Hemophilia A is an X-linked recessive bleeding disorder that is caused by the inadequate activity of clotting factor VIII. There is a wide spectrum of clinical variation depending on the plasma levels of this factor.
When untreated, the clotting activity of FVIII determines the age of the patient at diagnosis and the frequency of bleeding episodes. Furthermore, without treatment, patients with hemophilia A will experience bleeding, rebleeding, or prolonged oozing following tooth extractions, surgical procedures, or injuries  . The clinical picture varies in severity from one patient to another.
Individuals with this form do not bleed spontaneously, although if left untreated, they will bleed abnormally after surgical procedures and major injuries. With regards to frequency of bleeding, it is variable and less often. It may occur annually or even once per decade. Additionally, the diagnosis is usually made after undergoing such an event.
These patients seldom bleed as the episodes can occur monthly or annually. However, prolonged or delayed bleeding may arise from minor trauma. Furthermore, the diagnosis typically occurs prior to the age of 6.
The clinical features of moderate and severe hemophilia A are similar.
Severe cases are typically identified early such as in neonates or infants within the first 12 months of life  secondary to precipitating events during birth or early procedures. Young children not receiving therapy present most commonly with "goose eggs" sustained after minor head traumas. Additionally, they usually have exaggerated bleeding from small injuries to the mouth.
Spontaneous joint bleeding is a recurring feature in the growing child if not on treatment. This manifestation results in pain and limping. Unprovoked hemorrhage also occurs in the gastrointestinal tract, kidneys, and brain. Additionally, subcutaneous hematomas are prevalent. Overall, prolonged bleeding, pain, and swelling manifest after dental procedures, surgery, or injuries unless prophylactic treatment is instituted. Related bleeding frequency occurs at a pace of 2 to 5 spontaneous events monthly.
Female carriers are relatively asymptomatic but may have similar manifestations to males with the mild form of the disorder.
Remarkable findings on the exam may include bruises, subcutaneous hematomas, deformed joints, and muscle contractures.
Patients with abnormal bleeding responses and/or a positive family history should raise suspicion for hemophilia A. Clinical assessment includes a thorough personal and family history, a complete physical exam, and the appropriate workup.
The initial assessment includes a complete blood cell count (CBC), coagulation panel, and an FVIII assay. The CBC will reveal normal platelet levels while the coagulation studies demonstrate normal bleeding time (BT) and prothrombin time (PT) but prolonged activated partial thromboplastin time (APTT). Note that the latter may be normal in mild or moderate hemophilia but is profoundly prolonged in severe cases.
The FVIII assay confirms the diagnosis  , which demonstrates a reduced activity of FVIII. The defined activity for mild is above 5%, moderate is 1 to 5% while severe has less than 1%.
Note that conditions or medications that alter hormone levels such as aging and pregnancy, or use of oral contraceptives or estrogen can increase levels of FVIII.
In actively bleeding patients not responding to treatment, they should be tested for FVIII inhibitor.
For head and other injuries, imaging techniques such as computed tomography (CT) scans without contrast and magnetic resonance imaging (MRI) are used for assessment of bleeding.
Also, ultrasonography is helpful for evaluation of the joints.
The mainstay therapy for hemophilia A is the replacement of FVIII with recombinant or plasma-derived products. Preventative treatment aims to increase the activity of FVIII to moderate levels . Additionally, it seeks to decrease the frequency of bleeding and to avoid damage to target sites such as the joints .
Randomly-controlled trials have reported that prophylactic treatment improves the quality of life and decreases the recurrence of bleeding and joint damage . Another study demonstrated that prophylactic therapy can successfully prevent hemophilic arthropathy .
Note that this drug is burdensome since it is given intravenously 3 times weekly   and is difficult for those with poor venous access .
