Hemophilia (Year of the Zebra)

Summary

Hemophilia is a genetic bleeding disorder affecting the blood's ability to clot due to deficiencies in clotting factors. The coagulation cascade, involving both intrinsic and extrinsic pathways, is impaired, leading to prolonged bleeding. Hemophilia A and B are caused by mutations in the genes for factors VIII and IX, respectively. Treatment involves clotting factor replacement, but complications like inhibitors can arise. Diagnosis is through lab tests, and individuals with hemophilia should avoid activities that increase bleeding risk.

Takeaways

• 🩸 Hemophilia is a genetic disorder characterized by impaired blood clotting, often due to a deficiency in clotting factors.
• 🛑 Hemostasis is the process that stops bleeding, and in hemophilia, this process is compromised, leading to prolonged bleeding.
• 🧬 The coagulation cascade involves a series of clotting factors that, when activated, form a clot to stop bleeding.
• 🔪 Primary hemostasis involves platelet plug formation at the site of injury, which is often normal in hemophiliacs.
• 🧬 Secondary hemostasis involves the coagulation cascade and is where deficiencies in clotting factors lead to hemophilia.
• 🌐 Hemophilia can be caused by deficiencies in various clotting factors, but most commonly factors VIII (Hemophilia A) and IX (Hemophilia B).
• 🧬 Hemophilia A and B are X-linked recessive disorders, predominantly affecting males due to their single X chromosome.
• 🏥 Diagnosis of hemophilia involves lab tests such as platelet count, Prothrombin time, and partial thromboplastin time, which are often abnormal in hemophiliacs.
• 💉 Treatment typically involves injections of the deficient clotting factor, but can be complicated by the development of inhibitors.
• 🚫 Individuals with hemophilia are advised to avoid activities and medications that increase the risk of bleeding.
• 🧬 Other causes of hemophilia-like symptoms include liver failure, vitamin K deficiency, autoimmunity against clotting factors, and disseminated intravascular coagulation.

Q & A

What is the meaning behind the term 'hemophilia'?

The term 'hemophilia' is derived from Greek words for 'blood' and 'love,' which metaphorically suggests that people with the condition have a hard time stopping bleeding.

What is the normal process called when the body stops bleeding after an injury?

The normal process is called 'hemostasis,' which involves immediate vasoconstriction, platelet plug formation known as primary hemostasis, and the activation of the coagulation cascade leading to secondary hemostasis and clot formation.

What are the clotting factors and where are they usually synthesized?

Clotting factors are a set of proteins in the blood, most of which are synthesized by the liver and are usually inactive until activated during the coagulation process.

How does the coagulation cascade work in terms of amplification?

The coagulation cascade works through a series of proteolytic cleavages that activate clotting factors in sequence, which has a huge degree of amplification and forms a clot within minutes of injury.

What is the final step in the coagulation process that leads to clot formation?

The final step is the activation of the protein fibrinogen to fibrin, which polymerizes to form a mesh that reinforces the platelet plug and results in a hard clot at the injury site.

What is the difference between primary and secondary hemostasis?

Primary hemostasis involves the formation of a platelet plug, while secondary hemostasis involves the coagulation cascade and the formation of a stable fibrin clot.

How does hemophilia affect the coagulation cascade?

In hemophilia, there is a decrease in the amount or function of one or more clotting factors, which makes secondary hemostasis less effective and allows more bleeding to occur.

What are the two pathways that can initiate the coagulation cascade?

The two pathways are the extrinsic pathway, which starts with tissue factor exposure, and the intrinsic pathway, which starts with platelet activation near blood vessel injury.

What are the most common types of hemophilia and the clotting factors they affect?

The most common types are Hemophilia A, which affects factor 8, and Hemophilia B, which affects factor 9.

How are Hemophilia A and B inherited and what chromosomes are the responsible genes located on?

