-13, yang memotong vWF,
lebih tinggi pada golongan O
o Kadar vWF lebih tinggi pada orang-orang keturunan Afrika hitam daripada di Kaukasia.
Kisaran normal untuk orang Afrika hitam golongan darah non-O hamper tidak tumpeng
tindih dengan kelompok Kaukasia dari golongan O. Kelompok darah lainnya memiliki
efek yang lebih rendah
 Variasi polimorfisme nukleotida tunggal pada gen vWF juga mempengaruhi kadar vWF,
sebagian berpengaruh kerentanan terhadap proteolysis.
Von Willebrand Disease

 Quantitive deficient:
o Partial loss D3, D4  type 1
o Complete loss D3, D4  type 3  FVIII ↓
 Qualitative defect:
o Type 2A :
Decerase plateletdependent function with absence of high molecular weight multimers
 Loss D2, A2, CK (vWF;CB ↓ or LPA collagen ↓)
o Type 2B :
Over expression A1  Increase affinity vWF to GPIb/IX  platelet ↓ especially after
DDAVP (LPA ristocetin ↓)
o Type 2M :
Decrease platelet dependent function with present high molecular weight multimers 
Loss A1, A3 (FVIII N/↓ and vFW:CB ↓ or LPA collagen ↓)
o Type 2N :
Decrease affinity vWF to FVIII  Loss D’, D3  (vWF:Rco ↓ or LPA ristocetin ↓)
o Platelet type :
 No defect on vWF
 Increase affinity Platelet to nonspecific glycoprotein ligand including vWF cofactors
 Platelet can be decrease
Ristocetin (vWF;Rco) Serum Normal Range :

 Newborn (< 6 mo)  Ristocetin Deficient

o 50-200% (IU/dL) o vWF;Rco <60%
 Children (1-10 y) o Defisiensi Multimers Factor von
o 40-130% (O blood type) Willebrand or
o 50-180% (non-O blood type) o Penurunan afinitas monomer D3, or
 Adults monomer C1, or both terhadap
o 50-150% (O blood type) Ristocetin
o 60-180% (blood type non-O)
Pathogenetic Mechanisms of Acquired vW Siyndrome (AvWS):

a. Auto-antibodi spesifik terhadap vWF:Fvm

b. Antibody nonspesifik yang membentuk circulating immune-comlexes dan mendukung
clearance vWF oleh sel-sel phagosit yang mempunyai reseptor Fc
c. Pengikatan vWF oleh klon sel ganas
d. Peningkatan degradasi proteolitik dari vWF (mis. ADAMTS-13)
e. Hilangnya vWF multimers oleh keadaan shear stress yang tinggi
f. Penurunan sintesis atau pelepasan vWF

Acquired von Willebrand Disease:

 Defects in vWF that are not inherited directly but are consequences of other medical
disorders:
o Concentration, or
o Structure, or
o Function
 Acquired vWD can occur in patients with autoantibodies:
o In this case the function of vWF is not inhitied but the vWF-antibody complex is rapidly
cleared from the circulation
DISSEMINATED INTRAVASCULAR COAGULATION (DIC)
DIC has several terms, such as (there’s more):

 Overt DIC : decompensated DIC

o A state in which the vascular endothelium and its components have lost the ability to
compensate and restore homeostasis in response to injury
o The result is a progressively decompensating state that is manifest as thrombotic
multiorgan dysfunction and/or bleeding
 Non overt DIC : compensated DIC
o A clinical vascular injury state that results in great stress to the hemostatic system, the
response to which, for the moment, is suffucient to forestall further rampant
inflammatory and hemostatic activation

DIC, Consumption Coagulopathy :

 One of the most common and clinically important acquired disorders of hemostasis
 DIC, intravascular activation of coagulation system results in:
o Widespread deposition of fibrin microthrombi in the microcirculation
o Consumption of platelets and clotting factors
o Activation of the fibrinolytic system
 At the same time that thrombin converts fibrinogen to fibrin:
o It also activated Factor XIII to form a plasma transglutaminase (Factor XIIIa)
o F XIII: stabilizes finrin by cross-linking the gamma chains of fibrinogen in the region
of the D-domain
 Plasmin: digest fibrin and fibrinogen to produce fibrin (ogen) degradation (FDP) (or split,
FSP) products (X,Y<D and E), which are removed from the circulation by the
reticuloendothelial system
Managenment of DIC :
 No specific therapy has been shown to alter survival or change DIC severity
 Diagnosis and treatment of underlying disorder may result in complete resolution of DIC

