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Acquired Hemophilia Workup

  • Author: Sara J Grethlein, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
Updated: Mar 24, 2016

Approach Considerations

In a patient with acquired hemophilia, the bleeding time, prothrombin time (PT), and platelet count are normal. However, the activated partial thromboplastin time (aPTT) typically shows a prolongation that is not reversed on a correction study (see the image below).[1, 5, 21] Heparin and lupus anticoagulant must be screened for. Factor VIII (FVIII) levels must be measured and evidence of FVIII inhibitor sought. Other factor levels should be determined to establish inhibitor specificity.

Workup for acquired hemophilia. Workup for acquired hemophilia.

Activated Partial Thromboplastin Time

An isolated prolongation of the aPTT that is not corrected when the patient’s plasma is incubated with equal volumes of normal plasma in a mixing study is a key component of the diagnosis of acquired hemophilia.[1, 5] Because the action of the inhibitor is often delayed, incubation for 2 hours is required before the correction study is initiated.[22]

Acquired hemophilia can occasionally be confused with disseminated intravascular coagulation (DIC) because of a prolonged aPTT; however, the prolonged PT, low fibrinogen, elevated fibrin degradation products and D-dimers, and thrombocytopenia[8] should allow the two bleeding conditions to be distinguished quite readily. Consequently, the presence of an isolated prolonged aPTT is a particularly important characteristic of acquired hemophilia.

Isolated prolongation of the aPTT may occur for a variety of reasons. For example, it may result from decreases in FVIII, factor IX (FIX), factor XI (FXI), factor XII (FXII), high-molecular-weight kininogen or prekallikrein or from the presence of anticoagulants, such as lupus anticoagulant or clotting factor inhibitors.[4] The clinician must determine whether the isolated aPTT results from the presence of a lupus anticoagulant or a circulating inhibitor or reflects a true quantitative deficiency of coagulation factor activity in plasma.[5]


Screening for Lupus Anticoagulant and Heparin

Because the most common cause of isolated prolonged aPTT is lupus anticoagulant,[23] it is essential to consider the presence of a lupus anticoagulant in patients with a prolonged aPTT.

The presence of lupus anticoagulant is suggested when aPTT values during the mixing study are similar at time 0 and after incubation at 37°C.[9] Lupus anticoagulant can then be confirmed by specific tests, such as the dilute Russell viper venom time and the kaolin clotting time.[24, 25, 9] Finding lupus anticoagulant in patients with acquired inhibitors may occur, but it is uncommon in most situations.[22]

The presence of heparin also must be excluded. It is suggested by a prolonged thrombin time in association with a normal reptilase time.[9] Heparin may be identified by conducting a clinical history and medication sheets, and its presence as a contaminant confounding coagulation assays can be determined specifically by treating the plasma to remove heparin using a heparin-absorbing resin or heparin-cleaving enzyme prior to assay.[4]


Coagulation Factor Assays

Reduced FVIII levels and evidence of an FVIII inhibitor are critical to the diagnosis of acquired hemophilia A. Although acquired hemophilia A is rare, FVIII inhibitors in very low concentrations (not typically detected in coagulation assays) are often present in healthy individuals with normal FVIII levels and no bleeding symptoms or history.[22] One study reported that a FVIII-neutralizing antibody was in 17% of healthy blood donors, usually in multiparous females.[26]

The levels of other intrinsic pathway factors (eg, FIX, FXI, and FXII) may be reduced in patients with acquired hemophilia A.[22, 11] Therefore, it is important to repeat factor assays using increasing dilutions of patient plasma to establish the specificity of the inhibitor.[19] Once the acquired inhibitor is detected, it should be quantified to project the severity of the disorder and the risk of hemorrhagic complications.

A specific inhibitor can be confirmed and quantified by using specific assays of the factor and the inhibitor.[27, 9] The methods used for quantifying FVIII inhibitors are the Bethesda assay and the Nijmegen modification of the Bethesda assay. One Bethesda unit (BU) is the quantity of inhibitor that inactivates 50% of FVIII in normal plasma after incubation at 37°C for 2 hours.

Both the Bethesda assay and the Nijmegen modification may underestimate the potency of the inhibitor due to its nonlinear complex reaction kinetics.[19] As a result of its kinetic profile, the recovery and half-life of exogenous FVIII may be considerably reduced, even in patients with low inhibitor titers.[15]

Searching for inhibitors for porcine FVIII concentrate is not recommended, because the porcine FVIII formulation is not currently available.[9] Clinical studies are examining the safety and efficacy of recombinant porcine FVIII concentrates in autoantibody inhibitors in acquired hemophilia A. According to an abstract from the American Society of Hematology, recombinant porcine FVIII concentrate is being used in a phase 2 trial in patients with hemophilia A and alloantibodies.[28]


Other Studies

Magnetic resonance imaging (MRI), computed tomography (CT), and ultrasonography may be indicated to localize, quantify, and serially monitor the location and response of bleeding. Other imaging tests may be used as needed to diagnose associated diseases.

