Bleeding disorders copy

Introduction
Bleeding disorders is a general term for a wide range of medical problems
that lead to poor blood clotting and continuous bleeding. Doctors also call them with
such terms as coagulopathy, abnormal bleeding and clotting disorders.
When someone has a bleeding disorder they have a tendency to bleed
longer. The disorders can result from defects in the blood vessels or from
abnormalities in the blood itself. The abnormalities may be in blood clotting factors
or in platelets.
Blood clotting, or coagulation, is the process that controls bleeding. It
changes blood from a liquid to a solid. It's a complex process involving as many as
20 different plasma proteins, or blood clotting factors. Normally, a complex chemical
process occurs using these clotting factors to form a substance called fibrin that
stops bleeding. When certain coagulation factors are deficient or missing, the
process doesn't occur normally.
History
Bleeding disorders have been recognized all the way back to ancient times. Though
not named, they were referenced extensively. In the Talmud, a collection of Jewish
Rabbinical writings from the 2nd century AD, it was written that male babies did not
have to be circumcised if two brothers had already died from the procedure. A 12th
century Arab physician named Albucasis also wrote about a family in which males
died of excessive bleeding from minor injuries. Bleeding disorders like hemophilia
have been recognized for hundreds of years to "run in" families.
In the U.S., the transmission of hemophilia from mothers to sons was first described
in the early 1800s. In 1803, a Philadelphia physician named Dr. John Conrad Otto
wrote an account of "a hemorrhagic disposition existing in certain families." He
recognized that a particular bleeding condition was hereditary and affected males.
He traced the disease back through three generations to a woman who had settled
near Plymouth, New Hampshire, in 1720. The word "Hemophilia" first appeared in a
description of a bleeding disorder condition at the University of Zurich in 1828.
1

A Royal Disease
Hemophilia has often been called the "Royal Disease." This is because Queen
Victoria, Queen of England from 1837 to 1901, was a carrier. She passed the
disease on to several royal families. Her eighth child, Leopold, had hemophilia and
suffered from frequent hemorrhages, which were reported in the British Medical
Journal in 1868. Leopold died of a brain hemorrhage at the age of 31, but not
before he had children. His daughter, Alice, was a carrier and her son, Viscount
Trematon, also died of a brain hemorrhage in 1928.
Nicholas and Alexandra
Hemophilia played an important role in the Russian Royal family, as well. Two of
Queen Victoria's daughters, Alice and Beatrice, were carriers of hemophilia. They
passed the disease on to the Spanish, German and Russian royal families.
Alexandra, Queen Victoria's granddaughter, married Nicholas, the Tsar of Russia in
the early 1900's. Alexandra was a carrier of hemophilia. Her first son, Alexei, was a
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hemophiliac. Nicholas and Alexandra were pre-occupied by the health problems of
their son at a time when Russia was in turmoil. A monk, Rasputin, gained great
influence in the Russian court, partly because he was the only one able to help the
young Tsarevich Alexei. He used hypnosis to relieve Alexei's pain. The use of
hypnosis not only relieved pain, but may have also helped slow or stop the boy's
hemorrhages. The illness of the heir to the Tsar's throne, the strain it placed on the
Royal family, and the power wielded by the mad monk Rasputin were all factors
leading to the Russian Revolution of 1917. In 1916, the 45-year old faith-healer
Rasputin was killed at Petrograd at the hands of a group of noblemen bent on
ridding Russia of the monk's corrupting influence on Nicholas II and Alexandra.
Finding the Cause
In the 20th century doctors looked for the cause of excessive bleeding. Until then,
they had believed that the blood vessels of hemophiliacs were simply more fragile.
1925
Although it is probably the most common hereditary bleeding disorder (affecting
approximately 1% to 2% of the population), von Willebrand disease was not
recognized until 1925.
1930s
Doctors looked at defective platelets as the likely cause of bleeding disorders and
hemophilia. Then in 1937, Patek and Taylor, two doctors at Harvard, found they
could correct the clotting problem by adding a substance which came from the
plasma in blood. They called it "anti-hemophilic globulin."
1944
Pavlosky, a doctor from Buenos Aires, Argentina, did a lab test which showed that
blood from one hemophilic patient could correct the clotting problem in a second
and vice-versa. He had stumbled upon two persons with hemophilia each with a
deficiency in different proteins - factor VIII and factor IX. This led to the recognition
in 1952 of hemophilia A and hemophilia B as two distinct diseases.
3

Identifying Clotting Factors
1960s
In the 1960s the clotting factors were identified and named. An article in Nature in
1964 described the clotting process in detail. The interaction of the different factors
in blood clotting was named the "coagulation cascade."
In the 1950s and early 1960s, hemophilia and other bleeding problems were treated
with whole blood or fresh plasma. Unfortunately, there wasn't enough of the factor
VIII or IX proteins in these blood products to stop serious internal bleeding. Most
people with severe hemophilia and some people with mild or moderate hemophilia
died in childhood or early adulthood. The most common causes of death were
bleeding in vital organs, especially the brain, and bleeding after minor surgery or
after an injury.
Those who survived were usually crippled by the long-term effects of repeated
hemorrhages into the joints. The pressure of massive bleeding into joints and
muscles made hemophilia one of the most painful diseases known to medicine.
Then, in the 1960s, cryoprecipitate was discovered by Dr. Judith Pool.
Cryoprecipitate is the factor-rich component of blood, containing concentrated factor
VIII. Dr. Pool found that the sludge on top of thawing plasma was rich in factor VIII.
For the first time, enough factor VIII clotting factor could be infused to control
serious bleeding. Even surgery became possible. This medical breakthrough ended
the need for high-volume whole plasma transfusions for persons with hemophilia
1970s
Then, later in the 1960s and early 1970s, concentrates containing factor VIII and IX
began to be available. These freeze-dried powdered concentrates could be kept at
home and used as needed. They revolutionized hemophilia care. Persons with
hemophilia were now independent of hospitals. They could travel, hold steady jobs
and hope to lead normal lives. Tragically, these same blood products carried blood-
borne viruses like hepatitis C and HIV. Many persons with hemophilia were infected.
4

1990s
In the 1990s, modern treatment, using safer factor concentrates, has again
improved the outlook. Most children born with hemophilia today can look forward to
long, healthy, active and productive lives. Recent progress includes:
• New clotting factor products and drugs such as desmopressin acetate (also known
as DDAVP, used to treat mild-to-moderate hemophilia A and von Willebrand
disease)
• New, synthetic (not derived from plasma) clotting products that take advantage of
recombinant technologies
• Better screening methods to detect and remove viruses and other agents from
factor concentrates and blood products
• Improved surgical options
• Advanced genetic testing methods
• Medically supervised home-infusion therapy
• Prophylactic treatment
HEMOSTASIS
I. PLATELETS:
Origin:
Platelets are developed in bone marrow from megakaryocyte.
Pluripotent stem cell
↓
Promegakaryoblast
↓
Megakaryoblast
↓
Megakaryocyte
5

↓
Platelets
1. FUNCTIONS :
1. Damage to vessel releases 5HT, TXA2
2. Platelet adhesion, platelet aggregation and platelet plug formation.
3. PF3 - which helps in clotting.
4. Helps in clot retraction
5. PDGF - Helps in growth and multiplication of vascular endothelial cells, vascular
submucosal cells and fibroblasts required for repair of damaged walls.
Life span: 7-14 days
Site of destruction : Spleen
Normal count: 1.5 - 4.5 lacks / cc
Increase in count: Thrombocytosis
Decrease in count: Thrombocytopenia
Decrease in platelet count below 40,000is associated with hemorrhagic disorders.
2 a) Physiological Variations :
1. Seasonal - Count is more during winter season.
2. Pregnancy - Count decrease
3. Exercise, excitement, injection of adrenaline, high altitude - Increased count.
b. Pathological Variations :
1. Increased platelet count seen after splenectomy idiopathic.
2. Decreased platelet count is seen in
- Viral infection
- Idiopathic
- Aplastic anaemia
6

