Hemophilia A

Hematology

Clinicals - History

Fact Explanation
Introduction Body’s normal mechanisms to stop the bleeding consists of main three responses: vascular, platelet and coagulatory response. Defect in any part of these responses can lead to abnormal bleeding manifestations. Coadulation cascade has main three pathways. Factors VII in extrinsic pathway, factors VIII, IX, XI and XII intrinsic pathway and V, X, fibrinogen and prothrombin in common pathway. Hemophilia A is due to the deficiency of functional plasma clotting factor VIII (FVIII), and is inherited as a X-linked, recessive manner and may be associated with spontaneous mutations. Acquired hemophilia is occurred due to the appearance of inhibitory antibodies to FVIII. Introduction
Body’s normal mechanisms to stop the bleeding consists of main three responses: vascular, platelet and coagulatory response. Defect in any part of these responses can lead to abnormal bleeding manifestations. Coadulation cascade has main three pathways. Factors VII in extrinsic pathway, factors VIII, IX, XI and XII intrinsic pathway and V, X, fibrinogen and prothrombin in common pathway. Hemophilia A is due to the deficiency of functional plasma clotting factor VIII (FVIII), and is inherited as a X-linked, recessive manner and may be associated with spontaneous mutations. Acquired hemophilia is occurred due to the appearance of inhibitory antibodies to FVIII.
Easy bruising, excessive bleeding with routine dental procedures, venepuncture, circumcision, bleeding from the umbilical stump and following trauma Defective clotting mechanism leads to easy bleeding particularly after trauma, and even may be spontaneous in severe disease.
Easy bruising will become more evident once the child starts the ambulation.
Easy bruising, excessive bleeding with routine dental procedures, venepuncture, circumcision, bleeding from the umbilical stump and following trauma
Defective clotting mechanism leads to easy bleeding particularly after trauma, and even may be spontaneous in severe disease.
Easy bruising will become more evident once the child starts the ambulation.
Joint and muscle problems: Tingling, cracking, pain, stiffness, and inability to move the joint Weight-bearing joints are commonly affected bleeding in patients with hemophilia. Knee, elbow and ankle are commonly affected. Flexor muscles of the arms and gastrocnemius of the legs and iliopsoas muscles are frequently affected. Joint injury in hemophilia are associated with swelling of the joint, bleeding into soft tissue, increased cellular proliferation in the synovial membrane and intense inflammation. Joint and muscle problems: Tingling, cracking, pain, stiffness, and inability to move the joint
Weight-bearing joints are commonly affected bleeding in patients with hemophilia. Knee, elbow and ankle are commonly affected. Flexor muscles of the arms and gastrocnemius of the legs and iliopsoas muscles are frequently affected. Joint injury in hemophilia are associated with swelling of the joint, bleeding into soft tissue, increased cellular proliferation in the synovial membrane and intense inflammation.
Nasal bleeds, gum bleeds Epistaxis is the bleeding from the nose that is due to the deficient clotting mechanism. Nasal bleeds, gum bleeds
Epistaxis is the bleeding from the nose that is due to the deficient clotting mechanism.
Headache, stiff neck, vomiting, lethargy, irritability Spontaneous bleeding inside the central nervous system can cause intracranial haemorrhages and meningeal irritation. Patients with factor VIII <1% of normal are more susceptible to spontaneous bleeding. ICH is the second most common initial hemorrhage occurring in all neonates with congenital hemophilia. Intracranial haemorrhages can cause damage to the brain by exerting a primary direct mechanical injury , increasing intracranial pressure with associated edema within the fixed intracranial space, decreased blood flow to the local area causesing neuronal ischemia, and cerebral herniation secondary to edema and mass effect. Headache, stiff neck, vomiting, lethargy, irritability
Spontaneous bleeding inside the central nervous system can cause intracranial haemorrhages and meningeal irritation. Patients with factor VIII <1% of normal are more susceptible to spontaneous bleeding. ICH is the second most common initial hemorrhage occurring in all neonates with congenital hemophilia. Intracranial haemorrhages can cause damage to the brain by exerting a primary direct mechanical injury , increasing intracranial pressure with associated edema within the fixed intracranial space, decreased blood flow to the local area causesing neuronal ischemia, and cerebral herniation secondary to edema and mass effect.
Hematemesis, melena, frank red blood per rectum Spontaneous bleeding from the mucosal surface of the gastrointestinal tract may cause passage of blood with vomitus, and black tary stools (malena) associated with upper GI bleeding. Hematemesis, melena, frank red blood per rectum
Spontaneous bleeding from the mucosal surface of the gastrointestinal tract may cause passage of blood with vomitus, and black tary stools (malena) associated with upper GI bleeding.
Hematuria, renal colics Same as above due to the bleeding tendency and clot colics may occur causing loin to groin pain. Haematuria may occur particularly after damaging to the urinary tract by any means. Hematuria, renal colics
Same as above due to the bleeding tendency and clot colics may occur causing loin to groin pain. Haematuria may occur particularly after damaging to the urinary tract by any means.
Muscle pain Bleeding into muscles may form haematoma and may cause severe pain. Muscle pain
Bleeding into muscles may form haematoma and may cause severe pain.
Excess menstrual bleeding Menorrhagia is a frequent finding in females. Excess menstrual bleeding
Menorrhagia is a frequent finding in females.
History of consanguity As this is a autosomal recessive condition, consanguity increases the risk of getting the disease to the offspring. History of consanguity
As this is a autosomal recessive condition, consanguity increases the risk of getting the disease to the offspring.
Family history As this is an autosomal recessive condition the there can be affected males in the family while females are the carriers. Family history
As this is an autosomal recessive condition the there can be affected males in the family while females are the carriers.

