Hemophilia B - Clinicals, Diagnosis, and Management

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. Coagulation 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 B is an X-linked, recessive coagulation disorder due to the deficiency or defect of factor IX. Factor IX hydrolyses one arginine-isoleucine bond in factor X to form the activated factor X (Xa). Activated factor VIII (FVIIIa) is important to improve the efficiency of this factor. Complex of FIXa, FVIIIa and FX, bound to the phospholipid membrane, is called “the X-ase” or “tenase” which helps to amplify the coagulation pathway. Haemophilia B affects 1:25,000 males accounting for 15% of all hemophilia cases. Hemophilia B is the second most common form of hemophilia and various mutations are known to associate with mutations of the FIX gene which located on the long arm of the X chromosome,such as missense, frameshift, or nonsense mutations. Acquired hemophilia is occurred due to the appearance of inhibitory antibodies to coagulatory factors. 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. Coagulation 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 B is an X-linked, recessive coagulation disorder due to the deficiency or defect of factor IX. Factor IX hydrolyses one arginine-isoleucine bond in factor X to form the activated factor X (Xa). Activated factor VIII (FVIIIa) is important to improve the efficiency of this factor. Complex of FIXa, FVIIIa and FX, bound to the phospholipid membrane, is called “the X-ase” or “tenase” which helps to amplify the coagulation pathway. Haemophilia B affects 1:25,000 males accounting for 15% of all hemophilia cases. Hemophilia B is the second most common form of hemophilia and various mutations are known to associate with mutations of the FIX gene which located on the long arm of the X chromosome,such as missense, frameshift, or nonsense mutations. Acquired hemophilia is occurred due to the appearance of inhibitory antibodies to coagulatory factors.
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 level <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 level <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 9 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 9 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 IX assay Is reduced in haemophilia A due to the deficiency of factor 9. Factor IX assay
Is reduced in haemophilia A due to the deficiency of factor 9.
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 IX 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 IX 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 IX 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 IX 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. Cranial trauma needs 50-100% correction and severe joint bleeding needs a 40-60U/kg. 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. Cranial trauma needs 50-100% correction and severe joint bleeding needs a 40-60U/kg.
Factor replacement Hemophilia B is treated with FIX concentrates. Initially Fresh frozen plasma was used, but now rarely used due to the concerns regarding volume overload and transmission of infections. Prothrombin complex concentrates (PCC), that contains pro-coagulation factors, including FII, FVII and FX is also less frequently used due to the risk of thrombotic episodes. Recombinant FIX products are now available to treat haemophilia B. Replacement of factor FIX will be either with a bleeding episodeas an on-demand treatment or by scheduled infusions several times per week as prophylaxis treatment. Target of replacement would be to achieve plasma FIX level of 60%–80% for major bleeds and 20%–40% for minor bleeds. rFIX is a single-chain glycoprotein that has a primary 415-amino-acid sequence identical to the Ala148 allelic form of pdFIX. Recombinant DNA technology and bioengineering have lead to the development of FIX products with longer half-life, that helps to decreas the frequency of infusions. eg:- glycoPEGylated rFIX has a half-life five times longer than that of rFIX. Dose of replacement for a minor haemarthroses would be 20-40 U/kg and moderate post traumatic bleeding, severe haemarthroses and external bleeding with anaemia will require correction around 40-60 U/kg. Factor replacement
Hemophilia B is treated with FIX concentrates. Initially Fresh frozen plasma was used, but now rarely used due to the concerns regarding volume overload and transmission of infections. Prothrombin complex concentrates (PCC), that contains pro-coagulation factors, including FII, FVII and FX is also less frequently used due to the risk of thrombotic episodes. Recombinant FIX products are now available to treat haemophilia B. Replacement of factor FIX will be either with a bleeding episodeas an on-demand treatment or by scheduled infusions several times per week as prophylaxis treatment. Target of replacement would be to achieve plasma FIX level of 60%–80% for major bleeds and 20%–40% for minor bleeds. rFIX is a single-chain glycoprotein that has a primary 415-amino-acid sequence identical to the Ala148 allelic form of pdFIX. Recombinant DNA technology and bioengineering have lead to the development of FIX products with longer half-life, that helps to decreas the frequency of infusions. eg:- glycoPEGylated rFIX has a half-life five times longer than that of rFIX. Dose of replacement for a minor haemarthroses would be 20-40 U/kg and moderate post traumatic bleeding, severe haemarthroses and external bleeding with anaemia will require correction around 40-60 U/kg.