II. COAGULATION :
Primary hemostasis is platelet plug formation. Secondary hemostasis is
coagulation. Coagulation is the convertion of fibrinogen to fibrin in the presence of
thrombin.
Clotting Factors:
I. Fibrinogen
II. Prothrombin
III. Tissue thromboplastin
IV. Calcium
V. Labile factor - Proaccelerin
VI. Does not exist
VII. Stable factor - Proconvertin
VIII. AIIG or AHF
IX. Christmas factor
X. Stuart Prower factor
XI. PTA - Plasma thromboplastin antecedent
XII. Hageman factor
XIII. Fibrin stabilizing factor
The coagulation proteins are divided into 3 groups on the basis of their biochemical
properties and function.
I. Vitamin K dependent coagulation proteins
II. Contact proteins
III. Thrombin sensitive proteins
I. These are prothrombin, factor VII, factor IX, and Factor X. These are
synthesized in liver.
II. These are XII, prekallikrein, factor XI and HMWC. They are produce in liver.
III. They are fibrinogen, V, VIII, XIII.
2) There are 3 essential steps in coagulation.
1. Formation of prothrombin activator in response to vessel or tissue damage.
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2. Conversion of prothrombin to thrombin
3. Conversion of fibrinogen to fibrin
SYNTHESIS OF PROTHROMBIN ACTIVATOR:
2 mechanisms.
1. Extrinsic mechanism
2. Intrinsic mechanism
3) EXTRINSIC MECHANISM:
It is so called because some factors necessary for the formation of PTA are
present outside i.e. in the tissue.
There are 3 important steps.
1. Traumatized tissue liberates tissue thromboplastin which includes
phospholipids and glycoproteins.
2. Factor X is activated in the presence of factor VII, phospholipids and calcium.
VII + III + Ca++
X Xa
3. Formation of PTA from Xa.
In the presence of factor V, Ca++
and phospholipids Xa forms prothrombin
activator.
Tissue trauma
↓
Tissue thromboplastin + glycoprotein + phospholipids
↓
Ca++ and VII
X Xa
Xa
Ca++
V
Phospholipids
PTA
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↓
PT Thrombin
When the tissue trauma is extensive Clotting occurs in 15 seconds.
INTRINSIC MECHANISM:
It is named so because all the factors necessary for the formation of PTA are
present in the blood. The mechanism is known as Macfarian's Cascade hypothesis.
As a resulting of injury blood is exposed to connective tissue. Inactive
precursor is converted to active enzyme which acts on the next precursor to form
next active enzyme and thus so on. Thus sequence of changes occurs.
1. Trauma to vessel wall causes factor XII. HMWK and PK to form a complex with
vascular and subendothelial collagen. After binding to HMWK inactive factor XII
is converted to active XII (XIIa). XIIa converts PK to kallikrein activates
conversion of XII to XIIa. This is positive feed back mechanism.
2. XIIa activates XI to XI a
3. XIa activates IX to IXa in presence of calcium.
4. IXa along with VII, Ca++
, platelet phospholipids converts X to Xa.
5. Xa in the presence V Ca+2
and platelet phospholipid forms PTA.
6. Except in the first two steps Ca is necessary for clotting. Formation of PTA by
intrinsic mechanism occurs in 4-8 minutes. Once PTA formed clot is formed in
10-30 seconds.
Fibrin monomer forms the fibrin threads, these threads are not cross linked.
Hence clot is weak. In the presence of factor XIII a firm polymer is formed.
INTRINSIC EXTRINSIC
Surface contact Tissue damage
↓
XII XIIa
↓
XI XIa Tissue factor
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↓
IX IXa
Ca++
Ca++
VII
VIII
Phospholipid
X Xa
Ca++
Phospholipid
V
(II) Prothrombin Thrombin (IIa)
↓
XIII XIIIa
↓
Fibrinogen Fibrin Stabilized
Fibrin
ROLE OF THROMBIN:
1. Converts fibrinogen to fibrin
2. Activates factor VIII
3. Activates factor V
4. Activates factor XIII
5. Promotes aggregation of platelets this increases available phospholipids.
Thrombin intensifies the reactions promoting local clotting but only for short
time i.e. until a firm clot is formed. Then it inactivates clot formation spread of clot
does not occur because 85 - 90% of thrombin is absorbed Remaining thrombin
combines with antithrombin III which inactivates it.
Composition of Clot:
It contains fibrin, threads spreading in all directions in which RBC, WBC,
platelets and plasma are entrapped.
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Clot Retraction:
Clot retracts to 40% of original size in 30-60 minutes and becomes tough.
This is because of contractile proteins present in the platelets. As clot retracts,
edges of broken vessels are pulled together. Thus ultimately haemostasis is
achieved.
BLEEDING DISORDERS
Hemophilia A(Factor VIII Deficiency)
What Is It?
Hemophilia is a bleeding disorder caused by a deficiency in one of the blood clotting
factors. Hemophilia A (often called classic hemophilia) accounts for about 80% of all
hemophilia cases. It is a deficiency in clotting factor VIII.
Hemophilia A is a hereditary disorder in which the clotting ability of the blood is
impaired and excessive bleeding results. Small wounds and punctures are usually
not a problem, but uncontrolled internal bleeding can result in pain and swelling and
permanent damage, especially to joints and muscles.
Severity of symptoms can vary and severe forms become apparent early on.
Prolonged bleeding is the hallmark of hemophilia A and typically occurs when an
infant is circumcised. Additional bleeding manifestations make their appearance
when the infant becomes mobile. Mild cases may go unnoticed until later in life
when there is excessive bleeding and clotting problems in response to surgery or
trauma. Internal bleeding may happen anywhere, and bleeding into joints is
common.
The incidence of hemophilia A is one in 10,000 live male births. About 17,000
Americans have hemophilia. Women may have it, but it's very rare. With treatment
and management, the outcome is good. Most men with hemophilia are able to lead
relatively normal lives.
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Inheritance Pattern
Hemophilia A is caused by an inherited sex-linked recessive trait with the defective
gene located on the X chromosome. Females are carriers of this trait. Fifty percent
of the male offspring of female carriers have the disease, and 50% of their female
offspring are carriers. All female children of a male with hemophilia are carriers of
the trait.
One third of all cases of hemophilia A occur when there is no family history of the
disorder. In these cases, hemophilia develops as the result of a new or
spontaneous gene mutation.
Genetic counseling may be advised for carriers. Female carriers can be identified
by testing.
A woman is definitely a hemophilia carrier if she is:
• the biological daughter of a man with hemophilia;
• the biological mother of more than one son with hemophilia;
• the biological mother of one hemophilic son who has at least one other blood
relative with hemophilia.
A woman may or may not be a hemophilia carrier if she is:
• the biological mother of one son with hemophilia;
• the sister of a male with hemophilia;
• an aunt, cousin or niece of an affected male related through maternal ties;
• the biological grandmother of one grandson with hemophilia.
The only way a woman could ever have hemophilia is if her father has it and her
mother carries the gene. Women who are carriers can also be symptomatic carriers,
whereby they do experience factor deficiencies.
Symptoms & Diagnosis
Hemophilia is caused by several different gene abnormalities. The severity of the
symptoms of hemophilia A depends on how a particular gene abnormality affects
the activity of factor VIII. When the activity is less than 1 percent of normal,
episodes of severe bleeding occur and recur for no apparent reason.
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Symptoms include:
• Bruising
• Spontaneous bleeding
• Bleeding into joints and associated pain and swelling
• Gastrointestinal tract and urinary tract hemorrhage
• Blood in the urine or stool
• Prolonged bleeding from cuts, tooth extraction, and surgery
People whose clotting activity is 5 percent of normal may have only mild hemophilia.
They rarely have unprovoked bleeding episodes, but surgery or injury may cause
uncontrolled bleeding, which can be fatal. Milder hemophilia may not be diagnosed
at all, although some people whose clotting activity is 10 to 25 percent of normal
may have prolonged bleeding after surgery, dental extractions, or a major injury.
Generally, the first bleeding episode occurs before 18 months of age, often after a
minor injury. A child who has hemophilia bruises easily. Even an injection into a
muscle can cause bleeding that results in a large bruise (hematoma). Recurring
bleeding into the joints and muscles can ultimately lead to crippling deformities.
Bleeding can swell the base of the tongue until it blocks the airway, making
breathing difficult. A slight bump on the head can trigger substantial bleeding in the
skull, causing brain damage and death.
A doctor may suspect hemophilia in a child whose bleeding is unusual. A laboratory
analysis of blood samples can determine whether the child's clotting is abnormally
slow. If it is, the doctor can confirm the diagnosis of hemophilia A and can
determine the severity by testing the activity of factor VIII.
Treatments
Hemophilia is treated by infusing the missing clotting factor. The amount infused
depends upon the severity of bleeding, the site of the bleeding, and the size of the
patient. In the past, mild hemophilia A was typically treated with infusion of
cryoprecipitate or desmopressin acetate (DDAVP), which causes release of factor
VIII that, is stored within the body on the lining of blood vessels. Today, experts
recommend desmopressin injection or Stimate nasal spray.
13