Clinicals - Examination

Fact Explanation
Tachycardia, tachypnea, hypotension These signs are due to haemorrhage. Tachycardia, tachypnea, hypotension
These signs are due to haemorrhage.
Pallor Low hemoglobin due to anaemia may found as result of acute or chronic blood loss. Pallor
Low hemoglobin due to anaemia may found as result of acute or chronic blood loss.
Joint tenderness, warmth, decreased range of moments Joints are frequently affected with bleeding. Joint may be complicated with effusion on certain situations. Joint tenderness, warmth, decreased range of moments
Joints are frequently affected with bleeding. Joint may be complicated with effusion on certain situations.
Bruising Due to the inufficient clotting mechanism. Bruising
Due to the inufficient clotting mechanism.
Neck stiffness These are due to the bleeding that causes meningeal irritation. Neck stiffness
These are due to the bleeding that causes meningeal irritation.
Altered mental status, focal neurological signs, bulging fontanels Spontaneous bleeding inside the central nervous system can cause intracranial haemorrhages. ICH may increase the intracranial pressure, causes cerebral edema, even neuronal death due to the direct mechanical effect. Altered mental status, focal neurological signs, bulging fontanels
Spontaneous bleeding inside the central nervous system can cause intracranial haemorrhages. ICH may increase the intracranial pressure, causes cerebral edema, even neuronal death due to the direct mechanical effect.
Hepatic/splenic tenderness, and peritoneal signs Hepatic/ splenic haematoma may rarely occur. Hepatic/splenic tenderness, and peritoneal signs
Hepatic/ splenic haematoma may rarely occur.
Tenderness over the costovertebral angle Renal colics may occur due to bleeding inside the urinary tract that causes clot colics. Tenderness over the costovertebral angle
Renal colics may occur due to bleeding inside the urinary tract that causes clot colics.
Dyspnea Hematoma formation can lead to airway obstruction. Dyspnea
Hematoma formation can lead to airway obstruction.
Joint contractures Mismanaged haemophilia with recurrent haemarthrosis will lead to joint damage and contracures. Joint contractures
Mismanaged haemophilia with recurrent haemarthrosis will lead to joint damage and contracures.
Features of compartment syndrome: severe tenderness, decreased sensation, pallor, parasthesia of the limb Compartment syndrome can occur due to the hematoma formation increasing the pressure inside the compartment. Features of compartment syndrome: severe tenderness, decreased sensation, pallor, parasthesia of the limb
Compartment syndrome can occur due to the hematoma formation increasing the pressure inside the compartment.

