Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Hemophilia A Clinical Presentation

  • Author: Robert A Zaiden, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
 
Updated: Feb 29, 2016
 

History

For patients in whom hemophilia is suspected, inquire about any history of hemorrhage disproportionate to trauma, spontaneous hemorrhage, bleeding disorders in the family, concomitant illness (especially those associated with acquired hemophilia, such as chronic inflammatory disorders, autoimmune diseases, hematologic malignancies, and allergic drug reactions), and pregnancy.

For individuals with documented hemophilia, ascertain the type of deficiency (eg, factor VIII [FVIII], FIX, von Willebrand), degree of factor deficiency, known presence of inhibitors, and HIV/hepatitis status. 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, 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, 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, excessive bleeding with routine dental procedures

Evidence of infectious disease includes the following:

  • HIV/AIDS-related symptoms
  • Hepatitis-related symptoms

Newborn boys with severe hemophilia may present with prolonged bleeding at circumcision. Easy bruising may occur at the start of ambulation or primary dentition. Older patients may have a history of hemarthroses and prolonged bleeding with surgical procedures, trauma, and dental extraction, and may have spontaneous bleeding in soft tissues.

A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is diagnosed. Factors that elevate FVIII levels (eg, age, ABO blood type, stress, exercise) may mask mild hemophilia.

Weight-bearing joints and other joints are principal sites of bleeding in patients with hemophilia. The muscles most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is dangerous because of the large volumes of blood loss and because compression of the femoral nerve may occur.

In the genitourinary tract, gross hematuria may occur in as many as 90% of patients. In the GI tract, bleeding may complicate common GI disorders. Bleeding in the CNS is the leading cause of hemorrhagic death among patients with hemophilia.

Acquired hemophilia

Acquired hemophilia due to an autoantibody in previously hemostatically normal individuals tends to affect elderly people who have comorbid conditions, but may also develop post partum. Persons with acquired hemophilia may experience extensive, often life threatening, bleeding before the condition is recognized.

In contrast to persons with severe inherited hemophilia A, in whom joint bleeding is common, patients with acquired hemophilia present with large intramuscular, retroperitoneal, limb, subcutaneous, genitourinary, gastrointestinal, or excessive postoperative or postpartum bleeding. Bleeding into an extremity can result in findings that are easily confused with deep vein thrombosis. Massive upper extremity bleeding can be precipitated by a simple venipuncture. Bleeding can develop at any site.

Postpartum acquired hemophilia usually comes to attention 2 to 5 months after delivery, when bleeding symptoms supervene. Rarely, the inhibitor may develop during pregnancy.

Next

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, decreased 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 spasm/distension/pain and costovertebral angle pain
  • Other - Hematoma leading to location-specific signs (eg, airway obstruction, compartment syndrome)

Signs of infectious disease include the following:

  • HIV/AIDS-related signs
  • Hepatitis-related signs

Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. Other neonates may present with severe hematoma and prolonged bleeding from the cord or umbilical area.

After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers, when trauma-related soft-tissue hemorrhage occurs. 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.

As children grow and become more physically active, hemarthroses and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a serious life-threatening complication that requires urgent diagnosis and intervention.

Petechiae usually do not occur in patients with hemophilia. The reason is that petechiae are manifestations of capillary blood leakage, which is typically the result of vasculitis or abnormalities in the number or function of platelets.

Hemophilia is classified according to clinical severity as mild, moderate, or severe (see Table 1, below). Patients with severe disease usually have less than 1% factor VIII (FVIII) activity and experience spontaneous hemarthrosis and soft-tissue bleeding in the absence of apparent precipitating trauma. Patients with moderate disease have 1-5% FVIII activity and bleed with minimal trauma. Patients with mild hemophilia have more than 5% factor activity and bleed only after significant trauma or surgery.

