eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Hemophilia, Overview: Differential Diagnoses & Workup

Author: Dimitrios P Agaliotis, MD, PhD, FACP, Consulting Staff, Department of Medicine, Baptist Health System
Coauthor(s): Robert A Zaiden, MD, Fellow, Department of Hematology and Medical Oncology, University of Florida at Jacksonville; Saduman Ozturk, PA-C, Physician Assistant, Bone Marrow Transplant Center, Florida Hospital Cancer Institute
Contributor Information and Disclosures

Updated: Nov 24, 2009

Differential Diagnoses

Factor V
Factor VII
Factor XI Deficiency
Glanzmann Thrombasthenia
Platelet Disorders
von Willebrand Disease

Other Problems to Be Considered

Other congenital bleeding disorders must be excluded. These may include the following:

Differentiating between severe hemophilia A and hemophilia B is almost clinically impossible, but specific laboratory factor assays can help with the distinction. Conditions that can increase FVIII levels (eg, age, ABO blood type, stress, exercise) can obscure the diagnosis of hemophilia A. The diagnosis of hemophilia B may be delayed by physiologically low levels of all vitamin K–dependent coagulation factors. FIX Leyden, in which FIX levels progressively increase after puberty to nearly normal values, must also be considered when hemophilia B is diagnosed.

Workup

Laboratory Studies

  • The plasma concentration of FVIII or FIX determines the severity of hemophilia.
    • Levels of these factors are assayed against a normal pooled-plasma standard, which is designated as having 100% activity or the equivalent of FVIII or FIX 1 U/mL. Patients' tested values ranging from 50-150% are considered in the normal range of variance.
    • Aging, pregnancy, contraceptives, and estrogen replacement therapies are associated with increased levels.
    • In term and healthy premature neonates, FIX values are lowered (20-50% of the normal level) and rise to normal levels after 6 months (hepatic immaturity). FVIII levels are normal during that period of life.
    • Spontaneous bleeding complications are severe in individuals with undetectable activity (<0.01 U/mL), moderate in individuals with activity (2-5% normal), and mild in individuals with factor levels greater than 5%.
  • Hemophilia A and hemophilia B protein deficiencies of the intrinsic pathway result in abnormal whole-blood clotting times, prothrombin times (PTs), and activated partial thromboplastin times (aPTTs).
    • FVIII and FIX activities are usually determined by using the 1-stage assay based on the aPTT.
    • Chromogenic assays or 2-stage assays have also been used to determine FVIII levels.
  • Differentiation of hemophilia A from von Willebrand disease is possible by observing normal or elevated levels of von Willebrand factor antigen and ristocetin cofactor activity. Bleeding time is prolonged in patients with von Willebrand disease but normal in patients with hemophilia.
  • Laboratory confirmation of a FVIII or FIX inhibitor is clinically important when bleeding is not controlled after adequate amounts of factor concentrate are infused during a bleeding episode.
    • For autoantibody and alloantibody inhibitors, obtain a repeat measurement of the patient's prolonged aPTT after incubating the patient's plasma with normal plasma at 37°C for 1-2 hours.
    • If the prolonged aPTT is not corrected, use the Bethesda method to titrate the inhibitor biologic concentration. By convention, more than 0.6 BU is considered a positive result for an inhibitor, less than 5 BU is considered a low titer of inhibitor, and more than 10 BU is a high titer (neutralizing effectiveness of factor concentrate therapy to control bleeding).

Imaging Studies

  • Radiographs may show synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage that progress with subchondral bone cyst formation, which may occur in patients who are untreated or inadequately treated or in those with recurrent joint hemorrhages.
  • Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions. This technique is not helpful for evaluating the bone or cartilage.
  • MRI is useful in the evaluation of the cartilage, synovium, and joint space.

Procedures

  • Specific orthopedic procedures may be required in chronic, neglected cases with irreversible joint or muscular deformities.
  • Patients with portal hypertension due to hepatic cirrhosis secondary to chronic hepatitis have undergone portocaval shunt procedures or variceal sclerotherapy, with good palliative results.

Histologic Findings

Recurrent joint bleeds result in synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage.

Staging

Hemophilic arthropathy evolves through 5 stages, starting as an intra-articular and periarticular edema due to acute hemorrhage and progressing to stage 5, which consists of advanced erosion of the cartilage with loss of the joint space, joint fusion, and fibrosis of the joint capsules.7

More on Hemophilia, Overview

Overview: Hemophilia, Overview
Differential Diagnoses & Workup: Hemophilia, Overview
Treatment & Medication: Hemophilia, Overview
Follow-up: Hemophilia, Overview
References
Further Reading
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References

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Keywords

hemophilia, haemophilia, coagulopathy, hemophilia A, hemophilia B, Christmas disease, clotting disorder, coagulation disorder, factor VIII, factor IX, factor XIII, factor XI, hemophiliac, coagulation cascade, joint hemorrhage, hemophilic arthropathy, acute hemarthroses, gene, gene, hematologic disorder

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Contributor Information and Disclosures

Author

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.

Coauthor(s)

Robert A Zaiden, MD, Fellow, Department of Hematology and Medical Oncology, University of Florida at Jacksonville
Robert A Zaiden, MD is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.

Saduman Ozturk, PA-C, Physician Assistant, Bone Marrow Transplant Center, Florida Hospital Cancer Institute
Disclosure: Nothing to disclose.

Medical Editor

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; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

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 Society of Hematology
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

CME Editor

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 Osteopathic Internists, 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: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, 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 Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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