Both Hemophilia A and B are X-linked recessive conditions, meaning they are inherited on the X chromosome and usually affect men, who have only one X chromosome.

What are some of the complications that can arise from hemophilia?

Complications of hemophilia can include easy bruising, hematomas, prolonged bleeding after injuries or surgeries, gastrointestinal bleeding, severe nosebleeds, and dangerous bleeding into joints or the brain.

What are the typical diagnostic tests for Hemophilia A and B?

Diagnosis usually starts with lab tests including a platelet count, Prothrombin time (PT), and partial thromboplastin time (PTT), followed by specific factor activity tests and mutation testing of the clotting factor genes.

How is hemophilia typically treated and what challenges can arise with treatment?

Hemophilia is typically treated with injections of the missing or non-functional clotting factor. Challenges can include the development of inhibitors by the immune system, which can diminish treatment effectiveness and sometimes cause severe allergic reactions.

What is the role of desmopressin (DDAVP) in treating mild Hemophilia A?

Desmopressin (DDAVP) is helpful for patients with mild Hemophilia A as it stimulates the release of Von Willebrand factor from endothelial cells, which promotes the stabilization of residual Factor 8.

What lifestyle recommendations are there for individuals with hemophilia?

Individuals with hemophilia should avoid contact sports and medications that promote bleeding, such as aspirin.

Outlines

00:00

🩸 Understanding Hemophilia and the Coagulation Cascade

This paragraph explains hemophilia as a genetic disorder affecting blood clotting, characterized by prolonged bleeding due to impaired hemostasis. It details the normal blood clotting process involving vasoconstriction, platelet plug formation (primary hemostasis), and the coagulation cascade involving clotting factors synthesized by the liver (secondary hemostasis). Hemophilia results from a decrease in clotting factors, leading to less effective secondary hemostasis. The paragraph also describes the extrinsic and intrinsic pathways of the coagulation cascade, which converge on the common pathway to form a stable clot. Hemophilia is often due to deficiencies in factor 8 (hemophilia A) or factor 9 (hemophilia B), and can be caused by liver failure, vitamin K deficiency, or autoimmunity.

05:01

🧬 Hemophilia Genetics, Symptoms, and Treatment

This paragraph delves into the genetic aspects of hemophilia, noting that it is an X-linked recessive disorder, typically affecting men due to their single X chromosome. It outlines the symptoms of hemophilia A and B, which are clinically similar, including easy bruising, prolonged bleeding from injuries or surgeries, and internal bleeding such as hemarthrosis. The severity of symptoms is linked to the degree of clotting factor deficiency. Diagnostic methods include lab tests like platelet count, Prothrombin time, and partial thromboplastin time, which help identify the specific clotting factor deficiencies. Treatment usually involves injections of the missing clotting factor, but complications like inhibitors, which are antibodies against the infused factors, can reduce treatment effectiveness. Desmopressin is beneficial for mild hemophilia A, promoting factor 8 stabilization. The paragraph concludes with lifestyle recommendations for individuals with hemophilia to avoid activities and medications that increase bleeding risk.

Keywords

💡Hemophilia

Hemophilia is a genetic bleeding disorder characterized by the inability to properly form blood clots, leading to excessive bleeding after injury. It is the central theme of the video, which explains the condition's causes, symptoms, and treatments. The script mentions hemophilia as a combination of Greek words for 'blood' and 'love,' indicating the difficulty in stopping bleeding.

💡Hemostasis

Hemostasis is the process that stops bleeding by forming a clot. It is a key concept in the script, as it is impaired in hemophilia, leading to prolonged bleeding after injury. The script describes the normal hemostasis process involving vasoconstriction, platelet plug formation, and the coagulation cascade.

💡Coagulation Cascade

The coagulation cascade is a series of reactions involving clotting factors that lead to blood clot formation. The script explains that in hemophilia, this process is impaired, resulting in less effective secondary hemostasis and increased bleeding. It is a critical part of understanding the condition's pathology.

