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Hemophilia A Workup

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

Approach Considerations

Laboratory studies for suspected hemophilia include a complete blood cell count, coagulation studies, and a factor VIII (FVIII) assay. Never delay indicated coagulation correction pending diagnostic testing.

On the hemoglobin/hematocrit assay, expect normal or low values. Expect a normal platelet count. On coagulation studies, the bleeding time and prothrombin time (which assesses the extrinsic coagulation pathway) are normal.

Usually, the activated partial thromboplastin time (aPTT) is prolonged; however, a normal aPTT does not exclude mild or even moderate hemophilia because of the relative insensitivity of the test. The aPTT is significantly prolonged in severe hemophilia.

For FVIII assays, levels are compared with a normal pooled-plasma standard, which is designated as having 100% activity or the equivalent of FVIII U/mL. Normal values are 50-150%. Values in hemophilia are as follows:

  • Mild: >5%
  • Moderate: 1-5%
  • Severe: < 1%

Aging, pregnancy, oral contraceptive use, and estrogen replacement therapy are associated with increased FVIII levels. Because FVIII is a large molecule that does not cross the placenta, the diagnosis can be made at birth with quantitative assay of cord blood.

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.

In patients with an established diagnosis of hemophilia, periodic laboratory evaluations include screening for the presence of FVIII inhibitor and screening for transfusion-related or transmissible diseases such as hepatitis and HIV infection. Screening for infection may be less important in patients who receive only recombinant FVIII concentrate.

Imaging studies for acute bleeds

Early and aggressive imaging is indicated, even with low suspicion for hemorrhage, after coagulation therapy is initiated. Imaging choices are guided by clinical suspicion and the anatomic location of involvement.

Head CT scans without contrast are used to assess for spontaneous or traumatic intracranial hemorrhage. Perform magnetic resonance imaging (MRI) on the head and spinal column for further assessment of spontaneous or traumatic hemorrhage. MRI is also useful in the evaluation of the cartilage, synovium, and joint space.

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. Special studies such as angiography and nucleotide bleeding scan may be clinically indicated.

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Testing for Inhibitors

Laboratory confirmation of a FVIII inhibitor is clinically important when a bleeding episode is not controlled despite infusion of adequate amounts of factor concentrate. For the assay, the aPTT measurement is repeated after incubating the patient's plasma with normal plasma at 37°C for 1-2 hours. If the prolonged aPTT is not corrected, the inhibitor concentration is titrated using the Bethesda method. Ideally, the Nijmegen modification of the Bethesda inhibitor assay should be used to detect an inhibitor if the mixing test result is positive.[10]

By convention, more than 0.6 Bethesda units (BU) is considered a positive result for an inhibitor. Less than 5 BU is considered a low titer of inhibitor, and more than that is a high titer. The distinction is clinically significant, as patients with low-titer inhibitors may respond to higher doses of FVIII concentrate while those with high-titer inhibitors require treatment with agents that bypass FVIII and consideration for induction of immune tolerance.

Caution is warranted when obtaining blood samples for coagulation assays from heparinized central lines because of the effect of heparin contamination on all coagulation test results. The excess heparin causes false-positive results and/or higher inhibitor titer values than are actually present in the patient, because heparin is also an inhibitor of coagulation.

One study found significant heparin contamination in 45% of all specimens obtained through implanted venous access devices. These researchers suggested that all blood samples obtained from such devices, which are usually flushed with heparin, should be treated with heparinase before performing an inhibitor assay.[22]

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Carrier Testing and Fetal Testing

Screening for carrier status can be performed by measuring the ratio of FVIII coagulant activity to the concentration of vWF antigen. A ratio that is less than 0.7 suggests carrier status.

Direct genetic testing for known gene mutation is more accurate. Linkage analysis by restriction fragment length polymorphism (RFLP) in multiple family members can be used. Direct mutation analysis is available in several laboratories for unknown FVIII mutations. Inversion of the FVIII gene can be detected by Southern blot.

For prenatal testing, carriers whose mutation has been identified can have chorionic villus sampling at approximately 10-12 weeks' gestation or amniocentesis at 16-20 weeks' gestation to obtain fetal cells for DNA analysis or for linkage studies. If DNA analysis cannot be performed, then fetal blood obtained by fetoscopy at approximately 20 weeks' gestation can be assayed for factor VIII level.

All of those procedures carry a risk ranging from a low of 0.5% for maternal-fetal complications to a high of 1-6% for fetal death from fetoscopy. These procedures should be undertaken only after patients receive intense genetic and obstetric counseling. Genetic counseling before the woman becomes pregnant is ideal and may help couples make informed decisions before conception.

Noninvasive prenatal diagnosis using quantitative digital polymerase chain reaction testing of free fetal DNA in the maternal circulation has been reported. However, this technique remains a research tool.[23]

If the fetus is a female, the couple may elect to carry the pregnancy to term because carriers rarely have bleeding problems. If the fetus is a severely affected male, the couple must make a decision about continuing the pregnancy to term. With pregnancies that will be carried to term, prenatal diagnosis allows for planning of delivery so as to minimize the risk of intracranial hemorrhage (eg, avoidance of vacuum devices).[23]

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Radiography

Radiography for joint assessment is of limited value in acute hemarthrosis. Evidence of chronic degenerative joint disease may be visible on radiographs in patients who have been untreated or inadequately treated or in those with recurrent joint hemorrhages. In these patients, radiographs may show synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage that progresses with subchondral bone cyst formation.

Hemophilic arthropathy evolves through 5 stages, starting as an intra-articular and periarticular edema due to acute hemorrhage and progressing to advanced erosion of the cartilage with loss of the joint space, joint fusion, and fibrosis of the joint capsules.[6] See the image below. For discussion of the 5-stage Arnold-Hilgartner classification of hemophilic arthropathy, see Imaging in Musculoskeletal Complications of Hemophilia.

Photograph of a hemophilic knee at surgery, with s Photograph of a hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required.
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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.

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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
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