Hemophilia - Pathophysiology, Diagnosis and Treatment.

 

Hemophilia - Pathophysiology, Diagnosis and Treatment.

Hemophilia is an x-linked recessive bleeding disorder in which the blood lacks certain factors

for clotting, and thus tends to bleed more. 

While hemophilia is indeed an X-linked recessive disorder, men are primarily

affected by hemophilia because they only have one X chromosome, whereas women are

usually carriers who do not experience symptoms as they have two X chromosomes,

,allowing one to compensate for a defective gene on the other.

                                                     from rawpixel.com Public Domain

This lecture we will talk about

• The pathophysiology of hemophilia

• The clinical features

• Diagnosis and laboratory findings

• Management, treatment, complications

Pathophysiology of Hemophilia

Hemophilia results from an imbalance or a lack of clotting factors – proteins essential

for the cascade of coagulation that avoids excessive bleeding.

The two most common forms of hemophilia are those in which a specific clotting factor is missing:

Hemophilia A:

Cause: Lack of Factor VIII (FVIII).

High: Comprising between 80-85% of all cases of hemophilia.

Hemophilia B:

Cause: Lack of Factor IX (FIX).

Hemophilia rate: 15-15% of hemophilia patients.

Both disorders interfere with forming stable blood clots, which causes an extended bleeding

cycle after injury, surgery or even, in the worst cases, spontaneously.

Coagulation Cascade:

Coagulation cascade: A series of reactions involving clotting factors that create fibrin

(a clot closing the wound).

In hemophilia, the absence of FVIII or FIX hinders activation of factor X and,

in turn, production of thrombin, the key to the stable clot formation.

Clinical Features

Hemophilia can take a variety of different clinical forms depending on the degree of the factor deficiency.

Its hallmark is bleeding and can manifest as follows:

• Hemarthrosis (bleeding into joints):

            It is the symptom of severe hemophilia, which generally affects the

            heavy-duty joints (knees, elbows, ankles).
            If the joints bleed repeatedly, they can damage them and create disfigurement.

• Muscle Hematomas: There can also be bleeding in soft tissues (especially muscles) with pain, swelling and limited motion.
• Spontaneous Bleeding: Even severe hemophilia patients can experience spontaneous bleeding into soft tissue or the gut that could be fatal if not managed.
• Chronic Bleeding After Injury or Surgery: It’s common to get severe bleeding episodes from small scrapes, bruises or dental treatments.
• Intracranial Hemorrhage: During severest cases, there may be a bleed into the brain, and neurological damage, sometimes fatal.
• Mucosal Bleeding: Bleeding from the mucosa (gums, nosebleeds) is common 

Diagnosis

Hemophilia is diagnosed on clinical suspicion, by laboratory analysis and genetic testing.

Clinical History:

An untreated family history of bleeding disorders or repeated periods of unspecified bleeding are indicators.

A history of bleeding inclinations such as joint and muscle bleeds is important.

Laboratory Findings:

1. Extended Activated Partial Thromboplastin Time (aPTT): FVIII and FIX are intrinsic pathways,     so the aPTT is extended in hemophilia.
2. PT and INR Normal: Prothrombin time (PT) and international normalized ratio (INR) are normal

    as hemophilia affects the intrinsic pathway.
3. Factor VIII/IX Activity Assay: Checks the activity level for FVIII or FIX.

Factor VIII is reduced in Hemophilia A.

Factor IX production is decreased in Hemophilia B.

4. Genetic Testing:     genetic testing will detect mutations in the F8 or F9 gene for confirmation and carrier.

Classification of Hemophilia Severity

A Hemophilia’s severity depends on activity level of clotting factors in the blood.

1. Mild Hemophilia: Activity level of factor: 6-30% of normal.

The most frequent times of bleeding are after trauma or surgery.

2. Moderate Hemophilia: Activity level of factor: 1-5% normal.

Sometimes there is bleeding, in the aftermath of small injury or surgery, but this is rarer than

severe injuries.

3. Severe Hemophilia: Activity level of factor: less than 1 per cent of normal.

There is frequent bleeding, mainly from the joints and muscles, in patients.

Management

Replacement therapy of the missing clotting factor is the bedrock of hemophilia therapy.

Symptoms include bleed prevention, acute bleeding and quality of life.

1. Factor Replacement Therapy:

• Thrombocyte replacement factor with factor VIII Concentrates (Hemophilia A)

           or Factor IX Concentrates (Hemophilia B).

             These concentrates can be plasma based or recombinant (engineered).

• On-Demand Therapy: When a bleeding episode occurs, factor is given.

• Prophylactic Therapy: Subsequent infusions of clotting factor to stop unintentional bleeding

            and arthritis. Such an intervention is commonly undertaken in severe hemophilia,

            often from a young age.

2. Desmopressin (DDAVP): This medicine raises endothelial cell release of Factor VIII

            and is used in moderate Hemophilia A or von Willebrand disease.

             It doesn’t work for Hemophilia B.

2. Antifibrinolytics: Treatment can include drugs such as tranexamic acid or

            aminocaproic acid to inhibit the formation of clots and decrease bleeding,

             especially when you have a dental extraction or surgery.

2. Gene Therapy: A new therapy is gene therapy, which involves implanting a functional

            version of the defective gene (eg, the F8 or F9 gene) into the patient’s cells.

           Gene therapy, while still in the experimental phase, has been clinically effective.

Complications of Hemophilia

Haemophilia patients are vulnerable to some serious complications later on:

1. Joint Damage:

Hemarthrosis with repeated incidence results in joint loss, pain and disability.

It’s called hemophilic arthropathy.

2. Inhibitors to Clotting Factors:

In some patients, the infused clotting factor becomes antibodies (inhibitors) and not effective.

Inhibitor growth is more common in severe hemophiliacs (especially in Hemophilia A).

For inhibitors, clotting factor may be treated with additional dosages, immune tolerance induction (ITI)

or bypassing drugs such as activated prothrombin complex concentrate (aPCC).

3. Infectious Complications:

Plasma-based clotting factors previously carried a risk of blood-borne infection (HIV, hepatitis),

but now screening and recombinant drugs reduce this risk dramatically.

4. Psychosocial Impact:

A patient’s life could be affected if complications occur.

Regular checkups and counseling are necessary for any worries that arise from the chronicity of the disease.

Conclusion

Hemophilia is a chronic but curable bleeder.

Early diagnosis and care mean patients can live pretty normally, but severe hemophilia can mean

a lifetime of care and monitoring for complications. Factor replacement therapy and

new gene therapies promise to change that.

Key Takeaways:

• Hemophilia A and B are X-linked recessive conditions with deficiencies in Factor VIII and IX,

            respectively.

• Clinical features include spontaneous bleeding, joint pain (hemarthrosis)

           and persistent trauma-related bleeding.

• Diagnostic via prolonged aPTT and specific factor activity assays.

• Treatment consists largely of factor replacement on demand or prophylactically,

            and new therapies such as gene therapy are in the works.

Please watch the video on Hemophilia: Hemophilia Pathophysiology Diagnosis and Treatment

Sources: Bleeding Disorders: Explore, Discover, and Engage

               Hemophilia - PubMed