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Hemophilia A

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.

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Presentation

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 [3] [8]. The clinical picture varies in severity from one patient to another.

Mild

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.

Moderate

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

Severe cases are typically identified early such as in neonates or infants within the first 12 months of life [9] 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.

Carrier

Female carriers are relatively asymptomatic but may have similar manifestations to males with the mild form of the disorder.

Physical exam

Remarkable findings on the exam may include bruises, subcutaneous hematomas, deformed joints, and muscle contractures.

Prolonged Bleeding
  • Menorrhagia was predominant (13.6%) followed by epistaxis (9%), gingivorrhagia (9%), and prolonged bleeding after tooth extraction (9%).[ncbi.nlm.nih.gov]
  • However, some studies reported prolonged bleeding times in hemophilia, suggesting that also primary hemostasis is affected.[ncbi.nlm.nih.gov]
  • This may be referred to as prolonged bleeding or a prolonged bleeding episode. Hemophilia A can be mild, moderate or severe, depending on the baseline level of factor VIII made by that individual.[rarediseases.org]
  • Affected individuals suffer hemorrhage into joints and muscles, easy bruising, and prolonged bleeding from wounds. The disease is inherited as an X-linked trait, so males are affected and females carry the gene.[medicinenet.com]
  • Symptoms include prolonged bleeding, pain in joints, and bruising. Common symptoms reported by people with hemophilia A Reports may be affected by other conditions and/or medication side effects.[patientslikeme.com]
Easy Bruising
  • Affected individuals suffer hemorrhage into joints and muscles, easy bruising, and prolonged bleeding from wounds. The disease is inherited as an X-linked trait, so males are affected and females carry the gene.[medicinenet.com]
  • Patients with hemophilia A suffer from joint and muscle hemorrhage, easy bruising and prolonged bleeding time from wounds.[themedicalbiochemistrypage.org]
  • Affected individuals suffer joint and muscle hemorrhage, easy bruising, and prolonged bleeding from wounds. Because platelet function is not affected, blood loss from minor cuts and abrasions is not excessive.[ommbid.mhmedical.com]
  • bruising, excessive bleeding after surgery, trauma, dental procedures or circumcision; epistaxis, poor wound healing, intracranial hemorrhage, scalp hematoma, development of pseudotumors with repetitive hematoma formation, menorrhagia Incidence of sites[pathologyoutlines.com]
Spontaneous Hemorrhage
  • If the biological activity of factor VIII is below 1%, the hemophilia is severe and manifests as frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries, or following surgery or tooth extraction (severe hemophilia A; see this[orpha.net]
  • Disease definition Severe hemophilia A is a form of hemophilia A (see this term) characterized by a large deficiency of factor VIII leading to frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries, or following surgery or[orpha.net]
  • Christmas disease 20% of cases F9 gene mutation coagulation factor IX deficiency or absence 70% of patients have the severe form of the disease characterized by spontaneous hemorrhage or hemorrhage following minor trauma 1 Associations Transfusion-related[radiopaedia.org]
  • Clinical Presentation of Hemophila Often, there is a history of bleeding disproportionate to trauma and/or spontaneous hemorrhage. History of bleeding disorders in the family may be present.[medcaretips.com]
Pain
  • An 8y7m-old Chinese boy presented with half a day of right sided abdominal pain, fever, nausea, and vomiting.[ncbi.nlm.nih.gov]
  • Initial diagnosis was delayed because the patient presented with symptoms, such as throat pain and odynophagia, similar to those of common benign upper airway infections.[ncbi.nlm.nih.gov]
  • Author information 1 Division of Cardiac Anesthesia, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. mfitzsimons@partners.org Abstract Immunoglobulin A (IgA) deficiency may[ncbi.nlm.nih.gov]
  • Nevertheless this rare case must be considered in patients with coagulopathies presenting with abdominal pain. Prompt radiologic imaging and surgical consultation are of highest priority.[ncbi.nlm.nih.gov]
