Weekly objective

1. Able to describe the development of leukocyte.

EPO, erythropoietin; RBC, red blood cell; SCF :stem cell Factor; TPO:thrombopoietin.

Leukocyte maturation in the marrow is under the regulatory control of a number of different
factors, known as colony-stimulating actors (CSFs) and interleukins (ILs). Because an alteration
in the number and type of leukocytes is often associated with disease processes, total white
blood cell (WBC) count (cells per µL) and di erential counts are informative. T is chapter ocuses
on neutrophils, monocytes, and eosinophils.

(William’s hematology) Pada awal nya sel prekursor di sumsum tulang menjadi seri granulositik
— yaitu neutrofil, eosinofil, dan basofil — disintesis sedemikian rupa dan dibantu oleh protein,
SCF :stem cell Factor; TPO:thrombopoietin, IL-3 GM-CSF. Sintesis primer dari myeloblast dan
sel primitif yang hampir agranular dan merupakan prekursor granulosit paling awal akan
menjadi promyelocyte, yang kaya akan granul azurophilic. Munculnya granul spesifik ini
menandai perkembangan promyelocyte menjadi myelocyte lalu jadi neutrophilic, eosinofilik,
atau mielosit basofilik. Setelah itu, sel terus mengalami pematangan menjadi sel amitosis
dengan nukleus yang tersegmentasi, yang mampu melakukan kemotaksis, fagositosis, dan
pembunuhan mikroba. Granulosit yang matang juga nantinya mengembangkan sitoplasma dan
struktur permukaan yang memungkinkannya menempel dan menembus dinding dari venula.
Granulosit yang matang masuk ke dalam darah dari sumsum, bersirkulasi sebentar, dan pindah
ke jaringan untuk menjalankan fungsi utama sbagai host cell defense.

Neutrofil darah menunjukkan kapasitas untuk mengubah karakteristik fenotipikdan masa hidup
tergantung pada lingkungan perangsang sitokin dan kemokin.
Studi profil ekspresi gen menunjukkan bahwa neutrofil adalah transkripsi sel aktif, responsif
terhadap rangsangan lingkungan, dan mampu melakukan rangkaian yang kompleks

perubahan awal dan akhir dalam ekspresi gen.

Stem cells are multipotent cells that are the source of all descendant cells and have the capacity
to provide either long-term (measured in years) or short-term (measured in months) cell
production. Progenitor cells have a more limited spectrum of cells they can produce and are
generally a short-lived, highly proliferative population also known as transient amplifying cells.
Precursor cells are cells committed to a single blood cell lineage but with a continued ability to
proliferate; they do not have all the features of a fully mature cell. Mature cells are the terminally
diferentiated product of the differentiation process and are the effector cells of specific activities
of the blood and immune system. Progress through the pathways is mediated by alterations in
gene expression. The regulation of the differentiation by soluble factors and cell-cell
communications within the bone marrow niche are still being defined. The transcription actors
that characterize particular cell transitions are illustrated on the arrows; the soluble actors that
contribute to the differentiation process are in blue. This picture is a simplifi cation of the
process. Active research is revealing multiple discrete cell types in the maturation of B cells and
T cells and has identified cells that are biased toward one lineage or another (rather than
uncommitted) in their differentiation.

Neutrophils are phagocytic cells which migrate to the site of microbial infection, and kill the
microorganisms.

Monocytes and tissue macrophages also have microbicidal activity although, less effective than
that of neutrophils. They are also involved in phagocytosis and degradation of necrotic material.

Eosinophils are involved in defence against parasites and in allergic reactions.

Basophils along with mast cells are store houses of inflammatory mediators that are released
during IgE mediated hypersensitivity reactions and are responsible for the associated
inflammatory response and tissue injury.