Investigations - Diagnosis

Fact Explanation
Coagulation studies: Activated partial thromboplastin time, prothrombin time, bleeding time , clotting time Activated partial thromboplastin time (aPTT) (reference interval 23–36 s) measures the activity of the intrinsic pathway of the clotting mechanism, and is prolonged in factor 8 deficiency. Normal aPTT may be found in mild to moderate hemophilia. Bleeding time and prothrombin time (reference interval 11.0–15.0 s), and International Normalized Ratio (INR) (reference interval 0.9–1.2) are normal as they assess the extrinsic coagulation pathway. Coagulation studies: Activated partial thromboplastin time, prothrombin time, bleeding time , clotting time
Activated partial thromboplastin time (aPTT) (reference interval 23–36 s) measures the activity of the intrinsic pathway of the clotting mechanism, and is prolonged in factor 8 deficiency. Normal aPTT may be found in mild to moderate hemophilia. Bleeding time and prothrombin time (reference interval 11.0–15.0 s), and International Normalized Ratio (INR) (reference interval 0.9–1.2) are normal as they assess the extrinsic coagulation pathway.
Factor VIII assay Is reduced in haemophilia A due to the deficiency of factor 8. Factor VIII assay
Is reduced in haemophilia A due to the deficiency of factor 8.
Testing for inhibitors Patient's plasma is mixed with normal plasma at 37°C for 1-2 hours and aPTT is checked. If the prolonged aPTT is not corrected, that is due to the presence of inhibitors and then the level of inhibitors need to be measured using the Bethesda method. Testing for inhibitors
Patient's plasma is mixed with normal plasma at 37°C for 1-2 hours and aPTT is checked. If the prolonged aPTT is not corrected, that is due to the presence of inhibitors and then the level of inhibitors need to be measured using the Bethesda method.
Platelet count and morphology This is important to exclude the other bleeding disorders particularly thrombocytopenia and platelet dysfunction. Von Willibrand disease type 2 may also have decreased platelet count. Platelet count and morphology
This is important to exclude the other bleeding disorders particularly thrombocytopenia and platelet dysfunction. Von Willibrand disease type 2 may also have decreased platelet count.

Investigations - Management

Fact Explanation
Factor 8 level This will give a guide to the current state of disease. Particularly after a surgery, the factor level needs to be maintained at least 5-7 days following minor surgery and and 10-14 days after major surgery. Factor 8 level
This will give a guide to the current state of disease. Particularly after a surgery, the factor level needs to be maintained at least 5-7 days following minor surgery and and 10-14 days after major surgery.
Factor innhibitor testing It is important to check the level of inhibitors as patients with high-titer inhibitors (> 5-10 BU)may need bypass clotting factors such as activated prothrombin complex concentrate, or rVIIa. Factor innhibitor testing
It is important to check the level of inhibitors as patients with high-titer inhibitors (> 5-10 BU)may need bypass clotting factors such as activated prothrombin complex concentrate, or rVIIa.
Hemoglobin and hematocrit levels Hemoglobin and hematocrit levels may vary from normal to decreased depending on the type and severity of the bleeding problem in bleeding disorders. Hemoglobin and hematocrit levels
Hemoglobin and hematocrit levels may vary from normal to decreased depending on the type and severity of the bleeding problem in bleeding disorders.
Factor 8 level Should be done prior to any surgery as correction of the deficient state is needed before the surgery. (as mentioned in the management section) Factor 8 level
Should be done prior to any surgery as correction of the deficient state is needed before the surgery. (as mentioned in the management section)
Factor 8 level Depending on the values of factor level, hemophilia can be subdivided into three grades as mild >5%, moderate 1-5% and severe < 1% factor level. Factor 8 level
Depending on the values of factor level, hemophilia can be subdivided into three grades as mild >5%, moderate 1-5% and severe < 1% factor level.
Serum bilirubin Serum bilirubin may be elevated due to excessive catabolism of red blood cells. Serum bilirubin
Serum bilirubin may be elevated due to excessive catabolism of red blood cells.
Von willibrand factor testing To exclude the associated von willibrand disease. Von willibrand factor testing
To exclude the associated von willibrand disease.
CT / MRI scan of the brain Spontaneous or traumatic intracranial hemorrhage may be evaluated using CT/MRI scan. Joint cartilage, synovium, and joint space evaluation may also be possible with MRI. CT / MRI scan of the brain
Spontaneous or traumatic intracranial hemorrhage may be evaluated using CT/MRI scan. Joint cartilage, synovium, and joint space evaluation may also be possible with MRI.
Ultrasonography USS is useful to evaluate the joints with effusions. Ultrasonography
USS is useful to evaluate the joints with effusions.