Testing patients with pregnancy-associated acquired hemophilia for autoimmune disorders such as lupus and rheumatoid arthritis is recommended because the presence of an autoimmune disorder may require a change in therapeutic approach.[19, 29]

Contributor Information and Disclosures

Sara J Grethlein, MD Associate Dean for Undergraduate Medical Education, Indiana University School of Medicine

Sara J Grethlein, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.


Craig M Kessler, MD MACP, Professor, Department of Medicine and Pathology, Division of Hematology/Oncology, Georgetown University School of Medicine; Director, Clinical Coagulation Laboratory, Lombardi Comprehensive Cancer Center, Georgetown University Hospital

Disclosure: Received honoraria from NovoNordisk for consulting; Received grant/research funds from NovoNordisk for other; Received honoraria from Baxter-Immuno for consulting; Received honoraria from Octapharma for speaking and teaching; Received grant/research funds from Octapharma for none; Received consulting fee from Amgen for consulting; Received honoraria from Bayer for review panel membership.

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.


Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group

Disclosure: No financial interests None None

Pradyumna D Phatak, MBBS, MD Chair, Division of Hematology and Medical Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell Park Cancer Institute

Pradyumna D Phatak, MBBS, MD, is a member of the following medical societies: American Society of Hematology

Disclosure: Novartis 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

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Clinical presentation of acquired hemophilia.
Sites of bleeding in patients with acquired hemophilia (n = 149). This research was originally published in Blood. Collins PW, Hirsch S, Baglin TP, et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood. 2007;109(5):1870-7. © American Society of Hematology.
Workup for acquired hemophilia.
Management of bleeding in acquired hemophilia.
Eradication of the inhibitor for acquired hemophilia.
Table 1 below illustrates the frequency of underlying diagnoses in 3 cohort studies of patients with acquired hemophilia A. [10, 13, 14, 15, 16]
Disease Association Green 1981 (N = 215), % Morrison 1993 (N = 65), % Collins 2007 (N = 172), %
Idiopathic 46.1 55.0* 63.3
Collagen, vascular, and other autoimmune diseases 18.0 17.0 16.7
Malignancy 6.7 12.0 14.7
Skin diseases 4.5 2.0 3.3
Possible drug reaction 5.6 3.0 NR
Pregnancy 7.3 11.0 2.0
Other 11.8 NR NR
*In this trial, idiopathic and other were combined.

NR—not reported.

Table 2. Acquired Bleeding Disorders Associated With Inhibitors of Factors Other Than FVIII
Coagulation Factor Inhibited Most Commonly Associated Disorders Treatment
V Lymphoproliferative disorders, adenocarcinoma, tuberculosis, aminoglycosides, topical thrombin FFP, rFVIIa
IX Systemic lupus erythematosus, acute rheumatic fever, hepatitis, collagen vascular diseases, multiple sclerosis, postprostatectomy, and postpartum FIX concentrates, APCCs, rFVIIa, corticosteroids
XI Autoimmune diseases, prostate carcinoma, chronic lymphocytic leukemia, chlorpromazine FFP, FXI concentrates, rFVIIa, tranexamic acid, fibrin glue
XIII Idiopathic, isoniazid, penicillin FXIII concentrate, FFP, stored plasma, cryoprecipitate
VWF‡ Autoimmune disorders, monoclonal gammopathies, lymphoproliferative diseases, epidermoid malignancies, hypothyroidism, myeloproliferative disorders, and certain medications Desmopressin, infusion of FVIII that contains vWF, IVIG, plasma exchange
II Topical thrombin, idiopathic, autoimmune diseases, procainamide APCC, FFP
VII Bronchogenic carcinoma, idiopathic FIX concentrates, APCC, FVIII concentrates, rFVIIa, fibrin glue, tranexamic acid
X Amyloidosis, carcinoma, acute nonlymphocytic leukemia, acute respiratory infections, fungicide exposure, idiopathic APCC, tranexamic acid, fibrin glue, FFP
APCC—activated prothrombin complex concentrate; FFP—fresh frozen plasma; IVIG—intravenous immunoglobulin; vWF—von Willebrand factor.
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