Prophylaxis Prophylaxis regimens are beneficial older adolescents and adults with severe hemophilia as it reduced the severe complications such as intracranial haemorrhages. Scheduled infusions several times per week may be used as prophylaxis treatment. Primary prophylaxis is beneficial in patients with severe hemophilia to prevent joint damage, decrease the frequency of joint and other hemorrhages, and improve health-related quality of life. Dose of prophylaxis is usually 30-40 U/kg twice a weekly. Prophylaxis
Prophylaxis regimens are beneficial older adolescents and adults with severe hemophilia as it reduced the severe complications such as intracranial haemorrhages. Scheduled infusions several times per week may be used as prophylaxis treatment. Primary prophylaxis is beneficial in patients with severe hemophilia to prevent joint damage, decrease the frequency of joint and other hemorrhages, and improve health-related quality of life. Dose of prophylaxis is usually 30-40 U/kg twice a weekly.
Preparing for a surgery Maintenance of factor level should be above 50% for 7-15 days after a surgery. Preparing for a surgery
Maintenance of factor level should be above 50% for 7-15 days after a surgery.
Management of inhibitor formation Management of inhibitor formation Alloimmune inhibitory antibodies to FVIII are developing in 25% to 30% of patients with severe hemophilia. High-titer inhibitors (> 5-10 BU) will be treated with bypass clotting factors such as an activated prothrombin complex concentrate, or rVIIa. Management of inhibitor formation
Management of inhibitor formation Alloimmune inhibitory antibodies to FVIII are developing in 25% to 30% of patients with severe hemophilia. High-titer inhibitors (> 5-10 BU) will be treated with bypass clotting factors such as an activated prothrombin complex concentrate, or rVIIa.
forms of hemophilia are a particularly good target for gene therapy since they are caused by a well-known single gene defect and have a broad therapeutic wind Novel therapy for hemophilia with gene therapy is possible as it is caused by a single gene defect. Protein substitution therapy is available though there are some limitations such as no curative benefit, significant risk of bleeding episodes, chronic joint damage and high cost and limited availability. forms of hemophilia are a particularly good target for gene therapy since they are caused by a well-known single gene defect and have a broad therapeutic wind
Novel therapy for hemophilia with gene therapy is possible as it is caused by a single gene defect. Protein substitution therapy is available though there are some limitations such as no curative benefit, significant risk of bleeding episodes, chronic joint damage and high cost and limited availability.

Concise, fact-based medical articles to refresh your knowledge

Access a wealth of content and skim through a smartly presented catalog of diseases and conditions.