Lymphocytes are non phagocytic cells. Both B and T lymphocytes with their ubsets are actively
involved in humoral and cell mediated immunity through their interaction with monocyte –
macrophage system. Cells seen in peripheral smear Polymorphonuclear neutrophil: This cell
has an eosinophilic cytoplasm, coarsely clumped nuclear chromatin and a lobulated nucleus, in
which the lobes are connected by filamentous strands of chromatin. Two types of granules are
present in the mature neutrophils- primary granules or azurophilic granules which contain
myeloperoxidase, lysozyme, acid phosphatase and acid hydrolase mainly and secondary
granules or specific granules which contain lysozymes, alkaline phosphatase and lactoferrin
mainly. Eosinophil: These cells are about 8µ in diameter and are recognized by their coarse,
bright orange reddish granules and a bilobed nucleus. The lobes are larger than those of the
neutrophils.
 2. Knows the pathophysiology and investigation of leukemia in childhood and adult
Leukemia merupakan keganasan yang ditandai dengan proliferasi sel imatur di sumsum tulang,
darah tepi, dengan infiltrasi organ hati, limpa dan kelenjar limfe. Proliferasi sel imatur
mengakibatkan penumpukan sel leukemik di dalam sumsum tulang, sehingga fungsi
hematopoesis dan trombopoesis tertekan.

Children’s hospital of philadelphia edu

The most common in children is acute lymphoblastic leukemia (ALL). Most children with ALL are
between the ages of 2 and 4 years. Acute myelogenous leukemia (AML) is the second most
common type of leukemia in children. AML is usually seen in very young children and
teenagers. Other types of leukemia are rarely seen in children.

There are 3 main types of leukemia in children:

 Acute lymphoblastic leukemia (ALL) pada lymphoid progenitor

 Acute myelogenous leukemia (AML) gangguan pada myeloid progenitor
 Chronic myelogenous leukemia (CML)

Causes

(NCBI) ALL disebabkan Gangguan pada cytosolic signal transduction menyebabkan molecular
abnormality; the abnormalities include gene mutations, abnormal protein interaction, unarrested
cell cycle and increased autophagy
 malignancies of precursor-stage lymphoid cells inhibit lymphoid differentiation, leading to
abnormal cell proliferation and survival. The occurrence of B-ALL is known to correlate with a
series of gene mutations, which often start at the pluripotent stem cell stage, DIIKUTI OLEH
ADANYA PROSES dari clonal expansion, differentiation, cell proliferation and dysregulated cell
apoptosis; the end result is the replacement of normal lymphoid cells by malignant cells

The pluripotent stem cell is the first stage of development of all of the blood cells (white
blood cells, red blood cells, and platelets). This stem cell goes through stages of
development until it matures into a functioning cell. The type of leukemia is determined
by where the cell is in the stage of development when it becomes malignant, or
cancerous. When leukemia occurs, the abnormal cells (blasts) begin to reproduce very
rapidly and begin crowding out and competing for nutrients and space with the other
healthy cells.

The stem cell matures into either the lymphoid or myeloid cells. The lymphoid cells
mature into either B-lymphocytes or T-lymphocytes. If the leukemia is among these cells,
it is called acute lymphoblastic leukemia (ALL). If the leukemia is found even further
along this stage of development, it can be further classified as B-cell ALL or T-cell ALL.
The more mature the cell, the more difficult it is to treat.
The myeloid cells develop into platelets, red blood cells, and specialized white blood
cells, such as neutrophils and macrophages. There are many classifications of AML. The
type of leukemia is determined by the type of blood cell that is affected and the the stage
of development when the normal cells become leukemia cells.

The following are the most common symptoms of leukemia. However, each child may
experience symptoms differently. Symptoms may include:

