Bleeding Disorders.

Hemostasis is a complex interaction between vessels, platelets and coagulation proteins that, when
working properly, stops bleeding while maintaining blood flow in the vessel. Hemostasis involves four
distinct but at the same time interrelated functions: vessel wall function, platelet function, coagulation and
fibrinolysis. Specific tests are available to evaluate platelet function, coagulation proteins, natural occurring
inhibitors and fibrinolysis.

Platelets play an immediate and central role in hemostasis. Qualitative and/or quantitative defects may
exist which lead to excessive bleeding.

The   endothelial cells of intact vessels prevent blood clotting with a heparin-like molecule
and  thrombomodulin and prevent platelet aggregation with  nitric oxide and prostacyclin.

When endothelial injury occurs, the endothelial cells stop secretion of coagulation and aggregation
inhibitors and instead secrete von Willebbrant factor, which initiate the maintenance of hemostasis after
injury.

Definition of von Willebrand factor. : a large glycoprotein clotting factor circulating in blood plasma that
mediates platelet adhesion to collagen at sites of vascular injury, that binds to and protects factor VIII
from degradation, and that is deficient or defective in individuals affected with von Willebrand disease.
When a blood vessel is damaged, there are three stages in the normal formation of a clot. 

Stage 1: The blood vessels constrict to slow the flow of blood to the injured area

Stage 2: Platelets stick to, and spread on, the walls of damaged blood vessels. This is called platelet
adhesion. These spreading platelets release substances that activate other nearby platelets which
clump at the site of injury to form a platelet plug. This called platelet aggregation. 

Stage 3: The surface of these activated platelets then provides a site for blood clotting to occur.
Clotting proteins like factor VIII and IX circulating in the blood are activated on the surface of the
platelets to form a mesh-like fibrin clot. 

These proteins (factors I, II, V, VII, VIII, IX, X, XI, XII AND XIII and von Willebrand factor) work like
dominos, in a chain reaction. This is called the coagulation cascade. 
 BV Injury

Tissue Factor
Neural

Blood Vessel Platelet Coagulation

Constriction Aggregation Cascade
Primary hemostatic plug

Reduced Platelet
Activation Fibrin
Blood flow formation

Stable Hemostatic Plug

Bleeding disorders often develop when the blood can’t clot properly. For blood to clot, body needs
blood proteins called clotting factors and blood cells called platelets. Normally, platelets clump
together to form a plug at the site of a damaged or injured blood vessel. The clotting factors then
come together to form a fibrin clot. This keeps the platelets in place and prevents blood from flowing
out of the blood vessel.

Bleeding disorders are characterized by defects in hemostasis that lead to an increased

susceptibility to bleeding (also known as hemorrhagic diathesis).

They are caused either by platelet disorders (primary hemostasis defect), coagulation defects

(secondary hemostasis defect), or in some cases, a combination of both.

Definition of Primary hemostasis. During primary hemostasis, a platelet plug is formed to rapidly

stop the initial bleeding after injury. different steps involved in primary hemostasis: vasoconstriction,
platelet adhesion, activation and degranulation, platelet aggregation.
 
Definition of Secondary hemostasis is defined as the formation of insoluble, cross-linked fibrin by
activated coagulation factors, specifically thrombin.

Coagulation defects may be general or further divided into either intrinsic or extrinsic defects
according to the specific pathway of the coagulation cascade that is affected.

. 
• Primary hemostasis
• Sequence of events:  Normally, the intact
endothelium is a physical barrier separating
circulating platelets from thrombogenic
substances (such as extracellular matrix
proteins) in the extravascular space. When
the endothelium is injured, the procoagulant
subendothelial matrix (consisting of proteins
such as collagen, laminin, and fibronectin) is
exposed and immediately initiates primary
hemostasis, which consists of three main
events:

• Platelet adhesion: Platelets adhere to the

exposed subendothelial matrix (directly or
indirectly via vWf).
• Platelet activation: Once platelets adhere,
they then become activated and recruit (and
activate) additional platelets to the injured
site. Also, thrombin generated by the
coagulation cascade is an extremely powerful
platelet activator.
• Platelet plug formation: Fibrinogen forms
bridges between activated platelets to form
the platelet plug.
So What Causes Bleeding Disorders?. Bleeding disorders may be inherited or acquired.
VESSEL DEFECTS
PLATELET DISORDERS
FACTOR DEFICIENCIES

OTHER DISORDERS
VITAMIN C DEFICIENCY
BACTERIAL & VIRAL INFECTIONS
ACQUIRED & HEREDITARY CONDITIONS

Disorders affecting the vessel wall

Vascular hemorrhagic diathesis (e.g.,Henoch-Schonlein purpura)
Thrombotic microangiopathy (e.g.,hemolilytic-uremic syndrome,Hus)

PLATELET DISORDERS-Disorders of primary hemostasis

THROMBOCYTOPENIA
THROMBOCYTOPATHY
THROMBOCYTOPENIA----INADEQUATE NUMBER Of PLATELETS
THROMBOCYTOPATHY--- ADEQUATE NUMBER BUT ABNORMAL FUNCTION

FACTOR DEFICIENCIES-Disorders of secondary hemostasis (disorders of the coagulation cascade)

HEMOPHILIA A
HEMOPHILIA B
von WILLEBRAND’S DISEASE
Hemorrhage may be manifested by different appearances and clinical consequences.
Hemorrhage may be external or accumulate within a tissue as a hematoma, which ranges in significance
from trivial (e.g., a bruise) to fatal (e.g., a massive retroperito- neal hematoma resulting from rupture of a
dissecting aortic aneurysm)

Extensive hemorrhages can occasionally result in jaundice from the massive breakdown of red cells and
hemoglobin.