Table 1. Severity, Factor Activity, and Hemorrhage Type (Open Table in a new window)

Classification Factor Activity, % Cause of Hemorrhage
Mild >5-40 Major trauma or surgery
Moderate 1-5 Mild-to-moderate trauma
Severe < 1 Spontaneous

Direct the examination to identify signs related to spontaneous bleeding, or bleeding with minimal challenge, in the joints, muscles, and other soft tissues. Observe the patient's posture. Examine the weight-bearing joints, especially the knees and ankles, and, in general, the large joints for deformities or ankylosis. Look for jaundice and other signs of liver failure (eg, cirrhosis), and for signs of opportunistic infections in patients who are HIV positive.

Pseudotumors are produced by a slow expansion of repeated hemorrhages in bone or soft tissues. They can be restricted by the fascial planes of a muscle, cause resorption of neighboring bone by pressure-induced ischemia, or develop under the periosteum, leading to erosion of the bony cortex. They develop slowly over months to years and often are asymptomatic, unless pressure on the nerves or vascular compromise occurs.

Pseudotumors contain a brownish material and can become infected. The buttock, pelvis, and thighs are common locations for a pseudotumor (see the images below).

Transected pseudocyst (following disarticulation o Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional limb). This photo shows black-brown old blood, residual muscle, and bone.
Dissection of a pseudocyst. Dissection of a pseudocyst.
Transected pseudocyst with chocolate brown-black o Transected pseudocyst with chocolate brown-black old blood.
Photograph of a patient who presented with a slowl Photograph of a patient who presented with a slowly expanding abdominal and flank mass, as well as increasing pain, inability to eat, weight loss, and weakness of his lower extremity.
Plain radiograph of the pelvis showing a large lyt Plain radiograph of the pelvis showing a large lytic area.
Intravenous pyelogram showing extreme displacement Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.
Photograph depicting extensive spontaneous abdomin Photograph depicting extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
Previous
 
 
Contributor Information and Disclosures
Author

Robert A Zaiden, MD Assistant Professor, Division of Hematology/Oncology, Department of Medicine, University of Florida at Jacksonville College of Medicine

Robert A Zaiden, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Coauthor(s)

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Mary A Furlong, MD Associate Professor and Program/Residency Director, Department of Pathology, Georgetown University School of Medicine

Mary A Furlong, MD is a member of the following medical societies: United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Gary D Crouch, MD Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Uniformed Services University of the Health Sciences

Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Srikanth Nagalla, MBBS, MS, FACP Director, Clinical Hematology, Cardeza Foundation for Hematologic Research; Assistant Professor of Medicine, Division of Hematology, Associate Program Director, Hematology/Medical Oncology Fellowship, Assistant Program Director, Internal Medicine Residency, Jefferson Medical College of Thomas Jefferson University

Srikanth Nagalla, MBBS, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Nothing to disclose.

Acknowledgements

Dimitrios P Agaliotis, MD, PhD, FACP Consulting Staff, Department of Medicine, Baptist Health System

Dimitrios P Agaliotis, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Hematology, and Florida Medical Association

Disclosure: Nothing to disclose.

Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center

Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians

Disclosure: Nothing to disclose.

Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Max J Coppes, MD, PhD, MBA President, BC Cancer Agency, Vancouver

Max J Coppes, MD, PhD, MBA, is a member of the following medical societies: Alberta Medical Association, American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research

Disclosure: Astellas Pharma US Inc Honoraria Chair Endpoint Review Committee

Brendan R Furlong, MD Clinical Chief, Department of Emergency Medicine, Georgetown University Hospital

Brendan R Furlong, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Pere Gascon, MD, PhD Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain

Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, New York Academy of Medicine, New York Academy of Sciences, and Sigma Xi

Disclosure: Nothing to disclose.

William G Gossman, MD Associate Clinical Professor of Emergency Medicine, Creighton University School of Medicine; Consulting Staff, Department of Emergency Medicine, Creighton University Medical Center

William G Gossman, MD is a member of the following medical societies: American Academy of Emergency Medicine

Disclosure: Nothing to disclose.

