UNIVERSITAS MUSLIM INDONESIA MAKASSAR, 24 JULI 2018

FAKULTAS KEDOKTERAN

LAPORAN KELOMPOK PBL

“MODUL PERDARAHAN”
BLOK IMUNOLOGI DAN HEMATOLOGI

Pembimbing : dr. Edward Pandu Wiriansya, Sp.P

Disusun oleh Kelompok 15 :

Andi Azizah Nur F.S 11020170030 Siti Alzavira Chairunnisa 11020170095

Rahmi Utami 11020170024 Jihan Rana Mardhiyah 11020170115
Ari Savira Alda 11020170044 M. Ilhamsyah Dandung 11020170008
Muhammad Fakhri 11020170069 Adibah Afriastini Wenni 11020170133
M. Avizena Ilhami. S 11020170078 Afifah Syahbani Zainal 11020170110

FAKULTAS KEDOKTERAN
UNIVERSITAS MUSLIM INDONESIA
MAKASSAR
2018
SCENARIO

A 60 year old white male presented with a 4 day history of bleeding from the gums,
diffuse spontaneous ecchymoses, mild fatigue, and bone pain. The patient described
a 6 months history of pain localized to his right thigh with extension to the posterior
part of his right leg. His past medical history included atrial fibrillation,
hypercholesterolemia and hypertension, all well controlled with medication. He had
never smoked and had moderate alcohol consumption until 1 year ago. His blood
pressure was 138/64, his pulse rate was 57, and his temperature was 37.31c. There
was no peripheral lymphadenopathy. Chest was clear to auscultation and the lower
extremities showed confluent ecchymoses involving the left ankle, and the posterior
of both thighs.

DIFFICULT WORDS
 Ecchymoses
An ecchymosis is asubcutaneous spot of blleding (from
extravasation of blood) with diameter larger than 1 centimetre (0.39 in).
Reference: Ecchymosis, Department of Dermatology, University of
California San Francisco

 Atrial fibrillation
AF is a common and important disturbance of the electrical system
of the heart. It is one of a number of disorder commonly referred to as
‘arrhythmias’ or ‘dysrhythmias’ in which the heart beats with an abnormal
rhythm.
If not recognized and correctly treated, AF can result in significant
problem, including stroke and heart failure
Reference: Heart Foundation. 2016. National Heart Foundation of
Australia, ABN 98 008 419 761

 Hypercholesterolemia
Hypercholesterolemia is abnormally high levels of cholesterol in the
blood.
Reference: Durrington, P. 2012. “Dyslipidaemia”. The lancet. Pg 362

KEYWORDS
 A 60 year old white male.
 4 day bleeding from the gums.
 Diffuse spontaneous ecchymoses, mild fatigue, and bone pain.
 6 month history of pain localize to his right thigh.
 Medical history: atrial fibrillation, hypercholesterolemia, hypertension.
 Dry blood in his mouth, not active bleeding.
 Never smoke and had moderate alcohol for 1 year.
 Temperature 37,31c.
QUESTIONS
1. What is definition of the hemostasis and how is the mechanism?
2. Explain factors of hemostasis?
3. What is ecchymosis?
4. What are the DD and treatments?
5. What is the perspective islam based on the scenario?

ANSWERS

1. Hemostasis is the physiological process that stops bleeding at the site of an

injury while maintaining normal blood flow elsewhere in the circulation.
Blood loss is stopped by formation of a hemostatic plug. The endothelium
in blood vessels maintains an anticoagulant surface that serves to maintain
blood in its fluid state, but if the blood vessel is damaged components of the
subendothelial matrix are exposed to the blood. Several of these
components activate the two main processes of hemostasis to initiate
formation of a blood clot, composed primarily of platelets and fibrin. This
process is tightly regulated such that it is activated within seconds of an
injury but must remain localized to the site of injury.