Clotting factors are found in plasma and, to a greater extent, in plasma
concentrates. Some plasma concentrates are intended for home use and can be
self-administered, either on a regular basis to prevent bleeding or at the first sign of
bleeding. More often, they are administered three times a day, but both the dose
and frequency depend on the severity of the bleeding problem. The dose is
adjusted according to the results of periodic blood tests. During a bleeding episode,
more clotting factors are needed.
To prevent a bleeding crisis, people with hemophilia and their families can be taught
to administer factor VIII concentrates at home at the first signs of bleeding. People
with severe forms of the disease may need regular prophylactic infusions, which
bring factor levels higher than 1% to prevent bleeds.
Depending on the severity of the disease, DDAVP or factor VIII concentrate may be
given prior to dental extractions and surgery to prevent bleeding. Immunization with
hepatitis B vaccine is necessary because of the increased risk of exposure to
hepatitis due to frequent infusions of blood products.
Gene therapy and fetal tissue implant techniques are under study as possible
treatments.
People who have hemophilia should avoid situations that might cause bleeding.
They should be conscientious about dental care so they won't need to have teeth
extracted. People who have hemophilia should also avoid certain drugs that can
aggravate bleeding problems:
• Aspirin
• Heparin
• Warfarin
• Certain analgesics such as nonsteroidal anti-inflammatory drugs
Treatment should be coordinated by a healthcare practitioner who is expert in the
field, such as a hematologist of hemophilia treatment center nurse.
The National Hemophilia Foundation's Medical and Scientific Advisory Council
(MASAC) made recommendations for treatment of hemophilia in November of
1999.
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They include:
• Factor VIII products for patients who are HIV seronegative, including Recombinant
factor VIII, especially for young and newly diagnosed patients who have not
received any blood or plasma-derived products.
• Immunoaffinity purified factor VIII concentrates for patients who are HIV
seropositive.
• Cryoprecipitate is not recommended because of the risk of HIV and hepatitis
infection. Despite greatly improved screening and purification for viral inactivation in
blood products, cryoprecipitate can still contain viruses.
• Mild hemophilia A should be treated with desmopressin, in a DDAVP injection or
Stimate nasal spray.
Complications
• Chronic joint deformities, caused by recurrent bleeding into the joint, may be
managed by an orthopedic specialist
• Intracerebral hemorrhage is another possible complication.
Some persons with hemophilia develop antibodies to transfused factor VIII. As a
result, the transfusions are ineffective. If antibodies are detected in blood samples,
the dosage of the plasma concentrates may be increased, or different types of
clotting factors or drugs to reduce the antibody levels may be used.
In the past, the plasma concentrates carried the risk of transmitting blood-borne
diseases such as hepatitis and AIDS. About 60 percent of persons with hemophilia
who were treated with plasma concentrates in the early 1980s were infected with
HIV. However, the risk of transmitting HIV infection through plasma concentrates
has been virtually eliminated by today's use of screened and processed blood and a
genetically engineered factor VIII (Recombinant).
15

Hemophilia B
(Factor IX Deficiency)
What Is It?
Hemophilia is a bleeding disorder caused by a deficiency in one of the blood clotting
factors. Hemophilia B (also called "Christmas disease" after Stephen Christmas, a
British boy in the 20th century who was first diagnosed with it) is a deficiency in
clotting factor IX.
Hemophilia A is seven times more common than hemophilia B. The incidence of
hemophilia B is one in 34,500 men.
Hemophilia B is a hereditary disorder in which the clotting ability of the blood is
impaired and prolonged bleeding results. Small wounds and punctures are usually
not a problem. But uncontrolled internal bleeding can result in pain, swelling and
permanent damage, especially to joints and muscles.
The outcome is good with treatment and management. Most people with hemophilia
B are able to lead relatively normal lives.
Inheritance Pattern
Hemophilia B is caused by an inherited sex-linked recessive trait with the defective
gene located on the X chromosome. Females are carriers of this trait. Fifty percent
of the male offspring of female carriers will have the disease, and 50% of their
female offspring will be carriers. All female children of a male with hemophilia will be
carriers of the trait.
One fifth of all cases of hemophilia B occur when there is no family history of the
disorder. In these cases, hemophilia develops as the result of a new or
spontaneous gene mutation.
Genetic counseling may be advised for carriers. Female carriers can be identified
by testing.
A woman is definitely a hemophilia carrier if she is:
• the biological daughter of a man with hemophilia;
• the biological mother of more than one son with hemophilia; • the
Biological mother of one son with hemophilia and has at least one other
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blood relative with hemophilia.
A woman may or may not be a hemophilia carrier if she is:
• the biological mother of one son with hemophilia;
• the sister of a male with hemophilia;
• an aunt, cousin or niece of an affected male related through maternal ties;
• the biological grandmother of one grandson with hemophilia.
Symptoms and Diagnosis
Hemophilia is caused by several different gene abnormalities. The severity of
hemophilia B symptoms depends on how a particular gene abnormality affects the
activity of factor IX. When the activity is less than 1% of normal, episodes of
prolonged bleeding may occur for no apparent reason.
Severity of symptoms can vary, but severe forms become apparent early on.
Prolonged bleeding is the disease's hallmark and typically manifests itself when an
infant is circumcised. Additional bleeding manifestations make their appearance
when the infant becomes mobile. Mild cases may go unnoticed until later in life,
when they occur in response to surgery or trauma. Internal bleeding may occur
anywhere and bleeding into joints is common.
Risk factors are a family history of bleeding and being male. The incidence of
hemophilia B is one in 34,500 men.
Symptoms include:
• Nose bleeds
• Bruising
• spontaneous bleeding
• bleeding into joints and associated pain and swelling
• Gastrointestinal tract and urinary tract hemorrhage
• Blood in the urine or stool
• prolonged bleeding from cuts, tooth extraction and surgery
• prolonged bleeding following circumcision
People whose clotting activity is 5% of normal may have only mild hemophilia. They
rarely have unprovoked bleeding episodes, but surgery or injury may cause
17

uncontrolled bleeding, which can be fatal. Milder hemophilia may not be diagnosed
at all, although some people whose clotting activity is 10% to 25% of normal may
bleed excessively after surgery, dental extractions or a major injury.
Generally, the first bleeding episode occurs before 18 months of age, often after a
minor injury. A child who has hemophilia bruises easily. Even an injection into a
muscle can cause bleeding that results in a large bruise (hematoma). Continuous
bleeding into the joints and muscles can ultimately lead to crippling deformities.
Bleeding can swell the base of the tongue until it blocks the airway, making
breathing difficult. A slight bump on the head can trigger substantial bleeding in the
skull, causing brain damage and death.
A doctor may suspect hemophilia in a child whose bleeding is unusual. A laboratory
analysis of blood samples can determine whether the child's clotting is abnormally
slow. If it is, the doctor can confirm the diagnosis of hemophilia and determine the
severity by testing the activity of factor IX.
Coagulation studies involving many tests are performed if the person tested is the
first one in the family to have the bleeding disorder. Once the defect has been
identified, other family members will need less testing to diagnose the disorder.
Treatments
Like hemophilia A, hemophilia B is typically treated by infusing the missing clotting
factor. The amount infused depends upon the severity of bleeding, the site of the
bleeding and the size of the patient. A hepatitis B vaccine is recommended for
individuals with hemophilia B because they are at increased risk of developing
hepatitis due to exposure to blood products.
Clotting factors are found in plasma and, to a greater extent, in plasma
concentrates. Some plasma concentrates are intended for home use and can be
self-administered, either on a regular basis to prevent bleeding or at the first sign of
bleeding. More often, they are administered three times a week (prophylaxis), but
both the dose and frequency depend on the severity of the bleeding problem. The
18

dose is adjusted according to the results of periodic blood tests. During a bleeding
episode, more clotting factors are needed. Treatment should be coordinated by a
healthcare practitioner who is an expert on the disease.
To prevent a bleeding crisis, people with hemophilia and their families can be taught
to administer factor IX concentrates at home at the first signs of bleeding. People
with severe forms of the disease may need regular prophylaxis infusions two to
three times a week. Depending on the severity of the disease, factor IX concentrate
may be given prior to dental extractions and surgery to prevent bleeding.
Gene therapy and fetal tissue implant techniques are under study as possible
treatments.
People who have hemophilia should avoid situations that might provoke bleeding.
They should be conscientious about dental care so they won't need to have teeth
extracted. If people who have milder forms of hemophilia need to have dental or
other surgery, the drug desmopressin acetate (DDAVP) may be given to improve
clotting temporarily so that transfusions can be avoided.
People who have hemophilia should also avoid certain drugs that can aggravate
bleeding problems:
• aspirin
• heparin
• warfarin
• certain analgesics, such as nonsteroidal antiinflammatory drugs
(MASAC) made recommendations for treatment of hemophilia B in
November of 1999. They include
• Recombinant factor IX products for patients who are HIV seronegative, especially
for young and newly diagnosed patients who have not received any blood or
plasma-derived products.
19