Lawrence F Jardine, MD, FRCPC Associate Professor, Department of Pediatrics, Schulich School of Medicine and Dentistry, University of Western Ontario; Head, Section of Pediatric Hematology and Oncology, Children's Hospital of Western Ontario; Associate Scientist, Child Health Research Institute

Lawrence F Jardine, MD, FRCPC is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, Canadian Medical Protective Association, Children's Oncology Group, College of Physicians and Surgeons of Ontario, Hemophilia and Thrombosis Research Society, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada

Disclosure: Baxter Honoraria Consulting; Bayer Honoraria Consulting; Novartis Honoraria Speaking and teaching

Elzbieta Klujszo, MD Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce

Disclosure: Nothing to disclose.

Adonis Lorenzana, MD Consulting Staff, Department of Pediatric Oncology, St John Hospital and Medical Center

Adonis Lorenzana, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Saduman Ozturk, PA-C Physician Assistant, Bone Marrow Transplant Center, Florida Hospital Cancer Institute

Disclosure: Nothing to disclose.

Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching

Hadi Sawaf, MD Director, Pediatric Hematology Oncology, Van Elslander Cancer Center; Clinical Assistant Professor, Wayne State University School of Medicine

Hadi Sawaf, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Clinical Oncology, and American Society of Hematology

Disclosure: Nothing to disclose.

Rebecca J Schmidt, DO, FACP, FASN Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine

Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association

Disclosure: Renal Ventures Ownership interest Other

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, New York Academy of Medicine, and Sigma Xi

Disclosure: Nothing to disclose.

Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology

Disclosure: Novartis Honoraria Speaking and teaching; Novartis Consulting fee Speaking and teaching; Ariad Honoraria Speaking and teaching; Celgene Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Acknowledgments

The authors gratefully acknowledge the provision of several photographs used in this article by a dedicated colleague from Chicago, Margaret Telfer, MD. The authors would also like to acknowledge Professor K.N. Subramanian (Department of Molecular Genetics, University of Illinois Medical Center) for general discussions relating to some aspects of the gene structure and mutation of the FVIII gene.

References
  1. Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet. 2016 Feb 17. 3:15056. [Medline].

  2. Jones PK, Ratnoff OD. The changing prognosis of classic hemophilia (factor VIII "deficiency"). Ann Intern Med. 1991 Apr 15. 114(8):641-8. [Medline].

  3. Federici AB. The factor VIII/von Willebrand factor complex: basic and clinical issues. Haematologica. 2003 Jun. 88(6):EREP02. [Medline].

  4. Chorba TL, Holman RC, Strine TW, Clarke MJ, Evatt BL. Changes in longevity and causes of death among persons with hemophilia A. Am J Hematol. 1994 Feb. 45(2):112-21. [Medline].

  5. Mudad R, Kane WH. DDAVP in acquired hemophilia A: case report and review of the literature. Am J Hematol. 1993 Aug. 43(4):295-9. [Medline].

  6. Arnold WD, Hilgartner MW. Hemophilic arthropathy. Current concepts of pathogenesis and management. J Bone Joint Surg Am. 1977 Apr. 59(3):287-305. [Medline]. [Full Text].

  7. Pinto P, Ghosh K, Shetty S. F8 gene mutation profile in Indian hemophilia A patients: Identification of 23 novel mutations and factor VIII inhibitor risk association. Mutat Res. 2016 Feb 10. 786:27-33. [Medline].

  8. Reuters Health Information. Factor VIII Products Have Similar Risk of Inhibitor Development. January 17, 2013. Available at http://www.medscape.com/viewarticle/777816. Accessed: February 7, 2013.

  9. Gouw SC, van der Bom JG, Ljung R, Escuriola C, Cid AR, et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med. 2013 Jan 17. 368(3):231-9. [Medline].

  10. Verbruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, Mauser-Bunschoten E. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost. 1995 Feb. 73(2):247-51. [Medline].