 Anemia. When red blood cells are unable to be produced because of the crowding in
the marrow, anemia is present. With anemia, the child may appear tired, pale, and may breathe
faster to compensate for the decrease in oxygen carrying capacity. The number of red blood
cells on a blood count will be below normal.
 Bleeding and/or bruising. When platelets are unable to be produced because of the
crowding in the marrow, bleeding can occur and the child may begin to bruise more easily.
Petechiae are tiny red dots often seen on the skin of a child with low number of platelets.
Petechiae are very small artery that have leaked or bleed. The number of platelets on a blood
count will be below normal. Thrombocytopenia is the term used for a decreased number of
platelets.
 Recurrent infections. Although there may be an unusually high number of white blood
cells on a blood count of a child with leukemia, these white blood cells are immature and do not
fight infection. The child may have had repetitive viral or bacterial infections over the past few
weeks. The child with leukemia often shows symptoms of an infection such as fever, runny
nose, and cough.
 Bone and joint pain. Pain in bones and joints is another common symptom of leukemia.
This pain is usually a result of the bone marrow being overcrowded and ful oleh sel abnormal.
 Abdominal distress. Abdominal pain may also be a symptom of leukemia. Leukemia
cells can collect in the kidney, liver, and spleen, causing enlargement of these organs. Pain in
the abdomen may cause a child to have loss of appetite and weight loss.
 Swollen lymph nodes. The child may also have swelling in the lymph nodes under the
arms, in the groin, chest, or in the neck. Lymph nodes are responsible for filtering the blood.
Leukemia cells may collect in the nodes, causing swelling.
 Difficulty breathing (dyspnea). sel cancer dari ALL, cenderung menggumpal
bersamaan dengan T-CELL disekitar area thymus, a small organ just behind the breastbone.
This mass of cells present in the middle of the chest can cause pain and difficulty breathing
(dyspnea). Wheezing, coughing, and/or painful breathing requires immediate medical attention.

With acute leukemia (ALL or AML), these symptoms may occur suddenly in a matter of days or
weeks. With chronic leukemia (CML), these symptoms may develop slowly over months to
years (Williams and internet)

Lab

anak yang menderita LLA memiliki jumlah sel darah merah yang rendah, kadar hemoglobin yang rendah,
dan jumlah trombosit yang menurun. Jumlah sel darah putih biasanya meningkat (Leukemia Foundation,
2010). Sumsum tulang yang normal mengandung kurang dari 5% sel blast. Pada penderita leukemia
sumsum tulang diinfiltrasi oleh blast leukemia dan spesimen sumsum tulang menjadi hiperseluler.
Seseorang harus dicurigai menderita leukemia bila sumsum tulang mengandung lebih dari 5 % sel blast.
Diagnosis LLA ditegakkan apabila pada pemeriksaan aspirasi sumsum tulang didapatkan komponen
sumsum tulang mengandung 30% sel muda (blast)
 3. Able to differentiate acute and chronic leukemia

(NCBI) Acute lymphocytic leukemia occurs when a bone marrow cell develops changes
(mutations) in its genetic material or DNA. In acute lymphocytic leukemia, the mutations tell
the bone marrow cell to continue growing and dividing.

when this happens, blood cell production becomes out of control. The bone marrow
produces immature cells that develop into leukemic white blood cells called
lymphoblasts. These abnormal cells are unable to function properly, and they can build
up and crowd out healthy cells.

Etiology:

- Antecedent hematologic disorders: Myelodysplastic syndrome (MDS), aplastic anemia,

myelofibrosis
- Congenital disorders: predispose to AML includes Bloom syndrome, Down syndrome, Fanconi
anemia, neurofibromatosis
- Familial syndromes: Mutation of gene AML1; an autosomal dominant disorder
- Environmental exposure: radiation
- Chemotherapeutic agents
Clinical Features:

- Usually present with some combination of granulocytopenia, anemia, thrombocytopenia,

appearance of immature cells (blast) in blood and marrow
- In older patients: preexisting myelodysplastic syndrome
- In younger patients: catastrophic illness characterized by sudden appearance of fatigue, fever,
bacterial infections of the upper respiratory tract, bone pain, various bleeding manifestations
(petehiae, gum bleeding, nose-bleeds, menorrhagia, prominent bruising)
- Rarely, patients present with chloroma (tumor mass of myeloblast)

Acute myelogenous leukemia (AML) is the result of a sequence of somatic mutations in a

primitive multipotential hematopoietic cell. Exposure to radiation, chronic exposure to high
doses of benzene, and chronic inhalation of tobacco smoke increase the incidence of the
disease. Obesity has been found to be an endogenous risk factor.
CML – Chronic Myeloid Leukemia

Chronic myelogenous leukemia (CML), also called chronic myeloid leukemia, is a clonal
myeloproliferative neoplasm of the primitive hematopoietic stem cell that is characterized by
overproduction of cells of the myeloid series, resulting in marked splenomegaly and leukocytosis.