• Today, plasma-derived factor IX products offer greatly reduced risk for HIV and
hepatitis B and C transmission, but there is still some risk. Dry heating, solvent-
detergent treatment, vapor treatment and sodium thiocyanate plus ultrafiltration and
are all effective purification steps, but there remains a slight possibility of viral
transmission.
• Patients who are HIV-seropositive should also be treated with high purity products
such as immunoaffinity purified and recombinant factor VIII products.
• For patients with inhibitors to factors VIII and IX, there is Recombinant Factor VIIa
(NovoSeven). Produced by baby hamster kidney cells, no human albumin or other
proteins are used in its production, reducing virus risk. There is also Porcine factor
VIII (Hyate C) and activated prothrombin complex concentrates.
Complications
• Chronic joint deformities, caused by recurrent bleeding into the joint, may be
managed by an orthopedic specialist.
• Intracerebral hemorrhage may also occur.
• Thrombosis may occur following use of factor IX concentrate.
Some persons with hemophilia develop antibodies to transfused factor IX. As a
result, transfusions become ineffective. If antibodies are detected in blood samples,
the dosage of the plasma concentrates may be increased, or different types of
clotting factors or drugs to reduce the antibody levels may be used.
In the past, plasma concentrates carried the risk of transmitting blood-borne
diseases such as hepatitis and AIDS. About 60% of persons with hemophilia who
were treated with plasma concentrates in the early 1980s were infected with HIV.
However, the risk of transmitting HIV infection through plasma concentrates has
been virtually eliminated by today's use of screened and processed blood.
20

Von Willebrand Disease
What Is It?
Von Willebrand disease is a hereditary deficiency or abnormality of the von
Willebrand factor in the blood, a protein that affects platelet function. It's the most
common hereditary disorder of platelet function, affecting both women and men.
The disease is estimated to occur in 1% to 2% of the population.
The disease was first described by Erik von Willebrand, a Finnish physician
who reported a new type of bleeding disorder among island people in Sweden and
Finland.
In von Willebrand disease, blood platelets don't stick to holes in blood vessel
walls. Platelets are tiny particles in the blood that clump together at the site of an
injury to prepare for the formation of a blood clot. Von Willebrand factor causes
them to bind to areas of a blood vessel that are damaged. If there is too little von
Willebrand factor or the factor is defective, platelets do not gather properly when a
blood vessel is injured.
Von Willebrand factor is found in plasma, platelets and blood vessel walls.
When the factor is missing or defective, the first step in plugging a blood vessel
injury (platelets adhere to the vessel wall at the site of the injury) doesn't take place.
As a result, bleeding doesn't stop as quickly as it should, although it usually stops
eventually.
There are no racial or ethnic associations with the disorder. A family history
of a bleeding disorder is the primary risk factor.
Researchers have identified many variations of the disease, but most fall into the
following classifications
• Type I: This is the most common and mildest form of von Willebrand disease.
Levels of von Willebrand factor are lower than normal, and levels of factor VIII may
also be reduced.
• Type II: In these people, the von Willebrand factor itself has an abnormality.
Depending on the abnormality, they may be classified as having Type IIa or Type
IIb. In Type IIa, the level of von Willebrand factor is reduced, as is the ability of
21

platelets to clump together. In Type IIb, although the factor itself is defective, the
ability of platelets to clump together is actually increased.
• Type III: This is severe von Willebrand disease. These people may have a total
absence of von Willebrand factor, and factor VIII levels are often less than 10%.
• Pseudo (or platelet-type) von Willebrand disease: This disorder resembles Type
IIb von Willebrand disease, but the defects appear to be in the platelets, rather than
the von Willebrand factor.
Once in a while, people develop what appears to be von Willebrand disease
later in life. When this occurs in those who have no family history of the disease, it is
thought that they're probably producing antibodies that destroy or decrease the
amount of von Willebrand factor. Some other people have "acquired" a form of the
disease in association with another disorder, such as rheumatoid arthritis, systemic
lupus erythematosus, kidney disease and certain cancers.
The life span of patients is usually normal length. Since the disease is
genetically transmitted, genetic counseling may be recommended for parents.
Von Willebrand disease can be more complicated for women because of obstetric
and gynecological issues.
Inheritance Pattern
Like hemophilia, the disease is passed down through the genes. But unlike
hemophilia, which usually affects only males, von Willebrand disease occurs in men
and women equally.
A man or woman with the disease has a 50% chance of passing the gene on to his
or her child. Types I and II are usually inherited in what is known as a "dominant"
pattern. This means that if even one parent has the gene and passes it to a child,
the child gets the disease. Whether the child has no symptoms, mild symptoms or,
less commonly, severe symptoms, he or she definitely has the disease. Regardless
of severity of the symptoms, the child can still pass the gene to his or her own
offspring.
22

Type III von Willebrand disease, however, is usually inherited in a "recessive"
pattern. This type occurs when the child inherits the gene from both parents. Even if
both parents have mild or asymptomatic disease, their children are likely to be
severely affected.
These patterns of inheritance differ from hemophilia, which is caused by a defect in
one of the "sex-linked" chromosomes. A man with hemophilia cannot pass the gene
on to a son, because the abnormality is carried on the X chromosome and a man
contributes only a Y chromosome to his male offspring. von Willebrand disease is
found on the autosomal chromosomes and therefore can be inherited by either
males or females.
von Willebrand disease can often be traced through several generations in a family.
Some have symptoms while others just carry the gene.
Diagnosis can be difficult. When a healthcare practitioner hears of recurrent
nosebleeds, easy bruising, heavy menstrual periods or longer than usual bleeding
after such routine operations as tonsillectomies or tooth extractions, diagnostic tests
should be performed to rule out the possibility of von Willebrand disease.
Usually, a person with von Willebrand disease has a parent with a history of
bleeding problems. Typically, a child bruises easily or has bleeds excessively after a
skin cut, tooth extraction, tonsillectomy or other surgery. A woman may have
increased menstrual bleeding. Bleeding may worsen at times. On the other hand,
hormonal changes, stress, pregnancy, inflammation and infections may stimulate
the body to increase production of the von Willebrand factor and temporarily
improve clot formation.
Laboratory tests may determine that the number of platelets is normal but bleeding
time is abnormally long. Bleeding time is the amount of time that elapses before
bleeding stops after a small cut is made on the forearm. To make the diagnosis,
23

doctors may order tests that measure the amount of von Willebrand factor in the
blood. Because the von Willebrand factor is the protein that carries factor VIII in the
blood, the blood level of factor VIII may also be decreased.
Diagnostic signs can include:
• normal platelet count
• prolonged bleeding time
• reduced von Willebrand factor level
• reduced platelet adhesion may occur
• reduced or increased platelet aggregation (platelet aggregation test)
• ristocetin cofactor is reduced
Treatments
There are a range of treatment choices that depend on whether the illness is mild or
severe. Many people with von Willebrand disease never even need treatment.
Stimate, desmopressin acetate (DDAVP), a drug sprayed into the nose, is the
treatment of choice for mild von Willebrand disease. Bleeding is usually controlled in
individuals with mild von Willebrand disease by using this nasal spray to boost their
own factor VIII and von Willebrand levels. DDAVP may be given to increase the
amount of the von Willebrand factor long enough for surgery or dental procedures to
be performed. DDAVP is a synthetic product that carries no risk of infectious
disease.
For excessive bleeding, infusions of a viral inactivated factor VIII product rich in von
Willebrand factor, such as Humate-P, Alphanate and Koate DVI, may be required. If
trauma occurs or surgery is scheduled, desmopressin acetate can be given to raise
the levels of von Willebrand factor, which will decrease the tendency toward
bleeding. Fresh plasma may also be used to decrease bleeding but the risk of viral
infection can be high.
Children with von Willebrand disease should avoid unnecessary trauma, and those
with severe disease should avoid certain contact sports. During menstruation,
24

adolescent females may want to take extra precautions to avoid accidents. During
bleeding episodes, they can elevate and apply cold compresses and gentle
pressure to the area. During nosebleeds, they can apply pressure over the bridge of
the nose lean forward to prevent blood running down the back of the throat and
being swallowed.
Aspirin and many of the drugs used for arthritis can aggravate bleeding because
they interfere with platelet function. People who have von Willebrand disease can
take acetaminophen for pain relief because it doesn't inhibit platelet function.
(MASAC) made recommendations for treatment of von Willebrand disease in
November of 1999. They include:
• Stimate, desmopressin acetate (DDAVP), a nasal spray or injection.
• For patients who have become unresponsive to DDAVP or need surgical
procedures, viral-inactivated factor VIII preparations rich in von Willebrand factor,
such as Alphanate, Humate-P and Koate DVI, are recommended.
• Cryoprecipitate is not recommended except in life-threatening emergencies
because of the risk of HIV and hepatitis infection. Despite greatly improved
screening and purification for viral inactivation in blood products, cryoprecipitate can
still be infectious.
Complications
After any kind of surgery, hemorrhaging may occur. The condition is worsened by
the use of aspirin and other nonsteroidal anti-inflammatory drugs.
Women may have heavy menstrual periods as well as risks during pregnancy and
childbirth. . Those who have this disorder and are scheduled for surgery or are in an
accident, should be sure to notify healthcare providers about the condition.
Factor I Deficiency
(Afibrinogenemia)
What Is It?
25

