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.

• Pain

  Pain Management Nonsteroidal anti-inflammatory drugs can be effective in managing acute and chronic arthritic pain. Avoid aspirin because of its irreversible effect on platelet function. [medcaretips.com]

  Clinical Manifestations: Hemarthrosis  The most common, painful and most physically, economically and psychologically debilitating manifestation.  Clinically:  Aura: tingling warm sensation  Excruciating pain  Generally affects one joint at the time [slideshare.net]

  Opiates can be used for severe pain. Splinting and immobilisation is an effective adjunct for reducing pain. [rch.org.au]

  An 8y7m-old Chinese boy presented with half a day of right sided abdominal pain, fever, nausea, and vomiting. [ncbi.nlm.nih.gov]

  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]

• Swelling

  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]

  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]

  For example, if you twist your knee or bang your leg, it may swell up with blood. Because people who have hemophilia are born with it, blood clotting problems usually show up in young children unless the problem is very mild. [msdmanuals.com]

• Weakness

  “Age has to be considered a minor modification factor, as there is a consistent, but weak, increase in FVIII levels with age.” Reference 1. Rejtö J, Königsbrügge O, Grilz E, et al. [hematologyadvisor.com]

  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]

• 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]

• Prolonged Bleeding

  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]

  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]

  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]

  The main symptom is bleeding that doesn't stop, also called prolonged bleeding. [nhs.uk]

• 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]

  Depending on the level of factor VIII activity, patients with hemophilia may present with easy bruising, inadequate clotting of traumatic injury or—in the case of severe hemophilia—spontaneous hemorrhage. [medcaretips.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]

• 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]

  Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. [prnewswire.com]

  Symptoms include: sudden chest pain that gets worse after coughing or taking a deep breath difficult or labored breathing (dyspnea) shortness of breath chest tightness tachycardia (rapid heart rate) pale or blue skin caused by lack of oxygen The pain [healthline.com]

• Tachypnea

  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]

  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]

  On admission, the patient was in shock state, having tachycardia and tachypnea. [omicsonline.org]

• 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]

  Symptoms include dizziness, paresthesia, rash, flushing, facial swelling, urticaria, dyspnea, pruritus, and vomiting. Discontinue ADVATE if hypersensitivity symptoms occur and administer appropriate emergency treatment. [prnewswire.com]

  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]

  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]

• 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]

  Relevant clinical features Patient 1 Patient 2 Patient 3 Patient 4 Age at presentation 22 21 26 46 Presenting symptom RTa loin pain extending to RT a iliac fosse RT a lower abdominal pain Right iliac fosse pain Lower backache Duration of pain in days [omicsonline.org]

  Consider transfer when All children with Suspected intracranial haemorrhage Bleeding into neck/throat Forearm/calf bleed at risk of compartment syndrome Bleeding into hip or inguinal area (due to risk of iliopsoas haemorrhage) Undiagnosed abdominal pain [rch.org.au]

• Melena

  Genitourinary and gastrointestinal bleeding may respectively cause blood in the urine (hematuria) and black or bloody stools (melena, hematochezia). [rarediseases.org]

  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]

  As gastrointestinal bleeding (melena, due to multiple peptic ulcers) occurred one year earlier, treated with endoscopic haemostasis and blood transfusion, aspirin was stopped and substituted for clopidogrel. [hindawi.com]

• 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]

• Rectal Bleeding

  This underlying immunologic disorder was therefore associated with AHA in this patient, in whom bleeding tendency had been triggered by NSAIDs. Case 3. A 87-year-old woman presented with persistent rectal bleeding and large ecchymoses. [hindawi.com]

  […] hemorrhage; the rectal bleeding was recurrent and eventually fatal. [nejm.org]

• Tachycardia

  Symptoms include: sudden chest pain that gets worse after coughing or taking a deep breath difficult or labored breathing (dyspnea) shortness of breath chest tightness tachycardia (rapid heart rate) pale or blue skin caused by lack of oxygen The pain [healthline.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]

• Hypotension

  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]

  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]

  Regarding safety issues, rituximab‐related adverse reactions have been reported to include the following: sinusitis ( Carcao 2006 ); nausea ( Collins 2009 ; Fox 2006 ); dyspnea ( Mateo 2006 ; Moschovi 2006 ); hypotension ( Mateo 2006 ); urinary infection [cochranelibrary.com]

• Oral Bleeding

  Oral bleeding is aggravated by the increased fibrinolytic activity of saliva. An antifibrinolytic agent (epsilon-aminocaproic acid [EACA]) to neutralize the fibrinolytic activity in the oral cavity should be used along with factor replacement. [medcaretips.com]

  A severe hemophiliac should be evaluated at a hospital's emergency department for any bleeding whatsoever, because his or her blood will not clot adequately on its own in these situations: Oral bleeding Bleeding from skin that does not stop with simple [emedicinehealth.com]

  […] edit] The oral manifestations are characterized by frequent bleeding of multiple sites, frequently seen as gingival and postextraction haemorrhages. [en.wikipedia.org]

• Bleeding Gums

  bleeding gums Moderate hemophilia Roughly 15 percent of people with hemophilia A have a moderate case. [healthline.com]