  11. Klinge J, Auerswald G, Budde U, Klose H, Kreuz W, Lenk H, et al. Detection of all anti-factor VIII antibodies in haemophilia A patients by the Bethesda assay and a more sensitive immunoprecipitation assay. Haemophilia. 2001 Jan. 7(1):26-32. [Medline].

  12. Bitting RL, Bent S, Li Y, Kohlwes J. The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis. Blood Coagul Fibrinolysis. 2009 Oct. 20(7):517-23. [Medline].

  13. Kazazian HH Jr, Tuddenham EGD, Antonarakis SE. Hemophilia A and parahemophilia: deficiencies of coagulation factors VIII and V. Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995. 3241-67.

  14. Roelse JC, De Laaf RT, Timmermans SM, Peters M, Van Mourik JA, Voorberg J. Intracellular accumulation of factor VIII induced by missense mutations Arg593-->Cys and Asn618-->Ser explains cross-reacting material-reduced haemophilia A. Br J Haematol. 2000 Feb. 108(2):241-6. [Medline].

  15. Spreafico M, Peyvandi F. Combined Factor V and Factor VIII Deficiency. Semin Thromb Hemost. 2009 Jun. 35(4):390-9. [Medline].

  16. Hemophilia: Data & Statistics. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/ncbddd/hemophilia/data.html. Accessed: May 6, 2014.

  17. Shetty S, Bhave M, Ghosh K. Acquired hemophilia a: diagnosis, aetiology, clinical spectrum and treatment options. Autoimmun Rev. 2011 Apr. 10(6):311-6. [Medline].

  18. Venkateswaran L, Wilimas JA, Jones DJ, Nuss R. Mild hemophilia in children: prevalence, complications, and treatment. J Pediatr Hematol Oncol. 1998 Jan-Feb. 20(1):32-5. [Medline].

  19. Di Michele DM, Gibb C, Lefkowitz JM, Ni Q, Gerber LM, Ganguly A. Severe and moderate haemophilia A and B in US females. Haemophilia. 2014 Mar. 20(2):e136-43. [Medline].

  20. Loveland KA, Stehbens J, Contant C, Bordeaux JD, Sirois P, Bell TS, et al. Hemophilia growth and development study: baseline neurodevelopmental findings. J Pediatr Psychol. 1994 Apr. 19(2):223-39. [Medline].

  21. Anagnostis P, Karras S, Paschou SA, Goulis DG. Haemophilia A and B as a cause for secondary osteoporosis and increased fracture risk. Blood Coagul Fibrinolysis. 2015 Jun 26. [Medline].

  22. Manco-Johnson MJ, Nuss R, Jacobson LJ. Heparin neutralization is essential for accurate measurement of factor VIII activity and inhibitor assays in blood samples drawn from implanted venous access devices. J Lab Clin Med. 2000 Jul. 136(1):74-9. [Medline].

  23. Abdul-Kadir R, Davies J, Halimeh S, Chi C. Advances in pregnancy management in carriers of hemophilia. J Appl Hematol [serial online] 2013 [cited 2014 May 6];4:125-30. Available at http://www.jahjournal.org/text.asp?2013/4/4/125/127894. Accessed: May 6, 2014.

  24. Berntorp E, Astermark J, Björkman S, Blanchette VS, Fischer K, Giangrande PL, et al. Consensus perspectives on prophylactic therapy for haemophilia: summary statement. Haemophilia. 2003 May. 9 Suppl 1:1-4. [Medline].

  25. Ljung RC. Prophylactic infusion regimens in the management of hemophilia. Thromb Haemost. 1999 Aug. 82(2):525-30. [Medline].

  26. Iorio A, Marchesini E, Marcucci M, Stobart K, Chan AK. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database Syst Rev. 2011 Sep 7. 9:CD003429. [Medline].