  • We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: January 31, 2019[patientslikeme.com]
Swelling
  • Large fluctuant swelling on his head was noted. He developed severe anemia and hypovolemia as a result of massive subgaleal hemorrhage. After successful treatment, the baby fully recovered.[ncbi.nlm.nih.gov]
  • You may feel a warm prickly sensation before you develop pain and swelling in the joint. The degree of swelling does not match the severity of your bleeding. You may be bleeding significantly but show only a little swelling.[emedicinehealth.com]
  • Bleeding that occurs in deep muscle can cause your limbs to swell. The swelling may press on nerves and lead to numbness or pain. Damage to joints. Internal bleeding may also put pressure on your joints, causing severe pain.[mayoclinic.org]
  • Individuals with this disease may experience spontaneous bleeding, pain and swelling in their joints due to excess bleeding, and bruising.[clinicaltrials.gov]
Weakness
  • Signs and symptoms include: Painful, prolonged headache Repeated vomiting Sleepiness or lethargy Double vision Sudden weakness or clumsiness Convulsions or seizures When to see a doctor Seek emergency care if you or your child experiences: Signs or symptoms[mayoclinic.org]
  • For patients with mild-to-moderate disease, determine responsiveness to desmopressin acetate (DDAVP). [5] Signs and symptoms of hemorrhage include the following: General - Weakness and orthostasis Musculoskeletal (joints) - Tingling, cracking, warmth,[emedicine.medscape.com]
  • It’s rare, but if you have a head bump -- even if it's minor -- and you have any of these symptoms, call your doctor: Prolonged headache Throwing up Sleepiness/tiredness Sudden weakness or problems walking Double vision Continued Getting a Diagnosis If[webmd.com]
  • HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. Thromb Haemost 1997 ;77: 234 - 237 7. Oldenburg J, Picard JK, Schwaab R, et al.[nejm.org]
Limb Pain
  • These types of bleeding can lead to throwing up blood or passing blood in the stool, stroke, and sudden severe pain in the joints or limbs. Painful bleeding into the soft tissues of the arms and legs can lead to nerve damage.[genome.gov]
Soft Tissue Swelling
  • If it does not present earlier, infants older than 6 months of age can present with soft tissue swelling after they become more mobile.[clinicaladvisor.com]
Dyspnea
  • The possibility of spontaneous retropharyngeal or epiglottic hemorrhage or hematoma should be considered as a cause of rapidly progressing odynophagia and dyspnea by hemophilia patients.[ncbi.nlm.nih.gov]
  • […] lethargy, irritability, spinal cord syndromes Gastrointestinal (GI) - Hematemesis, melena, frank red blood per rectum, abdominal pain Genitourinary - Hematuria, renal colic, post-circumcision bleeding Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea[emedicine.medscape.com]
Tachypnea
  • Physical Examination Systemic signs of hemorrhage include the following: Tachycardia Tachypnea Hypotension Orthostasis Organ system–specific signs and symptoms of hemorrhage include the following: Musculoskeletal (joints) - Tenderness, pain with movement[emedicine.medscape.com]
  • In acute bleeding patient may have tachycardia, tachypnea , hypotension etc. There would be organ specific signs. For example, joint pain or muscle pain in bleeding in joints and muscles.[medcaretips.com]
Hemoptysis
  • […] vomiting, lethargy, irritability, spinal cord syndromes Gastrointestinal (GI) - Hematemesis, melena, frank red blood per rectum, abdominal pain Genitourinary - Hematuria, renal colic, post-circumcision bleeding Other - Epistaxis, oral mucosal hemorrhage, hemoptysis[emedicine.medscape.com]
Vomiting
  • An 8y7m-old Chinese boy presented with half a day of right sided abdominal pain, fever, nausea, and vomiting.[ncbi.nlm.nih.gov]
  • Signs of bleeding in the brain may include changes in behavior, excessive sleepiness, persistent headaches and neck pain, double vision, vomiting, and convulsions or seizures. Cleveland Clinic is a non-profit academic medical center.[my.clevelandclinic.org]
  • Signs and symptoms include: Painful, prolonged headache Repeated vomiting Sleepiness or lethargy Double vision Sudden weakness or clumsiness Convulsions or seizures When to see a doctor Seek emergency care if you or your child experiences: Signs or symptoms[mayoclinic.org]