Management - Supportive

Fact Explanation
Immediate management Assessment of airway and breathing, is particularly important as they can present with upper airway obstruction following retropharyngeal. The immediate surgical airway may be needed. Circulatory collapse may occur in a massive haemorrhage. Disability and exposure will follow later. Immediate management
Assessment of airway and breathing, is particularly important as they can present with upper airway obstruction following retropharyngeal. The immediate surgical airway may be needed. Circulatory collapse may occur in a massive haemorrhage. Disability and exposure will follow later.
Multidesciplinary approach Haematologist, physician, orthopedic surgeon, physiotherapist etc should be involved in the management of haemophilic patients. Multidesciplinary approach
Haematologist, physician, orthopedic surgeon, physiotherapist etc should be involved in the management of haemophilic patients.
Management of other complications Upper GI bleeding, haematuria, intracranial haemorrhage may need specific supportive management after correcting the factor level. Associated psychological disturbances , learning problems due to recurrent school abstinence may need special attention. Management of other complications
Upper GI bleeding, haematuria, intracranial haemorrhage may need specific supportive management after correcting the factor level. Associated psychological disturbances , learning problems due to recurrent school abstinence may need special attention.
Patient education Parents of the affected child need a full explanation of the nature of the disease, its complications and importance of complying with the treatment. Precautions to minimize bleeding tendency such as avoiding contact sports, injuries when handling the equipments are needed. It is better to inform the teachers at school with permission of the parents and educate them on what to do as immediate measures. Patient education
Parents of the affected child need a full explanation of the nature of the disease, its complications and importance of complying with the treatment. Precautions to minimize bleeding tendency such as avoiding contact sports, injuries when handling the equipments are needed. It is better to inform the teachers at school with permission of the parents and educate them on what to do as immediate measures.
Follow up Apart from the routine assessment for features of bleeding manifestations, patients with complications such as intracranial haemorrhages need specific attention as they are more likely to have neurocognitive, academic, behavioral, adaptive, and motor functioning deficienciesrequiring long-term follow-up. Follow up
Apart from the routine assessment for features of bleeding manifestations, patients with complications such as intracranial haemorrhages need specific attention as they are more likely to have neurocognitive, academic, behavioral, adaptive, and motor functioning deficienciesrequiring long-term follow-up.