A characteristic cytogenetic abnormality, the Philadelphia (Ph) chromosome, which produces the fusion
oncogene BCR-ABL, is present in the bone marrow cells in more than 90% of cases . Most patients (85 to
90%) present in the chronic phase.
CLL – Chronic Lymphoblastic Leukemia

CLL is a neoplasm characterized by the accumulation of monoclonal lymphocytes of B-cell origin. The
cells accumulate in the bone marrow, lymph nodes, liver, spleen, and occasionally other organs.
4. Knows the pathophysiology and investigation of Myeloproliferatif disorders,  Multiple
myeloma, Langerhans  cell histiositosis, Hodkins Disease and Non Hodkins lymphoma

Penyakit mieloproliferatif (myeloproliverative neoplasms/MPN) merupakan kelainan hematologik yang terdiri

dari polisitemia vera (PV), trombositemia esensial (ET) dan myelofibrosis primer (PMF), dan thrombosis
arteri-vena merupakan komplikasi yang sering terjadi pada pasien MPN. Dapat dijumpai komplikasi
trombosis multipel dan trombosis vena splanknik berupa trombosis vena porta, vena mesenterika, arteri
mesenterika pada subjek dengan MPN

Johns hopkins medicine

Penyakit Myeloproliferative Neoplasms (MPN) terdiri atas beberapa kelainan darah,
diantaranya Chronic Myeloid Leukemia (CML), Polyctyhemia Vera (PV), Essential
Thrombocythemia (ET) dan Primary Myelofibrosis (PMF). Kelainan fungsi darah tersebut
disebabkan oleh adanya translokasi gen BCR-ABL1 dan mutasi JAK2. Kelainan genetik
tersebut mengakibatkan aktivasi terus-menerus enzim tirosin kinase. 

The chronic myeloproliferative disorders (also known as myeloproliferative neoplasms)

are a unique group of hematopoietic stem cell disorders that share in common mutations
which continuously activate JAK2 (Janus kinase 2), an enzyme that normally stimulates
the production of red blood cells, white blood cells (granulocytes, monocytes, basophils
and eosinophils) and platelets. JAK2 is normally only activated when additional blood
cell production is needed.  Because the blood cells in the myeloproliferative disorders
are usually normal in appearance, these disorders mimic clinically benign or reactive
blood conditions in which blood production is increased because of stimuli such as
hypoxia, inflammation or infection as well as certain blood malignancies such as chronic
myelogenous leukemia and myelodysplasia.
 Langerhans cell histiocytosis
Definition

A group of idiopathic disorder characterized by the presence of cells with characteristic similar
to bone marrow derived langerhans cells (immature langerhans cell). In LCH, too many
langerhans cells are produced and build up in certain parts of the body where they can damage
the organs. LCH may occur at any age, but is most common in young children. LCH dibagi jadi
2 berdasarkan organ yang terpengaruh:

 Low-risk (less extensive) LCH involves either:

1. Skin only;
2. Bone only, either a single bone or multiple bones; or
3. Multiple organs but not the liver, bone marrow or spleen.
 High-risk (more extensive) LCH:
1. involves multiple organs including the liver, bone marrow or spleen; and is more
common in children younger than 2 years old.
Symptoms

Bergantung pada akumulasinya dimana dan dapat mempengaruhi lebih dari 1 organ:

 Skin : scaly, waxy rash, or lesions, hair loss

 Bones : bone pain, headaches, inability to walk
 Bone marrow : Low blood counts (either RBC, wbc, platelet bisa rendah)
 Lungs : chest pain, shortness of breath, dry cough
 Teeth : loss of teeth, ulceration, swelling
 Ears : chronic ear infection, balance problems, decreased hearing
 Endocrine system : fatigue, sweats, weight gain or loss
 Liver/spleen/lymph nodes: swelling
 GI tract : diarrhea, nausea, vomiting
 CNS : seizure, weakness
Risk factor

 Having a parent who was exposed to certain chemicals such as benzene.