💡Clotting Factors

Clotting factors are proteins in the blood that play a role in the coagulation process. The script specifies that most clotting factors are synthesized by the liver and are involved in the coagulation cascade. Hemophilia often involves a deficiency in one or more of these factors, such as factor 8 or factor 9.

💡Primary Hemostasis

Primary hemostasis refers to the initial stage of clotting where platelets adhere to the damaged vessel wall and form a plug. The script mentions this as the first step in the hemostasis process, which is not typically affected in hemophilia.

💡Secondary Hemostasis

Secondary hemostasis involves the coagulation cascade and results in a hard clot at the site of injury. The script explains that in hemophilia, this process is less effective due to a decrease in the amount or function of clotting factors, leading to more bleeding.

💡Extrinsic Pathway

The extrinsic pathway is one of the ways the coagulation cascade can be initiated, starting with tissue factor exposure. The script describes this pathway in detail, emphasizing its role in turning factor 7 into its active form, which is crucial for the cascade in hemophilia.

💡Intrinsic Pathway

The intrinsic pathway is another initiator of the coagulation cascade, starting with platelet activation near a blood vessel injury. The script explains how this pathway leads to the activation of factor 9 and eventually converges with the extrinsic pathway on the common pathway.

💡Common Pathway

The common pathway is the final stage of the coagulation cascade where both the extrinsic and intrinsic pathways converge. The script mentions that this pathway leads to the activation of factor 10 and the subsequent formation of a stable clot, which is impaired in hemophilia.

💡Factor 8 and Factor 9

Factor 8 and factor 9 are specific clotting factors that, when deficient, cause hemophilia A and hemophilia B, respectively. The script explains that these factors work together in the coagulation cascade and that their deficiencies are the most common forms of hemophilia.

💡X-linked Recessive

X-linked recessive is a pattern of inheritance where the gene causing the disorder is located on the X chromosome. The script notes that both hemophilia A and B are X-linked recessive disorders, typically affecting males, who have only one X chromosome, more severely than females.

💡Inhibitors

Inhibitors are antibodies that can develop in response to infused clotting factors in severe hemophilia, recognizing them as foreign and attempting to eliminate them. The script mentions that inhibitors can diminish the effectiveness of hemophilia treatments and sometimes cause severe allergic reactions.

💡Desmopressin (DDAVP)

Desmopressin, also known as DDAVP, is a medication that can be helpful in treating mild hemophilia A by stimulating the release of von Willebrand factor, which stabilizes factor 8. The script mentions its use as a treatment option for mild cases of hemophilia.

Highlights

Hemophilia is a genetic disorder characterized by impaired blood clotting, stemming from the Greek words for blood and love, indicating difficulty in stopping bleeding.

Hemostasis, the normal process to stop bleeding, involves vasoconstriction, platelet plug formation, and the coagulation cascade.

The coagulation cascade is initiated by the activation of clotting factors, most of which are proteins synthesized by the liver.

Primary hemostasis is the formation of a platelet plug, while secondary hemostasis involves the reinforcement of this plug with fibrin.

Hemophilia is typically caused by a decrease in clotting factors, leading to less effective secondary hemostasis and increased bleeding.

The coagulation cascade can start through the extrinsic pathway, initiated by tissue factor exposure, or the intrinsic pathway activated by platelets near the injury.

Both pathways converge on the common pathway, which ultimately leads to the formation of a stable clot.

Hemophilia can be caused by insufficient concentration or decreased activity of any coagulation factor except Factor 12 deficiency, which is asymptomatic.

Hemophilia A and B are the most common forms, caused by deficiencies in clotting factors 8 and 9, respectively, and are X-linked recessive disorders.

Von Willebrand disease mimics Hemophilia A and is caused by a deficiency of Von Willebrand factor, affecting primary hemostasis.