  • Symptoms of brain bleeding can include headaches, vomiting, lethargy, behavioral changes, clumsiness, vision problems, paralysis, and seizures. Diagnosis Blood testing is key to diagnosing hemophilia.[medicalnewstoday.com]
Abdominal Pain
  • An 8y7m-old Chinese boy presented with half a day of right sided abdominal pain, fever, nausea, and vomiting.[ncbi.nlm.nih.gov]
  • Nevertheless this rare case must be considered in patients with coagulopathies presenting with abdominal pain. Prompt radiologic imaging and surgical consultation are of highest priority.[ncbi.nlm.nih.gov]
  • A 58-year-old caucasian male with hemophilia A presented to the emergency room of another institution with abdominal pain, blood in the stool, and a history of diverticulosis and symptomatic hemorrhoids.[ncbi.nlm.nih.gov]
  • pain Genitourinary - Hematuria, renal colic, post-circumcision bleeding Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, contusions, excessive bleeding with routine[emedicine.medscape.com]
Melena
  • Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, refusal to use the joint (young children) Central nervous system (CNS) - Headache, stiff neck, vomiting, lethargy, irritability, spinal cord syndromes Gastrointestinal (GI) - Hematemesis, melena[emedicine.medscape.com]
  • Genitourinary and gastrointestinal bleeding may respectively cause blood in the urine (hematuria) and black or bloody stools (melena, hematochezia).[rarediseases.org]
Hematemesis
  • […] orthostasis Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, refusal to use the joint (young children) Central nervous system (CNS) - Headache, stiff neck, vomiting, lethargy, irritability, spinal cord syndromes Gastrointestinal (GI) - Hematemesis[emedicine.medscape.com]
Hematochezia
  • Genitourinary and gastrointestinal bleeding may respectively cause blood in the urine (hematuria) and black or bloody stools (melena, hematochezia).[rarediseases.org]
Oral Bleeding
  • These medications are useful in oral bleeding in either hemophilia A or B. You may be given an IV clotting factors. You are given purified Factor VIII(8) or IX (9) depending on the type of hemophilia you have.[emedicinehealth.com]
  • Eruption of teeth may be associated with oral bleeding. As children grow and become more physically active, hemarthroses and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis.[medcaretips.com]
  • Young children may also have oral bleeding when their teeth are erupting. Bleeding from gum and tongue lacerations is often troublesome because the oozing of blood may continue for a long time despite local measures.[emedicine.medscape.com]
Bleeding Gums
  • gums, and excessive menstrual periods.[medicalnewstoday.com]
  • Spontaneous bleeding can cause the following: blood in the urine blood in the stool deep bruises large, unexplained bruises excessive bleeding bleeding gums frequent nosebleeds pain in the joints tight joints irritability (in children) The following symptoms[healthline.com]
  • gums Moderate hemophilia Roughly 15 percent of people with hemophilia A have a moderate case.[healthline.com]
Hypotension
  • Physical Examination Systemic signs of hemorrhage include the following: Tachycardia Tachypnea Hypotension Orthostasis Organ system–specific signs and symptoms of hemorrhage include the following: Musculoskeletal (joints) - Tenderness, pain with movement[emedicine.medscape.com]
  • In acute bleeding patient may have tachycardia, tachypnea , hypotension etc. There would be organ specific signs. For example, joint pain or muscle pain in bleeding in joints and muscles.[medcaretips.com]
Tachycardia
  • Physical Examination Systemic signs of hemorrhage include the following: Tachycardia Tachypnea Hypotension Orthostasis Organ system–specific signs and symptoms of hemorrhage include the following: Musculoskeletal (joints) - Tenderness, pain with movement[emedicine.medscape.com]
  • In acute bleeding patient may have tachycardia, tachypnea , hypotension etc. There would be organ specific signs. For example, joint pain or muscle pain in bleeding in joints and muscles.[medcaretips.com]
Joint Deformity
  • In severe cases, patients tend to develop spontaneous bleeding into large joints, yielding recurrent hemarthroses that over time result in significant joint deformity.[pathwaymedicine.org]
  • Insufficient or incorrect treatment of recurrent hemarthroses and hematomas leads to motor impairment with severe disability associated with stiffness, joint deformation and paralysis.[orpha.net]