In bleeding events, aggressive hemostatic techniques must be applied with the assistance of parents. If the bleeding is mild then ice and pressure may successful alleviate it. Minor episodes affecting the oral mucosa, joint spaces or muscle will be treated with FVIII products. The goal is to correct to 30% to 50% of the normal FVIII activity level. Furthermore, epistaxis and hemorrhage in the GI, GU, and CNS warrant FVIII replacement that should be corrected up to 100% of the normal activity levels.
Desmopressin, or DDAVP, can be used in for minor hemorrhages in those with mild hemophilia A. This drug elevates the concentration of FVIII.
Emicizumab is a monoclonal antibody that mimics FVIII . One of its significant advantages is less frequent administration.
Treatment of those with inhibitors of FVIII includes recombinant activated FVII or activated prothrombin complex concentrates , or induction of immune tolerance .
Current prophylactic therapy and prompt treatment have changed the overall prognosis and improved the quality of life for patients with severe hemophilia A. Prior to replacement therapy, the lifespan for these patients was shortened. Additionally, arthropathy and joint deterioration made it difficult for patients to cope.
Mortality has improved significantly as patients with a severe form of this disorder live closer to the normal life expectancy than in previous decades .
It is notable to report that in the late 1970s and 1980s, FVIII products contaminated with HIV and hepatitis led to infections and AIDS-related deaths in hemophiliacs. However, improved donor screening and purification techniques have helped nearly eliminate this issue.
Devastating manifestations include destructive arthritis secondary to repeated hemarthrosis and structural joint changes. Hence, prophylactic therapy instituted in young patients is regarded as standard management to prevent these conditions.
Another sequela of hemophilia A is intracranial hemorrhage, which is the most common cause of mortality due to bleeding and is implicated in about one-third of deaths. The lifetime risk for developing this complication is 2% to 8%. About 10% of those with severe hemophilia develop intracranial bleeding. Furthermore, hemorrhage can occur in vital organs, which is another life-threatening consequence.
The etiology of hemophilia A is attributed to either a genetic mutation (inherited or spontaneous) that causes a deficiency in FVIII or an acquired inhibitor of FVIII. The consequence of these defects affects the intrinsic pathway of the coagulation cascade since FVIII plays a significant role in the production of blood clots.
Hemophilia A is typically an X-linked inherited recessive disorder  although some cases occur due to spontaneous mutations. Furthermore, the mutation is in the FVIII gene located on the long arm of the X-chromosome.
The worldwide birth prevalence of hemophilia A is about 1 of 4,000 to 5,000 live male births. Prevalence is approximately 1 in 10,000 in the United States and other countries in which appropriate treatment is available . Some studies note that the birth prevalence is equivocal across the globe among all races, although others note that it is varied .
FVIII is synthesized in the liver and the reticuloendothelial system. This essential clotting factor circulates in the plasma while bound to von Willebrand factor (vWF). The latter is integral for the production, stabilization, and function of FVIII . Additionally, vWF prevents the degradation of FVIII and prolongs its half-life from 2 hours to 12 hours .
The clotting cascade consists of the intrinsic and extrinsic pathways. The former is launched when the injured endothelium triggers a chain of mechanisms involving numerous of clotting factors that ultimately form a blood clot. With regards to FVIII, its activation causes it to disengage from vWF and to serve as a cofactor for FIX to activate FX, which is essential in the conversion of prothrombin to thrombin. Hence, the role of FVIII is crucial for homeostasis.
A deficiency or dysfunction in FVIII interrupts the intrinsic cascade, which consequently leads to abnormal hemorrhage whether provoked by trauma or spontaneous. Bleeding occurs in the joints and muscles as well as systems such as the CNS, GI, GU, pulmonary, and cardiovascular.
One of the main characteristics of hemophilia A is the chronic inflammation and destruction of the target joint. Repeated episodes of hemorrhage lead to hypertrophy of the synovium, fibrosis, deposition of hemosiderin, and other pathological changes in the joint. As a result, patients manifest with disability and deformities.