  27. Miners AH, Sabin CA, Tolley KH, Lee CA. Assessing the effectiveness and cost-effectiveness of prophylaxis against bleeding in patients with severe haemophilia and severe von Willebrand's disease. J Intern Med. 1998 Dec. 244(6):515-22. [Medline].

  28. Coppola A, Margaglione M, Santagostino E, Rocino A, Grandone E, Mannucci PM, et al. Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors. J Thromb Haemost. 2009 Nov. 7(11):1809-15. [Medline].

  29. Rodriguez-Merchan EC, De la Corte-Rodriguez H, Jimenez-Yuste V. Radiosynovectomy in haemophilia: long-term results of 500 procedures performed in a 38-year period. Thromb Res. 2014 Nov. 134 (5):985-90. [Medline].

  30. Chapman WC, Singla N, Genyk Y, McNeil JW, Renkens KL Jr, Reynolds TC, et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am Coll Surg. 2007 Aug. 205(2):256-65. [Medline].

  31. Zanon E, Martinelli F, Bacci C, Zerbinati P, Girolami A. Proposal of a standard approach to dental extraction in haemophilia patients. A case-control study with good results. Haemophilia. 2000 Sep. 6(5):533-6. [Medline].

  32. O'Connell N, Mc Mahon C, Smith J, Khair K, Hann I, Liesner R, et al. Recombinant factor VIIa in the management of surgery and acute bleeding episodes in children with haemophilia and high responding inhibitors. Br J Haematol. 2002 Mar. 116(3):632-5. [Medline].

  33. Siddiqui MA, Scott LJ. Recombinant factor VIIa (Eptacog Alfa): a review of its use in congenital or acquired haemophilia and other congenital bleeding disorders. Drugs. 2005. 65(8):1161-77. [Medline].

  34. McQuilten ZK, Barnes C, Zatta A, Phillips LE. Off-Label Use of Recombinant Factor VIIa in Pediatric Patients. Pediatrics. 2012 Jun. 129(6):e1533-e1540. [Medline].

  35. von Depka M. Immune tolerance therapy in patients with acquired hemophilia. Hematology. 2004 Aug. 9(4):245-57. [Medline].

  36. Hay CR, DiMichele DM. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood. 2012 Feb 9. 119(6):1335-44. [Medline]. [Full Text].

  37. Carcao M, St Louis J, Poon MC, Grunebaum E, Lacroix S, Stain AM, et al. Rituximab for congenital haemophiliacs with inhibitors: a Canadian experience. Haemophilia. 2006 Jan. 12(1):7-18. [Medline].

  38. Franchini M, Mannucci PM. Inhibitor eradication with rituximab in haemophilia: where do we stand?. Br J Haematol. 2014 Jun. 165(5):600-8. [Medline].

  39. Aggarwal A, Grewal R, Green RJ, Boggio L, Green D, Weksler BB, et al. Rituximab for autoimmune haemophilia: a proposed treatment algorithm. Haemophilia. 2005 Jan. 11(1):13-9. [Medline].

  40. Stachnik JM. Rituximab in the treatment of acquired hemophilia. Ann Pharmacother. 2006 Jun. 40(6):1151-7. [Medline].

  41. Personal communication with Dr. Troy H. Guthrie, Jr. MD. Jacksonville, Florida: Medical Director Baptist Cancer Institute;

  42. Hitt E. Hemophilia: contact sports pose little risk. Medscape Medical News. Available at http://www.medscape.com/viewarticle/772326. Accessed: October 16, 2012.

  43. Leissinger C, Gringeri A, Antmen B, Berntorp E, Biasoli C, Carpenter S, et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med. 2011 Nov 3. 365(18):1684-92. [Medline].

  44. Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014 Jan 16. 123(3):317-25. [Medline]. [Full Text].

  45. FDA approves the first antihemophilic factor, Fc fusion protein for patients with Hemophilia A. U.S. Food and Drug Administration. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm400167.htm. Accessed: June 17, 2014.