Fibrinogen, also known as factor I, is needed for most types of platelet aggregation.
It's the last step in the clotting process—the "glue" that holds the clot together.
People who have a factor I deficiency have a combined bleeding and clotting
disorder, meaning that both platelets and clotting are abnormal. Since its discovery
in 1920, there have only been about 200 cases of this disorder.
Included under factor I deficiency are several rare coagulation disorders known as
congenital fibrinogen defects. They include:
• afibrinogenemia
• hypofibrinogenemia
• dysfibrinogenemia
The first two are called quantitative abnormalities because they have to do with an
absent or low quantity of fibrinogen. The third is called a qualitative abnormality
because the fibrinogen does not work well.
Afibrinogenemia is the complete absence of fibrinogen.
Hypofibrinogenemia is a low level of fibrinogen—less than 100mg in 1dL of blood.
Both conditions are inherited in an autosomal fashion and can affect males and
females.
The severity of the disorder is related to the amount of fibrinogen. Afibrinogenemia
is usually discovered in newborns and can cause bleeding from the umbilical cord,
genitourinary tract or central nervous system. People with hypofibrinogenemia may
have little, moderate or severe bleeding.
Dysfibrinogenemias are due to variations in the factor I molecule. More than 70
different types of dysfibrinogenemia have been identified.
Inheritance Pattern
The disorder is not sex-linked as is hemophilia. It affects both males and females
with equal frequency. It is autosomal recessive, which means that if the clotting
defect is inherited from a parent, the child will be a genetic carrier of the condition,
but may or may not have symptoms.
26

Few people who have any of these disorders suffer symptoms, although some are
predisposed to form blood clots (thrombosis).
Treatments
Many people with hypofibrinogenemia or dysfibrinogenemia need no treatment.
Those who require treatment may be given cryoprecipitate or fresh frozen plasma.
Anticoagulants are sometimes prescribed to reduce the risk of thrombosis. The goal
of treatment is to raise the patient's fibrinogen level to 100 mg/dL for minor bleeding
and up to 200 mg/dL for surgery or severe bleeding. (One unit of fresh frozen
plasma has about 450 mg of fibrinogen.)
Complications
Plasma levels of fibrinogen exceeding 1,000 mg/dL have been reported to possibly
increase the risk of thrombosis. In women, menstrual bleeding can be a severe
problem and must be controlled
Factor II Deficiency
(Prothrombin)
What Is It?
Prothrombin is a vitamin K-dependent proenzyme that functions in coagulation.
There are two types of this deficiency, a congenital version called
hypoprothrombinemia, and an acquired version called dyspothrombinemia.
A life-long bleeding disorder when congenital, factor II deficiency is extremely rare.
In fact, only 30 cases of this hereditary clotting factor defect have been identified in
the whole world.
Acquired factor II deficiency is more common. It results from vitamin K deficiency,
severe liver disease and therapeutic use of anticoagulant drugs. Risk factors for
vitamin K deficiency are prolonged use of antibiotics, bile duct obstruction and
intestinal malabsorption (inadequate absorption of nutrients from the intestinal tract)
disorders. Some newborns are born with vitamin K deficiency
27

If the deficiency is caused by liver disease, the outcome depends on control of the
liver problem. Vitamin K administration will correct vitamin K deficiency.
Either form may lead to severe bruising, excessive menstrual bleeding,
postoperative hemorrhage or occasional muscle bleeds.
Inheritance Pattern
A congenital factor II deficiency is a very rare inherited disorder that results in
deficient blood clotting. The disorder is not sex-linked as is hemophilia. It affects
both males and females with equal frequency. It is autosomal recessive, which
means that if the clotting defect is inherited from a parent, the child will be a genetic
carrier of the condition, but may or may not have symptoms. A family history of
bleeding disorder is a risk factor.
Signs and symptoms vary with the level of prothrombin. Patients with levels greater
than 50% of normal have no bleeding problems, whereas people with levels from
2% to 50% may easily bruise or suffer from epistaxis, menorrhagia, muscle
hemorrhages, postpartum hemorrhages and hemorrhage following surgery and
trauma.
Symptoms include:
• umbilical cord bleeding at birth
• nose bleeds
• abnormal menstrual bleeding
• abnormal bleeding after delivery
• bleeding after trauma
• bleeding after surgery
• easy bruising
Signs and Tests:
• prolonged prothrombin time
• prolonged partial thromboplastin time
• factor II assay showing decreased activity
• levels of prothrombin ranging from 2% to 50% of normal
28

Treatments
Treatment depends on the severity of the disorder and the type of bleeding. Mild
cases may be treated with plasma infusion. Loss of blood can be controlled by
infusions of fresh frozen plasma. Severe factor II deficiencies may be treated with
prothrombin complex concentrates (PCCs). When necessary, it can be treated with
plasma replacement therapy. Effective control of a hemorrhage is achieved when
prothrombin levels are at 30% to 50% of normal.
Genetic counseling may be helpful in the case of congenital disorders. The use of
vitamin K in malabsorption and long-term antibiotic use may be preventative.
If the disorder is caused by vitamin K deficiency, then vitamin K is prescribed.
Diagnosis of a bleeding disorder is important so that precautionary measures can
be taken if surgery is needed or anticipated.
(MASAC) made recommendations for treatment of factor II deficiency in November
of 1999. They include:
• Prothrombin complex concentrates (PCCs) can be used, but these products vary
considerably in the amount of factors they contain.
• Fresh frozen plasma can be used as along as it is processed to reduce the risk of
viral infection.
Complications
Bleeding has to be controlled in instances of trauma or surgery, or else bleeding
into the brain or skull can occur.
Factor V Deficiency
(Parahemophilia, Labile factor or Proaccelerin Deficiency)
What Is It?
Factor V deficiency is also known as Owren's disease or parahemophilia. This
deficit was identified in Norway in 1943. Since then about 150 cases have been
29

reported, occurring in both men and women. The exact frequency of this rare
disorder is unknown, but is estimated to be one per 1 million.
The role of factor V is to accelerate the activity of thrombin. When levels of factor V
are low, blood clotting is delayed or it progresses slowly. People with this deficiency
may have occasional nosebleeds, excessive menstrual bleeding and bruising;
although, many have no symptoms. The first sign of this condition may be bleeding
following surgery.
In this disorder, bleeding ranges from mild to severe. The disease is similar to
hemophilia, except that bleeding into joints is uncommon. Bleeding can occur
almost anywhere in the body, and death from hemorrhage has occurred with this
disorder. Excessive bleeding with menstrual periods and postpartum hemorrhage
occurs frequently.
A family history of a bleeding disorder is a risk factor. Men and women are affected
equally.
The probable outcome is good with proper diagnosis and treatment.
Inheritance Pattern
with equal frequency. It is autosomal recessive, which means that if the clotting
but may or may not have symptoms.
Several families with combined deficiencies of factors V and VIII have been
reported.
Symptoms include:
• bleeding into the skin
• excessive bruising with minor injuries
• nose bleeds
• bleeding of the gums
• excessive menstrual bleeding
30