There are two main components of hemostasis. Primary hemostasis refers

to platelet aggregation and platelet plug formation. Platelets are activated in
a multifaceted process (see below), and as a result they adhere to the site of
injury and to each other, plugging the injury. Secondary hemostasis refers
to the deposition of insoluble fibrin, which is generated by the proteolytic
coagulation cascade. This insoluble fibrin forms a mesh that is incorporated
into and around the platelet plug. This mesh serves to strengthen and
stabilize the blood clot. These two processes happen simultaneously and are
mechanistically intertwined. The fibrinolysis pathway also plays a
significant role in hemostasis. Pathological thrombus formation, called
thrombosis, or pathological bleeding can occur whenever this process is dis-
regulated. The complexity of these systems has been increasingly
appreciated in the last few decades.

Multiple anticoagulant mechanisms regulate and control these systems to

maintain blood fluidity in the absence of injury and generate a clot that is
proportional to the injury. The proper balance between procoagulant
systems and anticoagulant systems is critical for proper hemostasis and the
avoidance of pathological bleeding or thrombosis.

 Primary Hemostasis
Platelets are small anuclear cell fragments that bud off from
megakaryocytes, specialized large polyploid blood cells that originate in the
bone marrow. Platelets are present at 150 to 400 million per milliliter of
blood and circulate for about ten days. In a healthy blood vessel, and under
normal blood flow, platelets do not adhere to surfaces or aggregate with
each other. However, in the event of injury platelets are exposed to
subendothelial matrix, and adhesin and activation of platelets begins

 Secondary Hemostasis

Secondary hemostasis consists of the cascade of coagulation serine

proteases that culminates in cleavage of soluble fibrinogen by thrombin.
Thrombin cleavage generates insoluble fibrin that forms a crosslinked fibrin
mesh at the site of an injury. Fibrin generation occurs simultaneously to
platelet aggregation. In intact and healthy blood vessels this cascade is not
activated and several anticoagulant mechanisms prevent its activation.
These include the presence of thrombomodulin and heparan sulfate
proteoglycans on vascular endothelium. Thrombomodulin is a cofactor for
thrombin that converts it from a procoagulant to an anticoagulant by
stimulating activation of the anticoagulant serine protease protein C.
Heparan sulfate proteoglycans stimulate the activation of the serine protease
inhibitor (or serpin) antithrombin, which inactivates thrombin and factor Xa
When the vascular system is injured, blood is exposed to extravascular
tissues, which are rich in tissue factor (TF), a cofactor for the serine protease
factor VIIa. The complex of TF and factor VIIa activates factor X and factor
IX. This activation pathway is historically termed the extrinsic pathway of
coagulation. Factor IXa also activates factor X, in the presence of its
cofactor factor VIIIa. Factor Xa, also in the presence of its cofactor factor
Va, then activates prothrombin to generate thrombin.

Thrombin is the central serine protease in the coagulation cascade, and it

executes several critical reactions. Thrombin critically cleaves fibrinogen to
generate insoluble fibrin. Thrombin activates platelets via cleavage of PAR1
and PAR4. Thrombin is also responsible for positive feedback activation of
coagulation that is critical for clot propagation. Thrombin activates factor
XI, which then activates factor IX and thrombin activates cofactors VIII and
V. This has historically been called the intrinsic pathway of coagulation, but
it is more appropriate to think of it as a positive feedback loop.

The updated cell-based model of hemostasis focuses on the important fact

that these reactions are controlled by their localization on different cellular
surfaces. Coagulation is initiated by the cofactor TF (the extrinsic pathway),
which is a transmembrane protein present on fibroblasts and other
extravascular tissues. The factor Xa generated here forms prothrombinase
complex on these surfaces sufficient to generate only a small amount of
thrombin. Then amplification and propagation of coagulation via the
positive feedback loop occurs on the surface of platelets, which are activated
near the site of injury by that trace thrombin and by adherence to
extracellular matrix. Thus, the active coagulation complexes of this positive
feedback loop form on the surface of activated platelets.