Acquired causes of Hemophilia include liver failure, vitamin K deficiency, autoimmunity against clotting factors, and disseminated intravascular coagulation.

Diagnosis of Hemophilia involves lab tests such as platelet count, Prothrombin time, and partial thromboplastin time, which reveal deficiencies in specific clotting factors.

Treatment for Hemophilia A and B involves injections of the missing or non-functional clotting factor, but can be complicated by the development of inhibitors.

Desmopressin (DDAVP) is beneficial for patients with mild Hemophilia A, as it stimulates the release of Von Willebrand factor, stabilizing residual Factor 8.

Individuals with Hemophilia are advised to avoid contact sports and medications that promote bleeding, such as aspirin.

Hemophilia A and B are treated by supplementing the missing clotting factor, with the goal of helping patients maintain a normal life.

Transcripts

foreign

hemophilia is a combination of the Greek

words for blood and love a way of saying

that people with hemophilia love to

bleed or rather that it's hard to stop

bleeding

this is because the process called

hemostasis literally meaning to stop the

flow of blood is impaired

normally after a cut and damage the

endothelium or the inner lining of blood

vessel walls there's an immediate

vasoconstriction or narrowing of the

blood vessel which limits the amount of

blood flow

after that some platelets adhere to the

damaged vessel wall and become activated

and then recruit additional platelets to

form a plug

the formation of the platelet plug is

called primary hemostasis

after that the coagulation Cascade is

activated

first off in the blood there's a set of

clotting factors most of which are

proteins synthesized by the liver and

usually these are inactive and just

floating around in the blood

the coagulation Cascade starts when one

of these proteins gets proteolytically

cleaved this active protein then

proteolytically Cleaves and activates

the next clotting factor and so on

this Cascade has a huge degree of

amplification and takes only a few

minutes from injury to clot formation

the final step is activation of the

protein fibrinogen to fibrin which

deposits and polymerizes to form a

measure on the platelets

so these steps leading up to fibrin

reinforcement of the platelet plug make

up the process called secondary

hemostasis and results in a hard clot at

the site of the injury

in most cases of Hemophilia there's a

decrease in the amount or function of

one or more clotting factors which makes

secondary hemostasis less effective and

allows more bleeding to happen

now that coagulation Cascade can get

started in two ways the first way is

called the extrinsic pathway which

starts when tissue Factor gets exposed

by the injury of the endothelium

tissue Factor turns inactive Factor 7

into activated Factor 7A a for active

and then tissue Factor goes on to bind

the newly formed Factor 7A to form a

complex that turns Factor 10 into active

Factor 10A

Factor 10A with Factor 5A as a cofactor

turns Factor 2 which is also called

prothrombin into Factor 2A also called

thrombin

thrombin then turns Factor 1 or

fibrinogen which is soluble into Factor

1A or fibrin which is insoluble and

precipitates out of the blood at the

site of the injury

thrombin also turns Factor 13 into

Factor 13A which cross-links with fiber

and to form a stable clot

the second way is called the intrinsic

pathway and it starts when platelets

near the blood vessel injury activate

Factor 12 into factor 12a which then

activates Factor 11 to factor 11a which

then activates Factor 9 to factor 9A and

Factor 9A along with Factor 8A work

together to activate Factor 10 to factor

10A

and from that point it follows the same

fate as before

so both the extrinsic and intrinsic

Pathways basically Converge on a single

final path called the common pathway

believe it or not this is a somewhat

simplified version of the coagulation

Cascade but it has all the key parts

needed to understand hemophilia

now an insufficient concentration or

decreased activity of any coagulation

Factor can cause hemophilia except

Factor 12 deficiency which is

asymptomatic

hemophilia usually refers to inherited

deficiencies of coagulation factors

which can be either quantitative or

qualitative

by far the most common of these are

deficiencies of factor 8 which gives

rise to factor 8A and is stabilized by

another Factor called Von Willebrand