• prolonged or excessive loss of blood with surgery or trauma
Diagnosing the deficiency involves tests and signs such as:
• factor V assay showing decreased activity
• slightly prolonged bleeding time (in some people)
• prolonged partial thromboplastin time
Treatments
There are no commercially available concentrates of factor V, so fresh plasma or
fresh frozen plasma infusions are used to correct the deficiency temporarily and
should be given daily during a bleeding episode. Other plasma is not given because
factor V deteriorates very rapidly. The half-life of factor V is 24 hours.
This is an inherited disorder; there is no known prevention.
Complications
Dangerous hemorrhaging can occur if bleeding isn't controlled quickly. If platelets
are used as a source of factor V, antiplatelet antibodies can be induced.
Factor VII Deficiency
(Proconvertin or Stable Factor)
What Is It?
This extremely rare disorder can be inherited or acquired by people who do not
have hemophilia who take Coumadin, a drug used to inhibit blood clotting.
With this disorder, bleeding can vary from mild to severe within the same person
over time. Bleeding doesn't always correspond with the severity of the deficiency
shown in blood tests. A history of bleeding may occur in infancy or childhood.
Gastrointestinal and central nervous system bleeding can also occur.
This disorder occurs in one in 500,000 males and females. Congenital factor VII
deficiency should be distinguished from acquired factor VII deficiency, which may
result from liver disease, vitamin K deficiency or other malabsorption conditions.
31

When levels of the factor are less than 1% of normal, bleeding can be severe. The
trauma of birth may cause bleeding in the head of a newborn. Circumcision may
cause prolonged bleeding. Children and adults may suffer bleeding from nose,
gums or gastrointestinal tract, and women may suffer excessive menstrual bleeding.
The probable outcome is good with proper treatment.
Inheritance Pattern
with equal frequency. It is also autosomal recessive, which means that if the clotting
but may or may not have symptoms. Those who have inherited a defective factor
VII gene from only one parent will usually have only moderate levels of the factor
but no symptoms.
Severity of bleeding episodes depends on the degree of the severity of the defect.
Symptoms include:
• bleeding of mucous membranes
• spontaneous nosebleeds
• excessive bruising
• prolonged menstrual bleeding
• bleeding into muscles
• bleeding into joints
Diagnosis is made by testing for factor VII in the blood. Signs and tests include:
• normal partial thromboplastin time
• decreased factor VII assay
32

Treatments
Bleeding episodes can be controlled with normal plasma or concentrates containing
factor VII. Severe bleeding may be treated with fresh frozen plasma or Prothrombin
complex concentrates (PCCs). Because the life span of infused factor VII is very
short (two to four hours), patients may require treatment every two to six hours for
severe bleeding or surgery. Menstrual bleeding can be controlled by the use of oral
contraceptives.
Note that factor VII concentrate is sold only in Europe, but is available in the US on
a compassionate basis from the manufacturer (Immuno Ag).
(MASAC) made recommendations for treatment of Factor VII deficiency in
November of 1999. They include:
• Recombinant factor VIIa (NovoSeven), which was recently licensed in the US and
is produced by baby hamster kidney cells. No human albumin is used.
• Prothrombin complex concentrates (PCCs) can be used, but these products vary
considerably in the amount of factors they contain.
• Fresh frozen plasma can be used as along as it is processed to reduce the risk of
viral infection.
Complications
These can include hemorrhages, strokes or other neurological problems related to
central nervous system bleeding. Fatal intracranial bleeding caused by birth trauma
has occurred. Menstrual bleeding may also be severe.
THROMBOCYTOPENIA
Definition
Thrombocytopenia is any disorder in which there are not enough platelets. Platelets
are cells in the blood that help blood to clot. This condition is sometimes associated
with abnormal bleeding.
33

Causes, incidence, and risk factors
Thrombocytopenia is often divided into three major causes of low platelets:
1. Low production of platelets in the bone marrow
2. Increased breakdown of platelets in the bloodstream (called intravascular)
3. Increased breakdown of platelets in the spleen or liver (called extravascular)
Disorders that involve low production in the bone marrow include:
• Aplastic anemia
• Cancer in the bone marrow
• Infections in the bone marrow (rare)
• Drugs (very rare)
Disorders that involve the breakdown of platelets include:
• Immune thrombocytopenic purpura (ITP)
• Drug-induced immune thrombocytopenia
• Drug-induced nonimmune thrombocytopenia
• Thrombotic thrombocytopenic purpura
• Primary thrombocythemia
• Disseminated intravascular coagulation (DIC)
• Hypersplenism (an enlarged spleen)
Symptoms
• Bruising
• Nosebleeds or bleeding in the mouth
• Rash (pinpoint red spots)
Other symptoms may be present as well, depending on the cause of the condition. Mild
thrombocytopenia can occur without symptoms.
34

Signs and tests
• CBC shows low platelets
• Bone marrow aspiration or biopsy may be normal or may show low
megakaryocytes (platelet precursors) or an infiltrating disease.
• PTT clotting study is normal
• PT clotting study is normal
• Platelet associated antibodies may be present
Treatment
Treatment depends on the cause of the condition. In some cases, a transfusion of
platelets may be required to stop or prevent bleeding.
Expectations (prognosis)
The outcome depends on the disorder causing the low platelet counts.
Complications
• Hemorrhage
• Gastrointestinal bleeding (vomiting blood or blood in the stools)
• Bleeding in the brain (intracranial hemorrhage)
Calling your health care provider
Call your healthcare provider if you experience unexplained bleeding or bruising.
Prevention
Prevention depends on the specific cause.
35

DISSEMINATED INTRAVASCULAR COAGULATION
DIC is a syndrome arising as a complication of many different serious and life-
threatening illnesses. In its acute (overt) form it is a hemorrhagic disorder,
characterized by multiple ecchymoses, mucosal bleeding, and depletion of platelets
and clotting factors in the blood. Chronic (nonovert) DIC, on the other hand, is more
subtle and involves thromboembolism accompanied by evidence of activation of the
coagulation system. With chronic DIC, coagulation factors may be normal,
increased, or moderately decreased, as may the platelet counts.
Successful management of acute DIC depends almost entirely on prompt, effective
control of the underlying disease. Chronic DIC usually can be treated with heparin
or low-molecular-weight heparin, but warfarin is sometimes ineffective for long-term
control. Successful treatment of the underlying disease is necessary to eliminate
DIC, whether it is acute or chronic.
Pathogenesis of DIC
DIC occurs when monocytes and endothelial cells are activated or injured by toxic
substances elaborated in the course of certain diseases. The response of
monocytes and endothelial cells to injury is to generate tissue factor on the cell
surface, activating the coagulation cascade (figure 1). In acute DIC, an explosive
generation of thrombin depletes clotting factors and platelets and activates the
fibrinolytic system. Bleeding into the subcutaneous tissues, skin, and mucous
membranes occurs, along with occlusion of blood vessels caused by fibrin in the
microcirculation.
36

In chronic DIC, the process is the same, but it is less explosive. Usually there is
time for compensatory responses to take place, which diminish the likelihood of
bleeding but give rise to a hypercoagulable state. These changes in the blood can
be detected by testing the coagulation system.1-4 Thromboembolism occurs in this
setting, and when oral anticoagulants are given following heparin therapy, there is a
tendency for it to recur. Long-term therapy with low-molecular-weight heparin may
be a solution to this problem until the underlying cause can be brought under
control.
37

Conditions associated with DIC
The conditions that regularly give rise to the DIC syndrome are outlined in table 1
(1,5-8). Knowledge of this association is helpful to the physician, who may then
anticipate onset and intervene in a timely manner.
Table 1. Conditions underlying DIC syndrome
Infections
Acute DIC: Bacteria and their toxins, fungi, viruses, rickettsiae
Chronic DIC: Any chronic infection (eg, tuberculosis, abscesses, osteomyelitis)
Noninfectious inflammatory diseases
Inflammatory bowel disease: Crohn's disease and similar disorders
Obstetrical complications
Acute DIC: Abruptio placentae, abortions (especially therapeutic abortions), amniotic
fluid embolism, hemorrhagic shock
Chronic DIC: Dead fetus syndrome
Malignancy
Acute DIC: Acute promyelocytic leukemia, acute myelomonocytic or monocytic
leukemia, disseminated prostatic carcinoma
Chronic DIC: Lung, breast, gastrointestinal malignancy
Vascular disease
Acute DIC: Brain infarction or hemorrhage
Chronic DIC: Aortic aneurysm, giant hemangioma
Venoms
Acute DIC: Snake, spider (rare)
Trauma ;
38