In other (sepsis, SIRS), resolution may be slow and may require prolonged supportive measures
(Transfusion Plasma, PCC, vit K replacement platelet)
REAKSI TRANSFUSI
 Transfusi Masif : penggantian volume darah total pasien <24 jam
 Reaksi transfuse Hipokalemia terjadi karena dalam darah terdapat sitrat yang akan
mengikat kalsium
 Premedikasi transfuse menggunakan steroid (dexametason) digunakan untuk kasus2
autoimun hemolitik
 Premedikasi diuretic untuk kasus2 gangguan ginjal, gagal jantung
 Washed eritrosit hanya diberikan pada PNH (Paroxysmal Nocturnal Hemoglobinuria)
Appropriate Use of Blood / Blood Products (Components) :

1. Transfusion of safe blood products only to treat a condition leading to significant morbidity
or mortality that cannot be prevented or managed effectively by other means (it’s
contraindicated if no strong indications of BT)
2. Transfusion carries the risk of adverse reactions and transfusion-transmissible infection (TTI)
ABO-Rh Typing :

 Donor
 Pasien
 Total 5-10 menit

Cross-Matching :

 Bila lancar : 60-100 menit

 Bila tidak lancer (karena ada incompatible  ulang lagi ) : 120 menit)
 Bila tidak ada yang cocok  minta ke UTD

Pemeriksaan Cross Matching (Reaksi Silang = Cocok Serasi)

 3 fase : Fase I, II, III

 Fase I
o Suhu kamar, antibody komplit (ABO)  15’
o ABO-incompatible, cold auto agglutinin, cold allo agglutinin (anti-A1, -M, -P1, -Lewis, dll)
 Fase II
o Suhu 37° C, antibody imun (inkomplit)  15 ( medium bovine) s/d 60 menit (medium
saline)
o Bereaksi sensitisasi (coated)
o Antibody Rhesus (-D, -C, -E)
 Fase III
o 30-45 menit
o Antiglobulin = tes Coombs indirect (antibody ??komplit dalam serum)
o ??komplit: anti-K, -k, -Fy, -Jk, dsb

Storage Conditions (Red Cells and Whole Blood)

 Red cell and whole blodd must always be stored at a temperature between +2°C and +6°C.
they must never be allowed to freeze
 Whole blood and red cell should be issued from the blood bank in a blood transport box or
insulted carrier that will keep the temperature under 10°C if the ambient (room)
temperature is greater than 25°C or there is a possibility that the blood will not be
transfused within 30 minutes
 Unless required for immediate transfusion, the packs should be stored in the ward or
operating theater blood refrigerator at a temperature between …. 6°C
METASTATIC BREAST CANCER (MBC)
When Do We Need Chemotherapy in MBC?

 Treatment of choice for:

o Patients with FR-positive cancer that has become refractory to multiple hormonal
agents; or with visceral crisis
o Patients whose disease is FR-negative or has other characteristics that predict a poor
response to hormonal therapy
 May be administered as sequential single-agent therapy or as combination therapy:
o In the metastatic setting, combination therapy is associated with higher RR and longer
TTP than single-agent therapy, but only a modest survival benefit
o Single-agent therapy avoids overlapping toxicities
CHRONIC MYELOGENOUS LEUKEMIA
First Line Treatment of Chronic Phase CML

 The three commercially available TKIs for the front-line treatment of CML are IM, Nil and
Das; options for first-line therapy in CML CP are IM 400-800 mg/day, Nil 300 mg twice daily
or Das 100 mg/day.
 TKI selection should be based on treatment goals, age and comorbidities and should take
into consideration the adverse event (AE) profile of the available drugs.
 With all three TKIs, overall survival (OS) after 5 years is 85%-95%.

Nilotinib (Nil)

 Five years the cumulative incidences of MMR by 60 mo’s: 77%, 77% and 60%, respectively
(P<0,0001)
 The incidences of DMR with BCR-Abl (IS) 0.0032% (equivalent to a 4.5 log reduction) by 72
months were 56%, 55% and 33%, repectively (P<0,0001)
 The incidences of transformation to AP or BP were 3,9%, 2,1% and 7,4% respectively (P 0,06
and 0,003, repectively)
 The estimated 5-year survival rates were 94%, 96%, and 92%, respectively.

Selecting First Line Therapy

 Therapy goals should be discussed with the patient and defined before the selection of the
first-line drug
 With all three TKIs licensed for first-line therapy, survival chances are similar
 However, the chances to achieve DMR with an option to discontinue therapy is higher with
Das and Nil as compared with IM

Take Home Messages

 The three commercially available TKIs for the front-line treatment of CML are: IM, Nil and
Das
 TKI selection should be based on treatment goals, age and comorbidities the adverse event
(AE) profile of the available drugs.
 With all three TKIs, overall survival (OS) after 5 years is 85%-95%.
Conclusion

 2G-TKI therapy can be safely and successfully discontinued in patients with CP-CML with
long-lasting undetectable BCR-ABL transcript levels
 Most molecular relapses observed had an early onset, and all were sensitive to the
resumption of 2G-TKI therapy.
 The recurrence of low levels of detectable residual disease below MMR after 2G-TKI
withdrawal did not automatically herald CML relapse and did not preclude the possibility of
remaining treatment free.