Petechiae are minute (1 to 2 mm in diameter) hemorrhages into skin, mucous membranes, or serosal
surfaces causes include low platelet counts (thrombocytopenia), defective platelet function, and loss of
vascular wall support, as in vitamin C deficiency.

Purpura are slightly larger (3 to 5 mm) hemorrhages. Purpura can result from the same disorders that
cause petechiae, as well as trauma, vascular inflammation (vasculitis), and increased vascular fragility

Ecchymoses are larger (1 to 2 cm) subcutaneous hematomas (colloquially called bruises). Extravasated
red cells are phagocytosed and degraded by macrophages; the characteristic color changes of a bruise
are due to the enzymatic conversion of hemoglobin (red-blue color) to bilirubin (blue-green color) and
eventually hemosiderin (golden-brown).
• Henoch-Schonlein purpura is a disorder that causes inflammation and
bleeding in the small blood vessels in skin, joints, intestines and kidneys. The most
striking feature of Henoch-Schonlein purpura is a purplish rash, typically on the
lower legs and buttocks.
•Pathophysiology

Henoch–Schönlein purpura is a small-vessel vasculitis(inflammation of blood vessels) in which

complexes of  immunoglobulin A (IgA) and complement component (C3) are deposited on arterioles,
capillaries, and venules .
(hence it is a type III hypersensitivity reaction ).

Symptoms can begin in children, most commonly between the ages of 4 and 7 years, soon after an
upper respiratory tract infection or a streptococcal pharyngitis (sore throat infection).
The four main characteristics of Henoch-Schonlein purpura include:
Rash (purpura). Reddish-purple spots, which look like bruises, are the most distinctive and
universal sign of Henoch-Schonlein purpura. The rash develops mainly on the buttocks, legs and feet,
but it can also appear on the arms, face and trunk and may be worse in areas of pressure, such as
the sock line and waistline.

Swollen, sore joints (arthritis). People with Henoch-Schonlein purpura often have pain and
swelling around the joints — mainly in the knees and ankles. Joint pain sometimes precedes the
classical rash by one or two weeks. These symptoms subside when the disease clears and leave no
lasting damage.

Gastrointestinal symptoms. Many children with Henoch-Schonlein purpura develop

gastrointestinal symptoms, such as abdominal pain, nausea, vomiting or bloody stools. These
symptoms sometimes occur before the rash appears .

Kidney involvement. Henoch-Schonlein purpura can also affect the kidneys. In most cases, this
shows up as protein or blood in the urine, which you may not even know is there unless you have a
urine test done. Usually this goes away once the illness passes, but in a few cases, kidney disease
may develop and even persist.
on Willebrand disease (VWD) is a genetic disorder caused by missing or defective von
Willebrand factor (VWF), a clotting protein. VWF binds factor VIII, a key clotting protein, and platelets
in blood vessel walls, which help form a platelet plug during the clotting process. The condition is
named after Finnish physician Erik von Willebrand, who first described it in the 1920s.
Symptoms
People with VWD experience frequent nosebleeds, easy bruising and excessive bleeding during and
after invasive procedures, such as tooth extractions and surgery. Women often experience
menorrhagia, heavy menstrual periods that last longer than average, and hemorrhaging after
childbirth

There are three main types of VWD based on qualitative or quantitative defects in VWF. A fourth
type, acquired VWD, is not hereditary.
Type 1 VWD is found in 60%-80% of patients. People with type 1 VWD have a quantitative
deficiency of VWF. Levels of VWF in the blood range from 20%-50% of normal. The symptoms are
usually mild.

Type 2 VWD is found in 15%-30% of patients. People with type 2 VWD have a qualitative
deficiency in their VWF. Type 2 is broken down into four subtypes: type 2A, type 2B, type 2M and type
2N, depending on the presence and behavior of multimers, molecular chains of VWF. Symptoms are mild
to moderate.

Type 3 VWD is found in 5%-10% of patients. People with type 3 VWD have a quantitative deficiency of
VWF. Symptoms are typically severe, and include spontaneous bleeding episodes, often into their joints
and muscles.

Acquired VWD. This type of VWD in adults results after a diagnosis of an autoimmune disease, such as
lupus, or from heart disease or some types of cancer. It can also occur after taking certain medications
Hemophilia.

Hemophilia is a rare condition in which the blood does not clot properly. It mostly affects men. It
happens  because of a defect in one of the clotting factor genes on the X chromosome

Proteins called clotting factors work with platelets to stop bleeding at the site of an injury.