Acute DIC: Massive tissue destruction, brain damage
Others
Acute DIC: Heparin-induced thrombocytopenia with thrombosis (HITT), purpura
fulminans in newborns (homozygous protein C deficiency)zDIC, disseminated
intravascular coagulation.
It is well known that Trousseau described an association between cancer and
venous thromboembolism. However, it is less well known that half of his patients did
not have cancer but rather had tuberculosis (9). Other inflammatory diseases are
also often associated with thromboembolism. Patients with these conditions have
the hypercoagulable state known as chronic DIC. Nonbacterial thrombotic
endocarditis and arterial thromboembolism constitute "arterial Trousseau's
syndrome."
Diagnosis of DIC
Diagnostic findings in DIC are outlined in table 2. The clinical and laboratory
features of acute DIC differ from those of chronic DIC. This is only a general rule,
however, in that chronic DIC in dead fetus syndrome and in certain vascular
disorders (eg, aortic aneurysm) may show coagulation abnormalities similar to
those found in acute DIC (10,11).
Table 2. Clinical and laboratory findings in DIC
Acute DIC
Clinical findings
• Multiple bleeding sites
• Ecchymoses of skin, mucous membranes
• Visceral hemorrhage
• Ischemic tissue
39

Laboratory abnormalities
• Coagulation abnormalities: prolonged prothrombin time, activated partial
thromboplastin time, thrombin time; decreased fibrinogen levels; increased
levels of FDP (eg, on testing for FDP, D dimer)
• Platelet count decreased as a rule but may be falling from a higher level yet
still be normal
• Schistocytes on peripheral smear
Chronic DIC
Clinical findings
• Signs of deep venous or arterial thrombosis or embolism
• Superficial venous thrombosis, especially without varicose veins
• Multiple thrombotic sites at the same time
• Serial thrombotic episodes
Laboratory abnormalities
• Modestly increased prothrombin time in some patients
• Shortened or lengthened partial thromboplastin time
• Normal thrombin time in most patients
• High, normal, or low fibrinogen level
• High, normal, or low platelet count
• Increased levels of FDP (eg, on testing for FDP, D dimer)
• Evidence of molecular markers* (eg, thrombin-antithrombin complexes,
activation markers on platelet membranes, prothrombin fragment F1+2)
DIC, disseminated intravascular coagulation; FDP, fibrin-fibrinogen degradation
products.
40

*These tests are used primarily in research.
Diagnosis of acute DIC can be established without performing all of the laboratory
tests we know to have abnormal findings in most cases of this syndrome. This is
especially true when the clinical setting is consistent with DIC and results of routine
tests (eg, platelet count, prothrombin time, partial thromboplastin time, fibrinogen
level) are all abnormal (table 2). Disorders such as hepatic insufficiency, hepatic
necrosis, anticoagulant overdose, and the presence of certain circulating
anticoagulants should also be considered in the differential diagnosis, particularly
when there is no obvious underlying disease to account for DIC (10-13).
A number of other laboratory markers are associated with DIC, including prolonged
thrombin time and decreased levels of antithrombin III, protein C, plasminogen, and
alpha2-antiplasmin. However, these same abnomalities may be seen in severe liver
disease and in severe hemorrhage caused by plasma loss. The one coagulation
system test that helps distinguish between DIC and liver disease is D dimer. This
test is usually negative in liver disease unless there is massive necrosis, which can
cause DIC.
Another laboratory clue to chronic DIC is a shortened activated partial
thromboplastin time (14,15). Platelet counts may be normal, high, or moderately
low. In addition, platelet counts may rise with heparin therapy and fall when heparin
is stopped in the presence of a hypercoagulable state or chronic DIC.
Management of DIC
Treatment of the underlying disease is the mainstay of management of either acute
or chronic DIC (table 3). Additionally, acute DIC is treated with blood products that
41

control bleeding if necessary. Experimental drugs (eg, concentrate of the tissue
factor pathway inhibitors antithrombin III, protein C, or thrombomodulin) are
currently undergoing clinical trials (5,16).
Table 3. Treatment options for DIC syndrome
Treat the underlying disease
Avoid delay
Treat vigorously (eg, shock, sepsis, obstetrical problems)
Manage the DIC
Acute DIC
Without bleeding or evidence of ischemia
No treatment
With bleeding
Blood components as needed
Fresh frozen plasma
Cryoprecipitate
Platelet transfusions
With ischemia
Anticoagulants (see "with thromboembolism" below) after
bleeding risk is corrected with blood products
Chronic DIC
Without thromboembolism
No specific therapy needed but prophylactic drugs
(eg, low-dose heparin, low-molecular-weight heparin)
may be used for patients at high risk of thrombosis
With thromboembolism
Heparin or low-molecular-weight heparin, trial of warfarin
sodium (Coumadin). (If warfarin is unsuccessful, long-term use
of low-molecular-weight heparin may be helpful.)*
42

DIC, disseminated intravascular coagulation.
*Some patients respond to warfarin, others do not. Use of low-molecular-weight
heparin for prolonged periods has potential hazards and is expensive but can be
useful when warfarin therapy fails despite good control (international normalized
ratio [INR], 2-3).
When there is no serious hemorrhage or unusual risk of bleeding or
thromboembolism in acute DIC, it is appropriate to observe rather than treat. As
Milton stated in On His Blindness, "They also serve who only stand and wait."
Chronic DIC is primarily a hypercoagulable state that may result in venous or
arterial thrombosis. In some vascular and obstetrical disorders, chronic DIC
manifests primarily by consumption coagulopathy of mild to modest degree.
Standard treatment of thromboembolism with heparin or low-molecular-weight
heparin is appropriate, although it is important to be aware of warfarin resistance.
Should thrombosis recur while a patient is receiving warfarin, it is advisable to use
heparin or low-molecular-weight heparin until the underlying disease is fully
controlled or cured.
IDIOPATHIC THROMBOCYTOPENIC PURPURA
What is ITP?
ITP stands for idiopathic thrombocytopenic purpura. "Idiopathic" means that the
cause is unknown. "Thrombocytopenic" means the blood doesn't have enough
platelets. "Purpura" means a person has excessive bruising. You may also hear ITP
called "immune thrombocytopenic purpura."
In people with ITP, all of the blood cells are normal except for the blood platelets.
Platelets are the tiny cells that seal minor cuts and wounds and form blood clots. A
person with too few platelets bruises easily and bleeds for a long time after being
43

injured. Tiny red dots on the skin, called petechiae (say "pe-TEEK-ee-ay") might
also appear. When the platelet count is very low, the person with ITP might have
nosebleeds that are hard to stop, or might have bleeding in the intestines.
What causes ITP?
The cause of ITP is not known. People with ITP form antibodies that destroy their
blood platelets. Normally, antibodies are a healthy response to bacteria or viruses.
In people with ITP, however, the antibodies attack the body's own blood platelets.
Who gets ITP?
There are 2 types of ITP. One type affects children, and the other type affects
adults. In children, the usual age for getting ITP is 2 to 4 years of age. Most adults
with ITP are young women, but it can occur in anyone. ITP does not run in families.
How does ITP affect children?
ITP is different in children than in adults. Most children with ITP have a very low
platelet count that causes sudden bleeding. The usual symptoms are bruises and
the tiny red dots on the skin. Nosebleeds and bleeding gums are also common.
How is ITP diagnosed?
Your doctor can diagnose ITP by asking questions about your health and doing a
physical exam. Your doctor may take a blood sample and look at it under a
microscope.
How is ITP treated in children?
Because most children recover with no treatment, many doctors recommend just
watching them carefully and taking care of the bleeding symptoms. Children don't
have to go to the hospital if good care is available at home. However, some doctors
recommend a short treatment with prednisone pills or intravenous infusions (given
44

in a vein) of gamma globulin to increase the platelet count more quickly. Both
medicines have some side effects.
How does ITP affect adults?
In most adults, ITP lasts much longer than it does in children. At the time of
diagnosis, most adults have noticed increased bleeding and easy bruising for
several weeks, or even months. In women, increased menstrual blood flow is a
major sign.
Many adults have only mild thrombocytopenia. In fact, quite a few people have no
bleeding symptoms. They are only diagnosed with ITP when their blood is checked
for another reason and a low blood platelet count is found.
How is ITP treated in adults?
Treatment of ITP in adults is aimed at increasing the blood platelet count. This is not
the same as curing the disease. Patients may take prednisone for several weeks,
even a month or longer. However, when the medicine is stopped, the platelet counts
may get low again.
If prednisone doesn't help enough, the spleen can be removed. The spleen makes
most of the antibodies that destroy the blood platelets. It also destroys old or
damaged blood cells. In an otherwise healthy young person, removal of the spleen
is not a serious operation.
What about ITP in pregnant women?
Diagnosing ITP during pregnancy can be difficult, because platelet counts may be
low for other reasons. About 5% of women have mildly low platelet counts at the
end of a normal pregnancy. The cause of this is unknown. The platelet count goes
back to normal right after delivery.
45

