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, 6, 22] 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.
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, 6] Because the action of the inhibitor is often delayed, incubation for 2 hours is required before the correction study is initiated. [23]
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 [9] 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. [5] 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. [6]
Screening for Lupus Anticoagulant and Heparin
Because the most common cause of isolated prolonged aPTT is lupus anticoagulant, [24] 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. [10] Lupus anticoagulant can then be confirmed by specific tests, such as the dilute Russell viper venom time and the kaolin clotting time. [10, 25, 26] It is possible for lupus anticoagulant to occur in patients with acquired inhibitors, but it is uncommon. [23]
The presence of heparin also must be excluded. It is suggested by a prolonged thrombin time in association with a normal reptilase time. [10] 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. [5]
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. [23] One study reported finding an FVIII-neutralizing antibody in 17% of healthy blood donors, usually in multiparous females. [27]
The levels of other intrinsic pathway factors (eg, FIX, FXI, and FXII) may be reduced in patients with acquired hemophilia A. [12, 23] Therefore, it is important to repeat factor assays using increasing dilutions of patient plasma to establish the specificity of the inhibitor. [20] 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. [10, 28] 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. [20] 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. [16]
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. [20, 29]
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Acquired Hemophilia. Clinical presentation of acquired hemophilia.
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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.
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Acquired Hemophilia. Workup for acquired hemophilia.
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Acquired Hemophilia. Management of bleeding in acquired hemophilia.
Tables
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. |
|||
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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