 Having a parent who was exposed to metal, granite, or wood dust in the workplace.
 A family history of cancer, including LCH.
 Having infections as a newborn.
 Having a personal history or family history of thyroid disease.
 Smoking, especially in young adults.
 Being Hispanic.
Pathophysiology

*masih belum jelas, tapi ini yang gw dapet

Somatic mutations in the BRAF gene have been identified in the Langerhans cells of about half
of individuals with Langerhans cell histiocytosis. Somatic gene mutations are acquired during a
person's lifetime and are present only in certain cells. These changes are not inherited.

The BRAF gene provides instructions for making a protein that is normally switched on and off
in response to signals that control cell growth and development. Somatic mutations cause the
BRAF protein in affected cells to be continuously active and to transmit messages to the
nucleus even in the absence of these chemical signals. The overactive protein may contribute to
the development of Langerhans cell histiocytosis by allowing the Langerhans cells to grow and
divide uncontrollably.

Diagnosing

A variety of tests and investigations may be needed to diagnose LCH. X-rays will often be taken
of the bones, the skull and the lungs. Blood tests will also be taken. These tests help the doctors
decide whether the disease is a single-system or multi system type.

Tests are likely to include the removal of a sample of cells (a biopsy), which is usually done in
an operation under a general anaesthetic. The cells are then examined under a microscope. An
MRI (magnetic resonance imaging) scan of the brain may also be carried out. Biopsy and
microscopic examination of the affected tissue may show birbeck granules (small tennis racket
shaped membrane bound granule)
Learning Objectives

Pathophysiology of Fever

GUYTON AND SHERWOOD

Demam yang berarti temperatur tubuh di atas batas normal, dapat disebabkan oleh kelainan di dalam
otak sendiri atau oleh bahan-bahan toksik yang mempengaruhi pusat pengaturan suhu. Demam terjadi
oleh karena pengeluaran zat pirogen dalam tubuh. Zat pirogen sendiri dapat dibedakan menjadi dua
yaitu eksogen dan endogen. Pirogen eksogen adalah pirogen yang berasal dari luar tubuh seperti
mikroorganisme dan toksin. Sedangkan pirogen endogen merupakan pirogen yang berasal dari dalam
tubuh meliputi interleukin-1 (IL-1), interleukin-6 (IL-6), dan tumor necrosing factor-alfa (TNF-A). Sumber
utama dari zat pirogen endogen adalah monosit, limfosit dan neutrophil. Seluruh substansi tersebut
nantinya menyebabkan sel fagosit mononuclear (monosit, makrofag, sel kupfeer) membuat sitokin yang
bekerja sebagai pirogen endogen atau suatu protein kecil yang mirip interleukin, yang merupakan suatu
mediator proses imun antar sel yang penting. Sitokin-sitokin tersebut dihasilkan secara sistemik ataupun
local dan memasuki sirkulasi. Interleukin-1, interleukin-6, tumor nekrosis factor α dan interferon α,
interferon β serta interferon γ berperan terhadap proses terjadinya demam. Sitokin-sitokin tersebut
juga diproduksi oleh sel-sel di Susunan Saraf Pusat (SSP) dan kemudian bekerja pada daerah preoptik
hipotalamus anterior. Sitokin akan memicu pelepasan asam arakidonat dari membrane fosfolipid
dengan bantuan enzim fosfolipase A2. Asam arakidonat selanjutnya diubah menjadi prostaglandin
karena peran dari enzim siklooksigenase (COX) dan menyebabkan demam pada tingkat pusat
termoregulasi di hipotalamus. Pirogen endogen bekerja secara langsung pada hypothalamus yang
mengatur termoregulasi