  • Repeated bleeding into the joints and muscles eventually causes permanent damage, such as joint deformity and reduced mobility. Bleeding in the brain is a very serious problem for those with severe hemophilia, and may be life-threatening.[my.clevelandclinic.org]
Joint Stiffness
  • If the bleeding in the joints is left untreated it will lead to severe swelling and pain, joint stiffness and inflammation.[themedicalbiochemistrypage.org]
  • Symptoms include: prolonged bleeding after injuries spontaneous bleeding without obvious cause bruising easily joint stiffness or pain Mild hemophilia About 25 percent of hemophilia A cases are considered mild.[healthline.com]
  • Tingling or "bubbling" feeling in a joint Stiffness and pain in a joint Swollen, tender, warm and painful joint Limited or painful movement of the joint Soft Tissue or Muscle Bleeding If your child has any of these signs of soft tissue or muscle bleeding[nationwidechildrens.org]
Contusion
  • […] melena, frank red blood per rectum, abdominal pain Genitourinary - Hematuria, renal colic, post-circumcision bleeding Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, contusions[emedicine.medscape.com]
Muscle Contracture
  • Physical exam 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.[symptoma.com]
Purpura
  • Coagulopathy Purpura secondary to clotting disorders Haemophilia at Curlie[en.wikipedia.org]
Delayed Wound Healing
  • Moderate to mild deficiency is associated with prolonged bleeding after tooth extractions, surgery, or injuries and recurrent or delayed wound healing. Incidence: 1 in 4,000-5,000 live male births worldwide, rare in females.[ltd.aruplab.com]
Epistaxis
  • Menorrhagia was predominant (13.6%) followed by epistaxis (9%), gingivorrhagia (9%), and prolonged bleeding after tooth extraction (9%).[ncbi.nlm.nih.gov]
  • Rarely affects females (see etiology) Female carriers are unaffected Sites Bleeding into muscle, soft tissue or joints (hemarthrosis), GI / GU tract bleeding, easy bruising, excessive bleeding after surgery, trauma, dental procedures or circumcision; epistaxis[pathologyoutlines.com]
  • Presentation This varies according to the extent of the deficiency: Bleeding tendency from mucosa - eg, epistaxis, menorrhagia (consider in women with no other obvious cause).[patient.info]
  • Common bleeding manifestations include epistaxis, hemarthroses, muscle hemorrhage, hematomas, and menorrhagia in women. Individuals with a family history of hemophilia and those who have experienced acute or recent-onset bleeding should be tested.[arupconsult.com]
  • Clinical manifestations Others  Gastrointestinal Bleeding:  Mucous Bleeding: Epistaxis, gum bleeding.  Genitourinary Bleeding: Frequently severe hemophiliac can experience hematuria and a structural lesion should be ruled out. 14.[slideshare.net]
Hematuria
  • Hematuria is frequent in hemophilia. Hematuria in hemophilia is generally considered benign and manageable with conservative therapy; however, severe hematuria requiring surgical therapy has rarely been reported.[ncbi.nlm.nih.gov]
  • .  Genitourinary Bleeding: Frequently severe hemophiliac can experience hematuria and a structural lesion should be ruled out. 14.[slideshare.net]
  • Spontaneous hematuria is a fairly frequent and highly characteristic sign of the disorder. Etiology Hemophilia A is caused by mutations in the F8 gene (Xq28) encoding coagulation factor VIII.[orpha.net]
  • Bleeding from the Urinary Tract (Hematuria) What Are the Causes of Blood in Urine? The causes of gross and microscopic hematuria are similar and may result from bleeding anywhere along the urinary tract.[medicinenet.com]
Bladder Spasm
  • […] range of motion, effusion, and warmth Central nervous system (CNS) - Abnormal neurologic exam findings, altered mental status, and meningismus Gastrointestinal (GI) - Can be painless; hepatic/splenic tenderness, and peritoneal signs Genitourinary - Bladder[emedicine.medscape.com]
Headache
  • These events were parathesia, headache, injection site inflammation, injection site pain, back pain, vertigo, and dry mouth.[octapharma.com]
  • Clinical manifestations Intracranial hemorrhage  Leading cause of death of hemophiliacs  Spontaneous or following trauma  May be subdural, epidural or intracerebral  Suspect always in hemophilic patient that presents with unusual headache 13.[slideshare.net]