As a hereditary or acquired disease, hemophilia A cannot be prevented. However, prophylactic treatment is very important in reducing the frequency of hemorrhagic episodes and complications such as joint bleeding. Additionally, parents of children with hemophilia A , and the patients themselves (when old enough) should be educated about the disease, how to apply hemostatic techniques, when to seek urgent care, etc. Also, patients should have medical emergency identification documents or bracelets to alert medical personnel in cases of trauma or injuries.
Another important principle in the overall care is genetic counseling for affected individuals and family members. Counseling will provide information on what the disease entails, its mode of transmission, and other significant details. It is imperative to identify who needs to be tested, or in other words, carriers such as female relatives.
Prenatal testing may be offered to pregnant women who are carriers of the disease.
Hemophilia A is a hereditary bleeding disorder that results from a deficiency of factor VIII (FVIII) activity. Most cases occur due to an inherited mutation in the FVIII gene located on the X-chromosome while some occur due to de novo mutations. The mode of inheritance for this disease is the X-linked recessive pattern. FVIII participates in the intrinsic coagulation cascade and is essential in clot formation.
This clinically heterogeneous disease exhibits variable degrees of severity. The disorder manifests as mild, moderate, or severe. The clinical picture is inversely proportional to the residual activity of the FVIII . A greater decrease of activity is characterized by more frequent bleeding episodes, greater exaggerated responses to trauma, and major organ involvement. Furthermore, complications of hemophilia A include bleeding into the joints, muscles, central nervous system (CNS), gastrointestinal (GI), genitourinary (GU), and cardiovascular (CV) systems. Untreated patients are at risk for developing joint deterioration, disability, and intracranial hemorrhage.
The clinical assessment of patients with suspected bleeding disorders includes a thorough personal and family history, a physical exam, and laboratory tests. The latter include the quantitation of FVIII as well as other blood studies. Specifically, the activity of FVIII assay will establish the diagnosis and reflect whether the disease is mild, moderate, or severe.
The standard treatment consists of the substitution of FVIII through plasma-derived or genetically engineered recombinant products. The management is applied into two contexts, which are prophylaxis and treatment of active bleeding. Note that preventative therapy is successful in reducing the frequency of bleeding and joint damage. There are other medications as well.
The prognosis and life expectancy has improved over the past decades due to initiation of FVIII replacement therapy. This plays a key role in the prevention of complications.
What is hemophilia A ?
What are the causes?
This develops due to genetic mutations in the factor VIII gene located on the X-chromosome. In fact, this disease is inherited in an x-linked recessive pattern although some may acquire this disease randomly.
In x-linked recessive diseases, the affected male receives a "bad" X chromosome from his mother. To explain further, carrier females will have the mutation present on one of their X chromosomes (while the other X chromosome is normal). The female carrier has a 50% chance of transmitting this chromosome to her son. Also, all daughter of an affected male will receive this X chromosome, and therefore they will be carriers.
What are the signs and symptoms?
Patients or parents of affected individuals will report excessive or prolonged bleeding as well bruising. The signs and symptoms include:
How is it diagnosed?
When a patient presents with abnormal bleeding in response to minor trauma, the clinician will ask details about the personal and family history, perform a full physical exam, and order the appropriate tests.
Numerous laboratory tests are obtained:
If head injury or other body traumas occur, imaging is obtained:
How is it treated?
Replacing the deficient Factor VIII is the main treatment. This can be done with plasma concentrates or Factor VIII produced by genetic recombination. Note that this can be given as:
Can it be prevented?
Since this disease is inherited, it cannot be prevented. However, preventative medicine is successful in decreasing the number of bleeding episodes and in preventing the development of bleeding in the joints. Also, the following are important strategies for affected children and their parents:
Also, genetic counseling is important for affected individuals and their family members. Genetic counseling will provide:
Prenatal testing may be offered to pregnant women who are carriers of the disease.