  […] helps avoid problems such as gum disease, which can cause bleeding. [nhs.uk]

  […] prone to frequent bleeding such as nosebleeds, bleeding gums, and excessive menstrual periods. [medicalnewstoday.com]

• Purpura

  Coagulopathy Purpura secondary to clotting disorders Haemophilia at Curlie [en.wikipedia.org]

  Soft tissue bruising (purpura) over trunk or extremities in an otherwise healthy person (particularly male), without accompanying systemic signs such as fever should prompt consideration of a diagnosis of hemophilia. [cancertherapyadvisor.com]

• 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]

• Joint Deformity

  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]

  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]

• Contusion

  30596069 2018 20 Gunshot Injury of Head and Neck Region with an Atypical Bullet Trajectory: The Importance of Whole Body Computed Tomography Scan. 38 Velioglu Y...Durgun B 30173703 2018 21 Heparin-free veno-venous ECMO applied to a patient with severe lung contusion [malacards.org]

  […] 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]

• Joint Stiffness

  The weight bearing joints are the ones most affected in the disease and include the hips, knees, ankles and elbows. 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]

  Bleeding into a joint not only makes that joint more likely to bleed in the future but also leads to progressive stiffness. This joint, which is now more prone to re-bleeding, is called the target joint. [emedicinehealth.com]

• Arthralgia

  Complications arthralgia 77.4% and hemorrhage 77.4%. Conclusion: qualified care by health professionals helps to prevent serious complications, resulting in quality of life for the hemophiliac. [pesquisa.bvsalud.org]

  The most common adverse reactions observed in clinical trials (frequency ≥5% of subjects) were pyrexia, headache, cough, nasopharyngitis, arthralgia, vomiting, upper respiratory tract infection, limb injury, nasal congestion, and diarrhea. [prnewswire.com]

  […] level (in three), fatigue (in three), and productive cough (in three); all these events were of mild severity except for one moderate event of arthralgia and one moderately increased level of aspartate aminotransferase. [doi.org]

• Joint Swelling

  As the bleeding begins, the person may experience a warmth or tingling in the joint. As bleeding progresses, there is usually a feeling of stiffness, fullness, and pain. The joint swells and may be warm and tender. [cvsspecialty.com]

• Epistaxis

  Menorrhagia was predominant (13.6%) followed by epistaxis (9%), gingivorrhagia (9%), and prolonged bleeding after tooth extraction (9%). [ncbi.nlm.nih.gov]

  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]

  […] delayed onset bleeding (joints, muscular and soft tissue, mucosa) in response to different degrees of trauma (see the table below) Repeated hemarthrosis (e.g., knee joint) → joint destruction Recurrent bruising or hematoma formation Oral mucosa bleeding, epistaxis [amboss.com]

  Treatment of epistaxis or oral bleeding may require 35 to 40 units of the deficient clotting factor per kg of body weight. [cancertherapyadvisor.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]

  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]

  Mild hematuria may subside spontaneously. Epistaxis and moderately severe hematuria require factor VIII levels in the range of 30-50%. Joint bleeds with intense pain require narcotic analgesics and adequate factor replacement. [medcaretips.com]

   Genitourinary Bleeding: Frequently severe hemophiliac can experience hematuria and a structural lesion should be ruled out. 14. [slideshare.net]

• 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

  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]

  Possible side effects of desmopressin include: headache stomach pain feeling sick (nausea) Haemophilia B On-demand treatment for haemophilia B usually involves injections of nonacog alfa. [nhs.uk]

  They included diarrhea, nausea, headache and flushing.– by Cameron Kelsall Disclosure: Baxalta provided funding for the study. [healio.com]

  ADVERSE REACTIONS Common adverse reactions (≥1% of subjects) reported in the clinical studies were headache and nausea. For Full Prescribing Information, visit http://baxalta.com/assets/documents/ADYNOVATE_PI.pdf. [prnewswire.com]

  These events were parathesia, headache, injection site inflammation, injection site pain, back pain, vertigo, and dry mouth. [businesswire.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]

  Untreated patients are at risk for developing joint deterioration, disability, and intracranial hemorrhage. [symptoma.com]

  Patients bleed into tissues (eg, hemarthroses, muscle hematomas, retroperitoneal hemorrhage) following minimal trauma; fatal intracranial hemorrhage may occur. [msdmanuals.com]

  Hemophilia A is an X-linked disorder characterized by spontaneous bleeding in muscles and joints as well as increased risk for intracranial hemorrhage. [stm.sciencemag.org]

• Seizure

  Seizure after primary intracerebral haemorrhage. Neurology ;39:1089-93. Chang BS, Lowenstein DH. Epilepsy. N Engl J Med ;349:1257-66. Sung CY, Chu NS. Epileptic seizures in intracerebral haemorrhage. J Neurol Neurosurg Psychiatry 1989;52: -6. [saripediatri.org]

  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 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]

  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]

• 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]

• 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. Medical history and blood tests are 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]

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

  time: normal Platelet count: normal Activated partial thromboplastin time (aPTT): usually prolonged If aPTT prolonged → mixing study If mixing study is positive (or if patient/family history are strongly positive) → quantitative assessment of factor [amboss.com]

  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]

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].

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.

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.

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].

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.

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 [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.

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.

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