  • These could be signs of bleeding inside the head: Headache with vomiting Severe headache Blurred vision Sleeping a lot Personality change or child's mood is different Seizures A child who gives himself factor at home should immediately give himself one[nationwidechildrens.org]
  • They included diarrhea, nausea, headache and flushing.– by Cameron Kelsall Disclosure: Baxalta provided funding for the study.[healio.com]
Seizure
  • Each topic is supported by excellent illustrations, diagrams, and, for the first time, video clips to show neonatal resuscitation and stabilizing the sick newborn, normal examination, the baby with hypoxic-ischemic encephalopathy, recognition of seizures[books.google.com]
  • Signs of bleeding in the brain may include changes in behavior, excessive sleepiness, persistent headaches and neck pain, double vision, vomiting, and convulsions or seizures. Cleveland Clinic is a non-profit academic medical center.[my.clevelandclinic.org]
  • Signs and symptoms include: Painful, prolonged headache Repeated vomiting Sleepiness or lethargy Double vision Sudden weakness or clumsiness Convulsions or seizures When to see a doctor Seek emergency care if you or your child experiences: Signs or symptoms[mayoclinic.org]
  • Symptoms of brain bleeding can include headaches, vomiting, lethargy, behavioral changes, clumsiness, vision problems, paralysis, and seizures. Diagnosis Blood testing is key to diagnosing hemophilia.[medicalnewstoday.com]
Intracranial Hemorrhage
  • Life expectancy in those without HIV is 62 years 2 . 15 times increased risk death from intracranial hemorrhage ( 1/3 of all deaths) 50 times increased risk death from non-intracranial hemorrhage polyarticular disease Promoted articles (advertising)[radiopaedia.org]
  • KEYWORDS: cohort study; epidemiology; hemophilia A; intracranial hemorrhage; mortality[ncbi.nlm.nih.gov]
  • Singleton TC, Keane M ; Diagnostic and therapeutic challenges of intracranial hemorrhage in neonates with congenital hemophilia: a case report and review. Ochsner J. 2012 Fall12(3):249-53. Ljung RC ; Intracranial haemorrhage in haemophilia A and B.[patient.info]
  • Untreated patients are at risk for developing joint deterioration, disability, and intracranial hemorrhage.[symptoma.com]
Irritability
  • Blood in the synovial fluid of the joints is highly irritating causing synovial overgrowth and a tendency to cause additional bleeding from the vascular tissues of the joint.[themedicalbiochemistrypage.org]
  • […] bleeding from cuts or injuries, or after surgery or dental work Many large or deep bruises Unusual bleeding after vaccinations Pain, swelling or tightness in your joints Blood in your urine or stool Nosebleeds without a known cause In infants, unexplained irritability[mayoclinic.org]
  • Spontaneous bleeding can cause the following: blood in the urine blood in the stool deep bruises large, unexplained bruises excessive bleeding bleeding gums frequent nosebleeds pain in the joints tight joints irritability (in children) The following symptoms[healthline.com]
  • Fecal transplant is used to treat gut infections and is now being studied as a treatment for obesity, urinary tract infections, irritable bowel syndrome and more.[nytimes.com]
Lethargy
  • Signs and symptoms include: Painful, prolonged headache Repeated vomiting Sleepiness or lethargy Double vision Sudden weakness or clumsiness Convulsions or seizures When to see a doctor Seek emergency care if you or your child experiences: Signs or symptoms[mayoclinic.org]
  • Symptoms of brain bleeding can include headaches, vomiting, lethargy, behavioral changes, clumsiness, vision problems, paralysis, and seizures. Diagnosis Blood testing is key to diagnosing hemophilia.[medicalnewstoday.com]
  • […] of hemorrhage include the following: General - Weakness and orthostasis Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, refusal to use the joint (young children) Central nervous system (CNS) - Headache, stiff neck, vomiting, lethargy[emedicine.medscape.com]
  • Intracranial hemorrhage (bleeding into the brain or skull) can lead to symptoms such as nausea , vomiting , and/or lethargy, and can lead to death. Increased bleeding after surgery or trauma is characteristic of hemophilia.[medicinenet.com]
  • Intracranial hemorrhage (bleeding into the brain or skull) can lead to symptoms such as nausea, vomiting, and/or lethargy, and can lead to death. Increased bleeding after surgery or trauma is characteristic of hemophilia.[medicinenet.com]