  1. BHARATI KP, PRASHANTH UR. Von Willebrand Disease: An Overview Indian J Pharm Sci [online] 2011, 73(1):7-16 [viewed 01 October 2014] Available from: doi:10.4103/0250-474X.89751
  2. BIRKHOLZ T, KRöBER S, KNORR C, SCHIELE A, BUMM K, SCHMIDT J. A retropharyngeal-mediastinal hematoma with supraglottic and tracheal obstruction: The role of multidisciplinary airway management J Emerg Trauma Shock [online] 2010, 3(4):409-411 [viewed 01 October 2014] Available from: doi:10.4103/0974-2700.70776
  3. FRANCHINI M, FRATTINI F, CRESTANI S, SISSA C, BONFANTI C. Treatment of hemophilia B: focus on recombinant factor IX Biologics [online] 2013:33-38 [viewed 06 October 2014] Available from: doi:10.2147/BTT.S31582
  4. HOOD J. L., EBY C. S.. Evaluation of a Prolonged Prothrombin Time. Clinical Chemistry [online] 2008 April, 54(4):765-768 [viewed 01 October 2014] Available from: doi:10.1373/clinchem.2007.100818
  5. JOSEPHSON N.. The hemophilias and their clinical management. Hematology [online] December, 2013(1):261-267 [viewed 01 October 2014] Available from: doi:10.1182/asheducation-2013.1.261
  6. JUNEJA S, GANJOO P, TANDON MS, SHARMA A. Perioperative management of a hemophilia B infant with intracranial hemorrhage J Pediatr Neurosci [online] 2012, 7(3):239-240 [viewed 06 October 2014] Available from: doi:10.4103/1817-1745.106494
  7. LJUNG R, VAN DEN BERG M, VALENTINO LA, MANCO-JOHNSON M. The Fourth Annual Meeting of the International Network for Pediatric Hemophilia: Current Challenges and Recommendations in the Clinical Care of Children with Hemophilia Transfus Med Hemother [online] 2010 Aug, 37(4):209-212 [viewed 01 October 2014] Available from: doi:10.1159/000317114
  8. ORLOVA NA, KOVNIR SV, VOROBIEV II, GABIBOV AG. Coagulation Factor IX for Hemophilia B Therapy? Acta Naturae [online] 2012, 4(2):62-73 [viewed 06 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408704
  9. PRASHANTH UR. Von Willebrand Disease: An Overview Indian J Pharm Sci [online] 2011, 73(1):7-16 [viewed 01 October 2014] Available from: doi:10.4103/0250-474X.89751ticles/PMC3448247
  10. RIZOLI SB, SCARPELINI S, CALLUM J, NASCIMENTO B, MANN KG, PINTO R, JANSEN J, TIEN H. Clotting Factor Deficiency in Early Trauma-Associated Coagulopathy J Trauma [online] 2011 Nov, 71(5 Suppl 1):S427-S434 [viewed 01 October 2014] Available from: doi:10.1097/TA.0b013e318232e5ab
  11. SAHU S, LATA I, SINGH S, KUMAR M. Revisiting hemophilia management in acute medicine J Emerg Trauma Shock [online] 2011, 4(2):292-298 [viewed 01 October 2014] Available from: doi:10.4103/0974-
  12. SAHU S, LATA I, SINGH S, KUMAR M. Revisiting hemophilia management in acute medicine J Emerg Trauma Shock [online] 2011, 4(2):292-298 [viewed 01 October 2014] Available from: doi:10.4103/0974-2700.82225
  13. SAHUD MA. Platelet disorders: a review of disturbances in adhesion, aggregation, and release reaction. Calif Med [online] 1972 Jan, 116(1):21-31 [viewed 01 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1518141
  14. SHARMA SK, KUMAR S, SETH T, MISHRA P, AGRAWAL N, SINGH G, SINGH AK, MAHAPATRA M, TYAGI S, PATI H, SAXENA R. Clinical Profile of Patients with Rare Inherited Coagulation Disorders: A Retrospective Analysis of 67 Patients from Northern India Mediterr J Hematol Infect Dis [online] , 4(1):e2012057 [viewed 01 October 2014] Available from: doi:10.4084/MJHID.2012.057
  15. SILVERBERG DS, DOSSETOR JB, EID TC, MANT MJ, MILLER JD. Arteriovenous fistula and prolonged hematuria after renal biopsy: treatment with epsilon aminocaproic acid Can Med Assoc J [online] 1974 Mar 16, 110(6):671-677 [viewed 01 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1947353
  16. SINGLETON TC, KEANE M. Diagnostic and Therapeutic Challenges of Intracranial Hemorrhage in Neonates With Congenital Hemophilia: A Case Report and Review Ochsner J [online] 2012, 12(3):249-253 [viewed 01 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448247
  17. STERNDALE H. Haemarthrosis and haemophilia. Proc R Soc Med [online] 1967 Jan, 60(1):37-38 [viewed 01 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1901393