Management - Specific

Fact Explanation
Management of high risk bleeding situations Central nervous system hemorrhage including intracranial hemorrhage and spinal hematoma, soft-tissue hemorrhage predisposing to airway compromise retropharyngeal hemorrhage, hemorrhage along facial planes, neck hematoma associated with dissection, large tongue hematoma, gastrointestinal bleeding including hematemesis, hematochezia or melena from bleeding telangiectasia, splenic rupture, kidney capsular rupture, liver laceration, hematoma of bowel wall and haemorrhage around the eye are some of these high risk bleeding manifestations. Hemostasis has to be restored and blood should be sent for investigations. Immediate infusion of factor 8, 50 IU/kg body weight. Continuous clotting factor infusions needs to be given with measured factor level til the acute bleeding is settled. Management of high risk bleeding situations
Central nervous system hemorrhage including intracranial hemorrhage and spinal hematoma, soft-tissue hemorrhage predisposing to airway compromise retropharyngeal hemorrhage, hemorrhage along facial planes, neck hematoma associated with dissection, large tongue hematoma, gastrointestinal bleeding including hematemesis, hematochezia or melena from bleeding telangiectasia, splenic rupture, kidney capsular rupture, liver laceration, hematoma of bowel wall and haemorrhage around the eye are some of these high risk bleeding manifestations. Hemostasis has to be restored and blood should be sent for investigations. Immediate infusion of factor 8, 50 IU/kg body weight. Continuous clotting factor infusions needs to be given with measured factor level til the acute bleeding is settled.
Factor VIII replacement Number of units needed to be given can be calculated by the following formula : plasma volume (ml/kg) × weight (kg) × percent activity increase. Factor VIII replacement
Number of units needed to be given can be calculated by the following formula : plasma volume (ml/kg) × weight (kg) × percent activity increase.
Desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]) FVIII levels can be corrected using desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]. It is available as intravenous, subcutaneous, or intranasal administration and availability in a subcutaneous or intranasal routes and reduced cost are some of the advantages of DDAVP. Desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP])
FVIII levels can be corrected using desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]. It is available as intravenous, subcutaneous, or intranasal administration and availability in a subcutaneous or intranasal routes and reduced cost are some of the advantages of DDAVP.
Preparing for a surgery Factor VIII level is are raised to around 100% of normal activity, and is maintained for the first three postoperative days. Further maintenance would be around 80% on day four and 40% of normal activity from the day seven. onwards. This may be nesessary even beforea invasive diagnostic procedure. Factor level should be maintained for 5-7 days after minor surgery, for 10-14 days after major surgery. Preparing for a surgery
Factor VIII level is are raised to around 100% of normal activity, and is maintained for the first three postoperative days. Further maintenance would be around 80% on day four and 40% of normal activity from the day seven. onwards. This may be nesessary even beforea invasive diagnostic procedure. Factor level should be maintained for 5-7 days after minor surgery, for 10-14 days after major surgery.
Prophylaxis Prophylaxis regimens are beneficial older adolescents and adults with severe hemophilia as it reduced the severe complications such as intracranial haemorrhages. Monthly FFP transfusion can be used but may lead to less compliance. Prophylaxis may also be beneficial in situations like carrying a pregnancy successfully to term, by preventing early miscarriages, and in afibrinogenaemia. Prophylaxis
Prophylaxis regimens are beneficial older adolescents and adults with severe hemophilia as it reduced the severe complications such as intracranial haemorrhages. Monthly FFP transfusion can be used but may lead to less compliance. Prophylaxis may also be beneficial in situations like carrying a pregnancy successfully to term, by preventing early miscarriages, and in afibrinogenaemia.
Management of inhibitor formation Alloimmune inhibitory antibodies to FVIII are developing in 25% to 30% of patients with severe hemophilia. Genetic mutation plays a role in the inhibitor development. Immune tolerance inductionis the therapy for inhibitor formation that is done using frequent dosing of FVIII concentrates over many months to 3 years. High-titer inhibitors (> 5-10 BU) or patients who are having an anamnestic response to FVIII will be treated with bypass clotting factors such as an activated prothrombin complex concentrate, or rVIIa. Management of inhibitor formation
Alloimmune inhibitory antibodies to FVIII are developing in 25% to 30% of patients with severe hemophilia. Genetic mutation plays a role in the inhibitor development. Immune tolerance inductionis the therapy for inhibitor formation that is done using frequent dosing of FVIII concentrates over many months to 3 years. High-titer inhibitors (> 5-10 BU) or patients who are having an anamnestic response to FVIII will be treated with bypass clotting factors such as an activated prothrombin complex concentrate, or rVIIa.

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