factor and this deficiency is called

hemophilia a or classic hemophilia

another common deficiency is deficiency

of factor 9 called hemophilia B which

used to be called Christmas disease

named after the patient who had it not

the holiday

now a mimic of Hemophilia a is Von

Willebrand disease which is an inherited

problem with primary hemostasis caused

by a deficiency of Von Willebrand factor

so in severe Von Willebrand deficiency

factor 8 gets broken down faster and can

become deficient too

as opposed to inherited forms of

Hemophilia one acquired cause of

Hemophilia is liver failure since the

liver synthesizes factors 1 2 5 7 8 9 10

11 and 13.

also vitamin K deficiency can cause

hemophilia since Vitamin K is needed by

the liver to synthesize and release

factors to 7 9 and 10.

another cause is autoimmunity against a

clotting factor and finally there's

disseminated intravascular coagulation

which consumes coagulation factors

now the mutated genes in hemophilia a

are called f8 and in hemophilia B

they're called F9 and these are both on

the X chromosome meaning both conditions

are x-linked recessive so it usually

affects men since they only have one X

chromosome and therefore only one copy

of the f8 and F9 genes

women with one mutated Gene copy have a

remaining healthy copy so they don't get

hemophilia unless X chromosome

inactivation turns off the normal copy

in the majority of cells but generally

women are carriers while men are

symptomatic with the disease

signs and symptoms of Hemophilia A and B

are nearly clinically identical which

makes sense since factors 8A and 9A work

together in the coagulation Cascade to

activate Factor 10.

both of these can cause easy bruising or

echymosis as well as hematomas which are

collections of blood outside the blood

vessels that are often deep in the

muscles

prolonged bleeding after a cut or

surgical procedure for example

circumcision

oozing after tooth extractions

gastrointestinal bleeding hematuria

which is blood in the urine severe

nosebleeds and hemarthrosis or bleeding

into joint spaces

a dangerous complication is bleeding

into the brain which can cause a stroke

or increased intracranial pressure

now the severity of the symptoms depends

on the severity of the underlying

mutation which determines the activity

of the factor

diagnosis of Hemophilia A and B usually

starts with lab tests including a

platelet count which is usually normal a

Prothrombin time and a partial

thromboplastin time

the Prothrombin time tests extrinsic and

common Pathways which means factors 7 10

5 2 which is prothrombin and one which

is fibrinogen

whereas the partial thromboplastin time

test the intrinsic in common Pathways

meaning factors 12 11 9 8 10 5 2 and 1.

since factors 8 and 9 are part of the

intrinsic pathway Prothrombin time is

normal and partial thromboplastin time

is prolonged in hemophilia A and B

in order to confirm hemophilia ARB test

to look at specific Factor activities

and mutation testing of the genes

encoding them can be done

treatment for hemophilia A and B is

usually done with injections of the

missing or non-functional clotting

Factor

unfortunately if the patient has severe

deficiency where intrinsic production of

the factor is absent or very low these

supplemental factors can be seen as

foreign by the immune system which

results in the production of antibodies

that try to eliminate the injected

clotting factors which are called

inhibitors

Inhibitors diminish the treatment's

effectiveness over time and can also

sometimes cause anaphylaxis which is a

severe allergic reaction

for hemophilia a desmopressin also

called ddavp

is helpful for patients with mild

quantitative factor 8 deficiency

desmopressin stimulates Von Willebrand

factor released from endothelial cells

which promotes the stabilization of the

residual Factor 8.

finally it's best for individuals with

hemophilia to avoid contact Sports and

medicines that promote bleeding like

aspirin

all right as a quick recap hemophilia is

a bleeding disorder that's caused by an

impaired coagulation Cascade

hemophilia a is caused by mutations in

the genes for factor 8 and B is caused

by mutations in the genes for factor

nine and these two are the most common

genetic hemophilias and are both treated

by supplementing the missing clotting

Factor

helping current and future clinicians

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