Ultimately thrombin also plays an important role in down regulation of the

coagulation cascade by binding to thrombomodulin on endothelial cells and
then activating protein C (APC). The activated protein C anticoagulant
system is important for the down regulation of the coagulation cascade.
APC cleaves and inactivates the procoagulant cofactors VIIIa and Va. This
reaction also requires a cofactor, protein S; in addition, factor V provides
anticoagulant function as a cofactor for APC/protein S in the inactivation of
factor VIIIa and factor Va. These complexes between proteases and
cofactors (procoagulant and anticoagulant) form on negatively charged
membrane surfaces that are provided by activated platelets. This
localization of the coagulation cascade reactions is critical to restrict
coagulation to the site of injury.

The coagulation cascade is also down-regulated by inactivation of all the

serine proteases by serine protease inhibitors. Most of these inhibitors are
in the serpin family of inhibitors. Antithrombin is arguably the most
important of these. Antithrombin inhibits thrombin and factor Xa, as well
as factor IXa and factor XIa in the presence of heparin or heparan sulfate.
Other serpins that play roles in coagulation include heparin cofactor II
(thrombin inhibitor), protein Z-dependent protease inhibitor (factor Xa
inhibitor), protein C inhibitor (APC inhibitor) and C1-inhibitor (factor XIa
inhibitor). Two non-serpin inhibitors, tissue factor pathway inhibitor and
alpha-2-macroglobulin, also play a significant role, inhibiting factor Xa and
thrombin, respectively.1
2. There are 4 factor that involved in hemostasis, such as

 Vascular system

 Thrombocyte system

 Coagulation system

 Fibrinolysis system

Thrombocyte is important in the beginning of process coagulation.

And then, finish with synthesis thrombocyte aggregation

(a) Platelet adhesion

(b) Platelet activation

(c) Platelet aggregation

4 main step of coagulation for produced fibrin

1. The first step: Involved intrinsic and extrinsic pathway

each produced tenase complex which can activate f.X
become f.X active.

2. The second step: Forming prothrombin activator

(prothrombin complex) which can cause prothrombin
become to thrombin.

3. The third step: prothrombin activator transforming

prothrombin to thrombin.

4. Fourth step: thrombin breaking fibrinogen to fibrin.

 Coagulation system

Coagulation factor or clotting factor is a protein in the plasma that

works in the coagulation factor. Protein is inactive (proenzyme or
zymogen) if activation is occurred, this active protein (enzyme) will
activated the circuit of the next activated, like a stairs (cascade or
like waterfall).

In the outline the process of blood clotting goes through three stages:
(1) activation of thromboplastin; (2) formation of thrombin from
prothrombin, and (3) fibrin formation of fibrinogen.
In vitro thromboplastin activation, which converts prothrombin
(factor II) to thrombin (factor IIa), occurs through two mechanisms,
namely extrinsic and intrinsic mechanisms. In the extrinsic
mechanism, tissue thromboplastin (factor III, derived from damaged
tissue) will react with factor VIIa which in the presence of calcium
(factor IV) activates factor X. Factor Xa together with factor Va,
calcium ions and platelet phospholipids will change prothrombin
become thrombin. By the influence of thrombin, fibrinogen (factor
I) is converted to unstable monomeric fibrin (factor Ia). Fibrin
monomers, under the influence of factor XIII, will become stable
and resistant to proteolytic enzymes such as plasmin.

In intrinsic mechanism, all the factors necessary for blood clotting

are in the blood. Freezing begins when the Hageman factor (factor
XII) contacts a negatively charged surface, such as damaged
subendothelial collagen. The reaction is accelerated by the
formation of a complex between factor XII, Fitzgerald factor and
precekrein. Factor XIIa will then activate factor XI, and factor XIa
with calcium ions will activate factor IX. Factor IX is active,
together with factor VIII, calcium ions and phospholipids will
activate factor X. The next sequence of blood clotting mechanisms
is the same as that which occurs in the extrinsic mechanism.
  Fibrinolysis system

The process of fibrinolysis is purposed to form plasmin which can

breaks the fibrin’s clot that over or it can breaks fibrin after
reparation process of blood vessel is done.