Workup

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.

Laboratory tests

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 [10] [11], 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.

Other

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.

Prothrombin Time Normal
  • In cases of moderate haemophilia symptoms are variable which manifest along a spectrum between severe and mild forms.In both haemophilia A and B, there is spontaneous bleeding but a normal bleeding time, normal prothrombin time, normal thrombin time,[en.wikipedia.org]

Treatment

The management of patients with hemophilia A is centered around prophylaxis and treatment of active bleeding.

FVIII replacement

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 [12]. Additionally, it seeks to decrease the frequency of bleeding and to avoid damage to target sites such as the joints [13].

Randomly-controlled trials have reported that prophylactic treatment improves the quality of life and decreases the recurrence of bleeding and joint damage [14]. Another study demonstrated that prophylactic therapy can successfully prevent hemophilic arthropathy [15].

Note that this drug is burdensome since it is given intravenously 3 times weekly [14] [16] and is difficult for those with poor venous access [17].

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.

Other

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 [18]. 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 [19], or induction of immune tolerance [20].

Prognosis

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 [7].

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.

Complications

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.

Etiology

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 [2] 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.

Epidemiology

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 [3]. Some studies note that the birth prevalence is equivocal across the globe among all races, although others note that it is varied [4].

Sex distribution
Age distribution

Pathophysiology

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 [5]. Additionally, vWF prevents the degradation of FVIII and prolongs its half-life from 2 hours to 12 hours [6].

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.

Pathological features

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.

Prevention

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.

Summary

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 [1]. 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.

Patient Information

What is hemophilia A ?

This is a bleeding disorder that occurs due to the absence of clotting factor VIII. When there are low levels of this factor, blood does not clot and bleeding cannot be controlled.

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:

  • Nosebleeds that occur randomly
  • Abnormal bleeding after small traumas
  • Bleeding that restarts after stopping
  • Excessive bleeding after tooth removal
  • Bleeding in a muscle or joint that causes pain and swelling
  • Bruising
  • Blood in urine
  • Blood in stool
  • Bleeding in the brain

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:

  • Complete blood count which will usually reveal normal platelet count
  • Coagulation studies which show: increased partial thromboplastin time (PTT), normal prothrombin time (PT), and normal bleeding time (BT)
  • Low levels of activity of factor VIII

If head injury or other body traumas occur, imaging is obtained:

  • CT of the head
  • MRI of the head, spine, and joints
  • Ultrasonography of the joints

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:

  • Prophylactic (preventative) in order to decrease the number of bleeding episodes and to prevent joint bleeding
  • Treatment of active bleeding

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:

  • Learn how to stop bleeding with ice and pressure in mild cases
  • Understand when to seek emergency care
  • Be fully knowledgeable about the patient's disease
  • Keep a record of the history of bleeding and medications used
  • Wear a medical emergency bracelet or have proper documentation in case of emergencies

Also, genetic counseling is important for affected individuals and their family members. Genetic counseling will provide:

  • Information on what the disease is
  • How it is inherited
  • Who should be tested: mother, sister, maternal aunt, and maternal cousins may be carriers; daughters of affected males are carriers

Prenatal testing may be offered to pregnant women who are carriers of the disease.

References

Article

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Last updated: 2017-08-09 17:30