  46. Duncan N, Kronenberger W, Roberson C, Shapiro A. VERITAS-Pro: a new measure of adherence to prophylactic regimens in haemophilia. Haemophilia. 2010 Mar. 16(2):247-55. [Medline].

  47. Den Uijl I, Mauser-Bunschoten EP, Roosendaal G, Schutgens R, Fischer K. Efficacy assessment of a new clotting factor concentrate in haemophilia A patients, including prophylactic treatment. Haemophilia. 2009 Nov. 15(6):1215-8. [Medline].

  48. Ingerslev HJ, Hindkjaer J, Jespersgaard C, Lind MP, Kølvraa S. [Preimplantation genetic diagnosis. The first experiences in Denmark]. Ugeskr Laeger. 2001 Oct 1. 163(40):5525-8. [Medline].

  49. Lissens W, Sermon K. Preimplantation genetic diagnosis: current status and new developments. Hum Reprod. 1997 Aug. 12(8):1756-61. [Medline].

  50. Wells D, Delhanty JD. Preimplantation genetic diagnosis: applications for molecular medicine. Trends Mol Med. 2001 Jan. 7(1):23-30. [Medline].

  51. Kumar R, Bouskill V, Schneiderman JE, Pluthero FG, Kahr WH, Craik A, et al. Impact of aerobic exercise on haemostatic indices in pediatric patients with haemophilia. Thromb Haemost. 2016 Feb 25. 115 (6):[Medline].

  52. Chuah MK, Collen D, VandenDriessche T. Gene therapy for hemophilia. J Gene Med. 2001 Jan-Feb. 3(1):3-20. [Medline].

  53. Matsui H. Endothelial progenitor cell-based therapy for hemophilia A. Int J Hematol. 2012 Feb. 95(2):119-24. [Medline].

  54. High KH, Nathwani A, Spencer T, Lillicrap D. Current status of haemophilia gene therapy. Haemophilia. 2014 May. 20 Suppl 4:43-9. [Medline].

  55. Sokal EM, Lombard C, Mazza G. Mesenchymal stem cell treatment for hemophilia: a review of current knowledge. J Thromb Haemost. 2015 Jun. 13 Suppl 1:S161-S166. [Medline].

  56. Rodriguez-Merchan EC, De La Corte-Rodriguez H. Radiosynovectomy in haemophilic synovitis of elbows and ankles: Is the effectiveness of yttrium-90 and rhenium-186 different?. Thromb Res. 2016 Feb 10. 140:41-45. [Medline].

  57. Antunes SV, Tangada S, Stasyshyn O, Mamonov V, Phillips J, Guzman-Becerra N, et al. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia. 2014 Jan. 20(1):65-72. [Medline].

  58. Bogdanova N, Markoff A, Pollmann H, Nowak-Göttl U, Eisert R, Wermes C, et al. Spectrum of molecular defects and mutation detection rate in patients with severe hemophilia A. Hum Mutat. 2005 Sep. 26(3):249-54. [Medline].

  59. Broderick CR, Herbert RD, Latimer J, Barnes C, Curtin JA, Mathieu E, et al. Association between physical activity and risk of bleeding in children with hemophilia. JAMA. 2012 Oct 10. 308(14):1452-9. [Medline].

  60. Brooks M. FDA OKs Turoctocog Alpha (NovoEight) for Hemophilia A. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/812759. Accessed: February 29, 2016.

  61. Castaman G, Mancuso ME, Giacomelli SH, Tosetto A, Santagostino E, Mannucci PM, et al. Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A. J Thromb Haemost. 2009 Nov. 7(11):1824-31. [Medline].

  62. Ewenstein BM, Wong WY, Schoppmann A. Bypassing agent prophylaxis for preventing arthropathy in patients with inhibitors. Haemophilia. 2010 Jan. 16(1):179-80. [Medline].