Demam dapat disebabkan oleh faktor infeksi dan non infeksi. Beberapa penyebab demam dari infeksi
meliputi infeksi dari virus, jamur, parasit maupun bakteri. Penyebab demam non infeksi bisa dari faktor
lingkungan seperti lingkungan yang padat dan dapat memicu timbulnya stres ataupun pengeluaran
panas berlebihan dalam tubuh.
The pathophysiology of tumor-induced fever may be due to several mechanisms of this

which include release of cytokines from tumor cells or infiltrating mononuclear cells (e.g., tumor necrosis factor and
interleukin-1); necrosis of tumoral tissue; or obstruction of a hollow duct or viscus resulting in proximal infection (e.g.,
a cholangiocarcinoma causing biliary obstruction and ensuing suppurative cholangitis). Other causes of fever in the
cancer patient include drug fever (e.g., antibiotics, chemotherapy drugs); thrombotic thrombocytopenic purpura (TTP;
which may result from chemotherapy or the tumor itself); and deep venous thrombosis/Trousseau’s syndrome.

Patients with previously undiagnosed, but suspected, cancer may develop fever from exposure to infectious agents,
especially if they have myeloma or leukemia. For instance, patients with chronic lymphocytic leukemia may be
hypogammaglobulinemic and be prone to infection with encapsulated bacteria such as Streptococcus pneumoniae.
Also, a patient with undiagnosed advanced Hodgkin’s lymphoma with splenic involvement

Chemotherapy-Induced Fever
Chemotherapeutic and biologic drugs that have been implicated in causing fever include azathioprine, hydroxyurea,
interleukin-2, rituximab, and interferon. Fever is attributed to numerous chemotherapy drugs as an uncommon or rare
occurrence. 

Definisi (cut-off) chronic fever berapa lama

buku understanding pathophysiology

by Sue E. Huether, Kathryn L. McCance 

2.Differential diagnosis dari chronic fever pada anak-anak (etiologies)

TB, Malignancy, demam tanpa penyebab jelas, leukemia, pasien dgn immunocompromised

3.Hubungan fever dan nosebleed pada anak-anak (pathophysiologynya juga)

5. Development of leukocytes

Nice to know: Liver and spleen function test

The liver-spleen test can indicate functional abnormalities of the liver and spleen based upon the
amount and location of the radioactive tracer that is phagocytized by each organ’s phagocytic cells. The
liver/spleen scan was utilized more frequently before the widespread adoption of CT, ultrasound, and
MRI to assess the severity of liver damage in patients with cirrhosis, elevated liver enzymes, and to
diagnose conditions such as focal nodular hyperplasia and assess splenic injury in trauma patients

Tc-99m sulfur colloid is injected through the veins and is subsequently taken up by the mononuclear
phagocyte system (aka reticuloendothelial system) of the patient’s liver, spleen, and bone marrow.
[4] The technician takes planar computerized images are using a scintillation gamma camera with the
patient in various anatomical positions. The interpreter of the test then compares the amount of Tc-99m
sulfur colloid phagocytosed by the liver’s Kupffer cells to the amount of Tc-99m colloid phagocytosed by
the spleen and bone marrow. A decrease in Tc-99m colloid uptake by the liver’s Kupffer cells along with
an increase in uptake by the spleen and bone marrow is known as the “colloid shift.” These findings
indicate damage to the phagocytic components of the liver and represent an increase in uptake by the
spleen and bone marrow. Areas with decreased uptake appear dark or non-existent on the scan while
areas of increased uptake appear bright. This planar imaging provides a qualitative view of the function
of the liver and spleen.

procedure may take approximately 45 minutes to complete. After obtaining written and verbal
consent, the patient is accompanied to the radiology suite, and a peripheral IV is placed in the
patient’s arm. Radioactive Tc-99m tracer is then injected into the patient’s veins. After
approximately 10 to 15 minutes, a scintillation gamma camera takes images while the patient is
placed in various positions. The patient is asked to lay in the anterior, posterior, and oblique right
positions as images are taken of the patient’s liver[4]Left-sided images are taken to evaluate the
patient’s spleen.[4] The patient is asked to lay still with minimal movement throughout the
procedure, except when repositioned. SPECT/CT may be performed following the liver/spleen
scan. SPECT/CT generally takes an additional 15 to 20 minutes to perform. Once the images are
obtained, and the scan is complete, the peripheral IV is removed