A baby born to a mother with ITP may have a low blood platelet count a few days to
a few weeks after birth. These babies are usually kept in the hospital for several
days for observation (watching to make sure they are ok) before they go can home.
Thrombotic thrombocytopenic purpura
What is thrombotic 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).
What causes TTP?
Until recently the cause of TTP remained elusive. However, recent research points
to the involvement of a protein in the plasma called von Willebrand factor (vWF).
DRUG-INDUCED IMMUNE THROMBOCYTOPENIA
DRUG-INDUCED IMMUNE THROMBOCYTOPENIA is a condition where the use of
certain drugs leads to the formation of antibodies against platelets. These
antibodies can cause a low platelet count, which make bleeding more likely. If these
antibodies are formed during pregnancy, they may pass from the mother to the
fetus.
Thrombocytopenia (nonimmune) drug-induced; Nonimmune
thrombocytopenia - drug-induced
Drug-induced nonimmune thrombocytopenia is a reduction in normally functioning
platelets that can be caused by certain drugs.
46

Platelets are important in forming blood clots. Certain drugs may decrease the
number of platelets by damaging the bone marrow where platelets are made.
Decreased platelets may cause easy bruising or abnormal bleeding.
Bleeding can be life-threatening if it occurs in the brain or other vital organ. Other
drugs can increase the risk of bleeding by preventing platelets from working
normally. A common example of this is aspirin
PRIMARY THROMBOCYTHEMIA
Essential thrombocythemia; Essential thrombocytosis
Primary thrombocythemia is a condition of overproduction of platelets without a
recognizable cause.
Causes, incidence, and risk factors
Primary thrombocythemia is a slowly progressing disorder caused by overgrowth of
a type of cell that is a precursor of blood cells. Although the platelets are primarily
affected, the red blood cells and white blood cells are also involved.
The disease has similarities to polycythemia vera, chronic myelogenous leukemia,
and myelofibrosis. Usually it affects people in middle age. Bleeding can occur from
the gastrointestinal tract, respiratory system, urinary tract, or skin.
The formation of blood clots, called thrombosis, may coincide with bleeding
episodes. It may even cause strokes in some people. Risk factors are unknown.
The incidence is about 3 out of 100,000 people.
Symptoms
• Nosebleeds (epistaxis )
• Bleeding from the gums
• Bleeding from the gastrointestinal tract
47

• Easy bruising
• Prolonged bleeding from surgical procedures or tooth extraction
• Enlarged lymph nodes (rare)
• Bloody stools
• Headache
• Numbness of hands or feet
• Dizziness
• Ulcers on fingers or toes
Signs and tests
Bone marrow aspiration.
• CBC that shows elevated platelet count.
• Uric acid level may be elevated.
• Physical examination may show enlarged spleen or liver.
Treatment
If a patient is having life-threatening complications, rapid decrease of the platelet
count may be achieved through platelet pheresis, a procedure to remove platelets
from the blood directly.
Long-term decrease of the platelet count using medications can reduce both
bleeding and clotting complications. Most common medications include
hydroxyurea, interferon-alpha, or anagrelide. For patients with a known clotting
tendency, aspirin may help decrease clotting episodes.
Some patients do not need any treatment.
Expectations (prognosis)
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The outcome varies with reports ranging from prolonged periods without
complications in some people, to fatalities from complications related to hemorrhage
and thrombosis in others.
Complications
• Severe hemorrhage
• Thrombotic episodes (stroke, heart attack, or blood clots in extremities)
• Acute leukemia or myelofibrosis can develop in some patients
Calling your health care provider
• If unexplained or prolonged bleeding occurs.
• If chest pain, leg pain, confusion, weakness, numbness, or other new
symptoms develop
HYPERSPLENISM
Hypersplenism is increased activity of the spleen caused by tumors, anemia,
malaria, tuberculosis, and various connective tissue and inflammatory diseases.
An enlarged spleen is often accompanied by a low level of one or more types of
blood cells. The enlarged spleen can cause stomach pain on the left side, as well as
feeling full prematurely after eating
DENTAL EVALUATION
• good thorough medical history
• a physical examination
• screening clinical lab tests
• excessive bleeding following surgical procedure
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good thorough history
• Family HX
• Personal HX
• Medications
• Past & Present Illness
• Spontaneous Bleeding
REVIEW PATIENT’S MEDS
FIVE DRUGS THAT INTERFERE WITH HEMOSTASIS
• ASPIRIN
• ANTICOAGULANTS
• ANTIBIOTICS
• ALCOHOL
• ANTICANCER
ORAL MANIFESTATIONS
• Petechiae & Ecchymosis
• Gingival Hyperplasia
• Spontaneous Gingival Bleeding
• Ulceration of Oral Mucosa
• Lymphadenopathy
50

DENTAL PATIENTS
 LOW RISK
 Patients with No Hx of Bleeding Disorders
 Normal Laboratory Results
 MODERATE RISK
 Patients on Chronic Oral Anticoagulant
 Therapy. PT is 1.5 - 2 Times Control Range
 Patients on Chronic Aspirin Therapy
DENTAL PATIENTS
 HIGH RISK
 Patients with Known Bleeding Disorders
 Patients without Known Bleeding Disorders Who Have Abnormal
Laboratory Results
DENTAL MANAGEMENT
 LOW RISK PATIENTS
 Normal Protocol
 MODERATE RISK PATIENTS
 Anticoagulants - Consult Physician
 Aspirin Therapy - BT, Consult Physician
 HIGH RISK PATIENTS
51

 Close Coordination with Physician
 Hospitalization (Platelet Transfusion) (Factor Replacement)(Vit K
Therapy)(Dialysis)
CONCLUSIONS
The history (medical /family history) is extremely important in evaluating patients
with disorders of hemostasis.The duration of the bleeding disorder must be
determined, since many of these disorders are inherited. Careful questioning may
be necessary to reveal a life long history of bleeding and bruising a family history of
bleeding may be elicited with a carefully taken history.
Dental extractions are a very common major stresses of the haemostatic
mechanism, and a prior history of excessive bleeding following an extraction is
important. In evaluating this history, one must consider the number of teeth
extracted, the location of teeth that were extracted, the time of onset and duration of
the hemorrhage, and the extent of blood loss. Bleeding brought on by platelet
abnormalities is likely to be immediate and to respond readily to direct pressure.
While bleeding secondary to coagulation factor disorders may be delayed a few
hours in onset and last for many days, often with recurrences.
So, thorough understanding and knowledge about bleeding disorders is very much
needed for dental professionals to minimize the complications of many treatment
procedures.
52

References
1) Davidson’s “principles and practice of medicine-19th
edition;-Hanslet,
Chilvers, Boon, Colledge, Hunters.
2) Medical emergencies in the dental practice –malammed; 5th edition
3) Bailey and Love’s Short practice of surgery-23rd
edition; Russel, Williams,
Bulstrode;
4) Complications in Oral and Maxillofacial surgery-1st
edition; Kaban, Pogrel,
Perrot.
5) Concise Medical Physiology;-5th
edition; Chaudhari
6) Systemic disease in dental treatment-1st
edition;-Michael.J.Tullman,
Spencer.W.Redding.
7) Clinical hematology-7th
edition;-Maxwell.M.Wintrobe.
53

8) www.hemophilia.org
9) www.google.com
10) Circulating factor VIII inhibitor: case report and review. J Oral
Maxillofac Surg. 2005 Feb;63(2):253-7. Review
11) Dental management considerations for the patient with an
acquired coagulopathy. Part 2: Coagulopathies from drugs.Br Dent J. 2003
Nov 8;195(9):495-501. Review
12) Management of dental extractions in patients with bleeding
disorders.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002 Mar; 93(3):247-50.
1. Human gene for factor VIII isolated.
2. B-domain removed from factor VIII gene.
3. B-domain-deleted (BDD) gene inserted into the production cells (Chinese hamster ovary cells).
4. BDD production cells grown in culture media that contain small amounts of human serum albumin.
5. BDD recombinant factor VIII (BDDrFVIII) production cells are frozen and stored.
6. BDDrFVIII production cells are obtained from the cell bank and thawed.
7. BDDrFVIII production cells grow inside bioreactors with human serum albumin in the culture
medium.
8. ReFacto is filtered away from production cells and purified and concentrated by a chromatography
step.
9. ReFacto is processed through a viral solvent-detergent step.
10. ReFacto is processed through monoclonal antibody purification and three additional chromatography
steps.
11. No albumin is added to the final formulation.
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