The injury (from kallikrein) is activate tPA so do the activate of

plasminogen become plasmin. Plasmin will break the fibrin to FDP.
For controlling the fibrinolysis process, so there are controlling
factor: plasminogen activator inhibitor which inhibits tPA and
alpha-2-antiplasmin which inhibits the plasmin works.2

3. Ecchymosis
Ecchymosis is a large area of discoloration caused by extravasation
of blood into the subcutaneous tissue. It is an objective physical finding that
may provide valuable clues as to its possible etiology. Ecchymosis is
associated with eponyms based on the physician who first described the
physical findings, which can be divided into 4 anatomical categories: base
of the skull, abdominal wall and retroperitoneum, groin and scrotum, and
lower extremity. Classic external signs and eponyms associated with
ecchymosis are reviewed. Knowledge of these signs on physical
examination may prove to be a useful clue directing the examiner to
consider potentially serious causes of disease.
Ecchymosis is defined as a large area of discoloration of the skin
due to extravasation of blood into the subcutaneous tissue. The term is often
used interchangeably with purpura, which describes similar characteristic
discoloration of the subcutaneous tissue but usually is reserved for a larger,
more extensive area of involvement. Ecchymosis is an objective physical
finding that may provide valuable clues as to its possible etiology. The
causes of ecchymosis are many; however, there are certain regions where
the discoloration aids in the search for the etiology. The color of the
subcutaneous tissue reflects the physiologic sequences of hemoglobin
catabolism and its conversion to bilirubin and hemosiderin. Thus, the tissue
progressively transforms over time from purple or black and blue to a
yellow and green color and finally a brownish discoloration. It is recognized
that the ecchymotic region will have different shades of color, reflecting
differential rates of hemoglobin catabolism. Ecchymosis caused by internal
conditions can be divided into 4 anatomical areas (Table 1). These regions
are assigned an eponym associated with the physician who first described
the physical finding. In this report, we review the classical signs and
 eponyms associated with ecchymosis that may be markers of potentially
serious internal bleeding. Furthermore, these signs may be potentiated by
anticoagulation therapy or qualitative and quantitative platelet
abnormalities. Prompt laboratory and imaging studies are important to
further elucidate the cause of the ecchymosis and guide appropriate
intervention. It is important that, in addition to a careful physical
examination, a thorough review of the patient’s medications and past
medical history be conducted.3

4. As the conclusion of our discussion, we diagnose in this scenario the disease

is Vitamin K insufficiency. Because, Vitamin K insufficiency causes by
alcoholism, cholestatic disease, chronic kidney injury, etc which involved
the complain of the patient in the scenario.

So, the DD that we though are ITP (Idiophatic Thrombocytopenia Purpura),

Leukemia, and Haemophilia.

a. Haemophilia

This is an inherited condition that impairs the body’s ability to

coagulate the blood

b. Leukemia

This is rare neoplasm of the blood or bone marrow. It’s classified

into lymphoid and myeloid neoplasms that may present chronically
or acutely. These 4 classifications are:

1. Acute Lymphoblastic Leukemia (ALL)

2. Chronic Lymphocytic Leukemia (CLL)
3. Acute Myeloid Leukemia (AML)
4. Chronic Myeloid Leukemia (CML)

c. ITP

Idiophatic Thrombositopenia Purpura is increase the destruction of

thrombocyte that make the age of thrombocyte is short. The
classification is

a. Acute ITP (85%-90%) = self limiting

The age is around 2-8 years old. It can be infected by virus, like
ISPA, hepatitis, MUMPS, Mononucleosus Infectiosa, etc

b. Chronic ITP (10%-15%) = adult

 Thrombocytopeni (<100.000/mm3). The oge around 10 years
old. Dominant in female than male.4

5. Perspective Islam
 REFERENCE

1. Gale, A. J. 2011. Current Understanding of Hemostasis. Toxicologic

Pathology, 39(1), 273–280.
2. Imade, Bakta. 2006. Hematologi Ringkas. Jakarta : Penerbit Buku
Kedokteran. Hal. 234-239
3. Narendranath Epperla, MD, et all. 2015. A Review of Clinical Signs
Related to Ecchymosis. Vol 114. No.2. pp. 61-65.
4. Smith, Olivia. 2015. Mind Maps for Medical Students. The Hull York
Medical School, UK. Page: 98-101