People with hemophilia produce lower amounts of either Factor VIII or Factor IX than those
without the condition. This means the person tends to bleed for a longer time after an injury, and they
are more susceptible to internal bleeding.
This bleeding can be fatal if it occurs within a vital organ such as the brain.

Hemophilia tends to occur in males, since the gene can be passed from mother to son.
Males typically lack a second X chromosome so they are unable to make up for the defective gene.
Most females have XX sex chromosomes while most males have XY sex chromosomes.

Females may be carriers of hemophilia, but they are unlikely to have the disorder. For a girl to have
hemophilia, she must have the abnormal gene on both of her X chromosomes, and this is very rare.
Hemophilia can generally be classified as ;

> HEMOPHILIA  A 

> HEMOPHILIA B

> HEMOPHILIA C 
  
The classification of Hemophilia is dependent on the defect in   specific clotting factor .

HEMOPHILIA A :
                                      Hemophilia A is due to insufficient clotting factor VIII.
HEMOPHILIA B :
                                   Hemophilia B is due to  insufficient clotting factor IX.

HEMOPHILIA C :
                                   Hemophilia C is due to  insufficient clotting factor XI .
•  SYMPTOMS :
•          > NOSE BLEED ( without any reason
)
•            > HEAVY BLEEDING FROM MINOR
INJURIES
           SYMPTOMS :
> NOSE BLEED ( without any reason )
> HEAVY BLEEDING FROM MINOR INJURIES
> HEAVY BLEEDING AFTER ANY MINOR PROCEDURE eg tooth removal.
> REPETITIONAL BLEEDING EVEN IF THE BLOOD STOPPED BLEEDING     
             
INITIALLY
> LARGE BRUISES UNDER THE SKIN 
> BLOOD IN THE URINE 
> BLOOD IN THE KNEE JOINT AND IN MUSCLES.
Signs and Symptoms
Symptoms of hemophilia vary, depending on the amount of clotting factor a person has and the
location of the bleeding.
External bleeding is easy to notice. A child may bleed more than usual after scraping the knee,
getting a paper cut, losing a tooth (or having one removed), or biting down on the lips or tongue.
Nosebleeds may last a while.
Internal bleeding is harder to identify if don't know the signs. These include bruising (especially
bruising with swelling), redness, or tenderness in an area, especially a muscle or joint (like the knee).
Kids with hemophilia usually can tell when internal bleeding is happening. They often describe a
"bubbly" feeling in an area like a joint. The area also may feel achy, stiff, or warm to the touch.
DIAGNOSIS :
 
COMPLETE BLOOD COUNT 
PROTHROMBIN TIME (PT) and ACTIVATED   
PARTIALTHROMBOPLASTIN TIME  (PTT)
SERUM FACTOR VIII:
For diagnosing HEMOPHILA A 
 SERUM FACTOR IX:
For diagnosing HEMOPHILA B
 SERUM FACTOR XI
DISSEMINATED INTRAVASCULAR COAGULATION

Disseminated intravascular coagulation (DIC) occurs as a complication of a wide variety of disorders.

Disseminated intravascular coagulation (DIC) is characterized by systemic activation of blood

coagulation, which results in generation and deposition of fibrin, leading to microvascular thrombi in
various organs and contributing to multiple organ dysfunction syndrome.
. It may be seen in disorders ranging from obstetric complications to advanced malignancy.

The thrombi are generally microscopic in size, yet so numerous as to often cause circulatory
insufficiency, particularly in the brain, lungs, heart, and kidneys.
To complicate matters, the widespread microvascular thrombosis consumes platelets and coagulation
proteins (hence the synonym consumption coagulopathy), and at the same time, fibrinolytic
mechanisms are activated.
• Fibrinogen, or factor I, is a blood plasma protein that's made in the liver. Fibrinogen is
one of 13 coagulation factors responsible for normal blood clotting.

• When blood clotting is activated, fibrinogen circulating in the blood is converted to

fibrin, which in turn helps to form a stable blood clot at the site of vascular disruption.

• Coagulation inhibitor proteins help to prevent abnormal coagulation

(hypercoagulability) and to resolve clots after they are formed.

• fibrinolysis, a fibrin clot, the product of coagulation, is broken down. Its main enzyme
plasmin cuts the fibrin mesh at various places, leading to the production of circulating
fragments that are cleared by other proteases or by the kidney and liver.
Thrombocytopenia is the medical term for a low platelet count. Idiopathic means unknown cause.
Purpura refers to the pin-prick bleeding under the surface of the skin that is a symptom of the low
platelet count.

In Idiopathic (or Immune) thrombocytopenic purpura (ITP), antibodies coat the surfaces of the
platelets, destroying them and causing their level to drop.
Hence, the term ITP is used to denote both idiopathic and immune thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare blood condition characterised by the formation
of small clots (thrombi) within the circulation, which results in the consumption of platelets and thus a
low platelet count (thrombocytopenia).

Haemolytic uraemic syndrome

HUS is a disorder characterised by thrombocytopenia, microangiopathic haemololytic anaemia
(anaemia secondary to red blood cell fragmentation) and kidney failure