  63. Konkle BA, Kessler C, Aledort L, Andersen J, Fogarty P, Kouides P, et al. Emerging clinical concerns in the ageing haemophilia patient. Haemophilia. 2009 Nov. 15(6):1197-209. [Medline].

  64. Tucker ME. FDA Approves Hemophilia Drug FEIBA for Bleeding Prophylaxis. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/818236. Accessed: February 29, 2016.

 
Previous
Next
 
Coagulation pathway.
The hemostatic pathway. APC = activated protein C (APC); AT-III = antithrombin III; FDP = fibrin degradation products; HC-II = heparin cofactor II; HMWK = high-molecular-weight kininogen; PAI = plasminogen activator inhibitor; sc-uPA = single-chain urokinase plasminogen activator; tc-uPA = two-chain urokinase plasminogen activator; TFPI = tissue factor pathway inhibitor; tPA = tissue plasminogen activator
Structural domains of human factor VIII. Adapted from: Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional structure of membrane-bound coagulation factor VIII: modeling of the factor VIII heterodimer within a 3-dimensional density map derived by electron crystallography. Blood. Feb 15 2002;99(4):1215-23; Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. NY: McGraw-Hill; 2001:1639-57; and Roberts HR. Thoughts on the mechanism of action of FVIIa. Presented at: Second Symposium on New Aspects of Haemophilia Treatment; 1991; Copenhagen, Denmark.
Possible genetic outcomes in individuals carrying the hemophilic gene.
Photograph of a teenage boy with bleeding into his right thigh as well as both knees and ankles.
Photograph of the right knee in an older man with a chronically fused, extended knee following open drainage of knee bleeding that occurred many years previously.
Photograph depicting severe bilateral hemophilic arthropathy and muscle wasting. The 3 punctures made into the left knee joint were performed in an attempt to aspirate recent aggravated bleeding.
Radiograph depicting advanced hemophilic arthropathy of the knee joint. These images show chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.
Radiograph depicting advanced hemophilic arthropathy of the elbow. This image shows chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.
Photograph of a hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required.
Large amount of vascular synovium removed at surgery.
Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, diffuse deposits would be demonstrated; iron-laden macrophages are present.
Large pseudocyst involving the left proximal femur.
Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional limb). This photo shows black-brown old blood, residual muscle, and bone.
Dissection of a pseudocyst.
Transected pseudocyst with chocolate brown-black old blood.
Photograph of a patient who presented with a slowly expanding abdominal and flank mass, as well as increasing pain, inability to eat, weight loss, and weakness of his lower extremity.
Plain radiograph of the pelvis showing a large lytic area.
Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.
Photograph depicting extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
Magnetic resonance image of an extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
Coagulation Cascade
Table 1. Severity, Factor Activity, and Hemorrhage Type
Classification Factor Activity, % Cause of Hemorrhage
Mild >5-40 Major trauma or surgery
Moderate 1-5 Mild-to-moderate trauma
Severe < 1 Spontaneous
Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia
Indication or Site of Bleeding Factor level Desired, % FVIII Dose, IU/kg* Comment
Severe epistaxis; mouth, lip, tongue, or dental work 20-50 10-25 Consider aminocaproic acid (Amicar), 1-2 d
Joint (hip or groin) 40 20 Repeat transfusion in 24-48 h
Soft tissue or muscle 20-40 10-20 No therapy if site small and not enlarging (transfuse if enlarging)
Muscle (calf and forearm) 30-40 15-20 None
Muscle deep (thigh, hip, iliopsoas) 40-60 20-30 Transfuse, repeat at 24 h, then as needed
Neck or throat 50-80 25-40 None
Hematuria 40 20 Transfuse to 40% then rest and hydration
Laceration 40 20 Transfuse until wound healed
GI or retroperitoneal bleeding 60-80 30-40 None
Head trauma (no evidence of CNS bleeding) 50 25 None
Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) 100 50 Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented
Trauma with bleeding, surgery 80-100 50 10-14 d
Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.