Bleeding is commonly encountered in outpatient and hospital-based medical practice and can have a wide variety of underlying causes. While bleeding may be relatively common, most acquired and congenital bleeding disorders are uncommon, and some, such as acquired hemophilia, are rare. Nevertheless, the consequences of failure to recognize promptly and treat properly a bleeding disorder may be significant.18
In the case of acquired hemophilia, morbidity and mortality rates are particularly high: severe bleeding is experienced by up to 90% of affected patients, and mortality rates are as high as 22%.11
This survey provided a step-wise methodology to tease out specialty-specific patterns of interpretation of clinical data to identify barriers to the diagnosis and treatment of underlying bleeding disorders. The sample size obtained across specialties was sufficient to generalize these findings, at least to the point of identifying specific issues for education and development of clinical decision-making pathways.
When presented with a clinical picture that includes a recent history or symptoms of active bleeding, clinicians typically obtain coagulation times, such as the PT/INR and aPTT, as part of the initial diagnostic evaluation. Proper interpretation of laboratory test results includes recognition of abnormal values and, more important, the potential clinical significance of such results. A common pitfall in the interpretation of coagulation times is failure to appreciate that even mildly abnormal values may represent a serious underlying coagulation deficit. Another important observation is to identify how an abnormal laboratory value may have changed over time, which can be facilitated by the ability of electronic medical record systems to display data trends. In the absence of iatrogenic causes, even a mildly elevated PT/INR or aPTT may be indicative of true coagulopathy and should not be ignored or dismissed, particularly when there is evidence of bleeding, as was the case with this patient, even at initial presentation.
After excluding laboratory error, the differential diagnosis of an isolated prolongation of aPTT includes heparin effect, lupus anticoagulant, and deficiency of or antibody against an intrinsic pathway factor (VIII, IX, XI, or XII).19
A detailed history, focusing on factors such as heparin exposure,19
history of thromboembolism (lupus anticoagulant),21
and prior personal or family history of bleeding,22
may provide diagnostic clues. Laboratory testing should include a 1:1 mixing test of patient plasma with control plasma to determine whether a prolonged aPTT is the result of an intrinsic pathway factor deficiency or an inhibitor that continues to block the activity of the intrinsic system even in the presence of control plasma. The majority of inhibitor antibodies identified in this manner will turn out to be lupus anticoagulants. Although far less common, this is the same diagnostic pathway that leads to the identification of the antifactor VIII antibodies associated with acquired hemophilia.23
Unlike acquired hemophilia, lupus anticoagulants typically do not present with bleeding, and the abnormal aPTT is due to interference with phospholipid-dependent coagulation reactions. Once an acquired antifactor VIII antibody is suspected, confirmatory testing includes measuring factor VIII activity, which should be significantly reduced, and the Bethesda assay,24
which is used to quantitate antifactor VIII antibodies inhibitor activity.
We found a general lack of appropriate consideration and response to the presenting symptom of bleeding and the prolonged aPTT throughout this case study. This is consistent with data from the European Acquired Haemophilia Registry (EACH-2), which reported a median delay of 3 days between onset of bleeding symptoms and the diagnosis of acquired hemophilia and a median delay of one day between the first abnormal aPTT test in those same patients and the established diagnosis.23
In addition, we found that emergency medicine and critical care physicians were reluctant to consider a bleeding disorder as the primary explanation for this patient’s clinical presentation. The disposition of a patient with active hemorrhage and evidence of coagulopathy should be based on several factors, including the patient’s current condition and anticipated clinical course, taking into account the presenting vital signs and evolving laboratory findings. At the time of the patient’s second presentation, vital signs were notable for mild tachycardia and a pulse pressure at the upper limit of normal, and subsequent laboratory findings indicated a decreasing hemoglobin level and an increasing aPTT. These findings alone prompted hospital admission, although the exact location (general floor versus intensive care unit) of admission may vary, based on the level of monitoring and nurse-to-patient ratios in a particular hospital. Another important variable is the anticipated potential for clinical deterioration, which is based in large part on clinician appreciation of the seriousness of the diagnosis. We found a consistent tendency to consider admission to a general floor bed with the second presentation, even though this was ultimately an unstable, critically ill patient with an undiagnosed bleeding disorder. This survey clearly highlights several pitfalls in the optimal management of acquired hemophilia.
We also found that the physicians who participated in this survey were reluctant to consult a hematologist as they worked through this case scenario, particularly given that options for additional testing (liver function, disseminated intravascular coagulation) were not available to evaluate for common causes of coagulopathy. This was particularly true of emergency medicine and critical care specialists. Relative to their reported historical experience with hematology consultations during an average practice experience of approximately 20 years, this survey finding was somewhat surprising. Rheumatologists and critical care specialists reported a greater frequency of hematology consultation relative to the other specialties (). We would expect the emergency medicine physicians to be most likely to consult a hematologist, yet 16% of them reported never having consulted a hematologist. The highest percentage (46%) had only consulted a hematologist 1 or 2 times, and almost one quarter of geriatricians and internists had never consulted a hematologist, even though these specialists would be expected to first encounter patients with undiagnosed bleeding disorders, including acquired hemophilia. One potential reason for not seeking hematology consultation might be the lack of availability of hematology/oncology specialists with expertise in coagulation disorders, including in rural and community hospitals.
A limitation of this survey was that one cannot interpret the thinking behind the responses of the individual participants. Therefore, 31 qualitative 45-minute interviews were conducted subsequent to the quantitative study and focused particularly on critical care (n = 7), emergency medicine (n = 6), hematology/oncology (n = 4), or hematology (n = 2) physicians to understand the reasoning behind their decisions and depth of knowledge (unpublished data). We found that the physicians’ focus was generally on finding the source (location) of bleeding and not on finding the underlying reason for bleeding. This could potentially lead to surgical intervention in the face of an underlying bleeding disorder, with subsequent adverse outcomes. In a series of 67 patients with acquired hemophilia at a single center in Bonn, Germany, 4 of 5 deaths were the result of surgical intervention for bleeding at outside hospitals in the setting of a delayed diagnosis of acquired hemophilia.13
When queried about their experience encountering and/or diagnosing underlying bleeding disorders, particularly acquired hemophilia, more than 85% of physicians in hematology, hematology/oncology, emergency medicine, and critical care medicine reported having ever discovered or diagnosed an underlying bleeding disorder, compared with 65%, 54%, and 47% of rheumatologists, internists, and geriatricians, respectively. While reports of ever specifically having encountered acquired hemophilia were high, it is unclear from this study whether the participants truly understood the diagnosis. This seems unlikely, given the rarity of acquired hemophilia, relative to the reported frequency of having encountered it. Except for hematology and/or oncology (77%) and critical care (36%) specialists, approximately one quarter of surveyed physicians had ever encountered acquired hemophilia. Although they accounted for the highest percentage of physicians who had ever encountered this condition, nearly one quarter of hematologists had never encountered acquired hemophilia. Subsequent unpublished data from the aforementioned qualitative research further suggest that, compared with hematology practitioners, specialists in hematology/oncology, who likely practice mostly oncology, might be able to identify “mixing studies” and “inhibitors” but might not fully understand the underlying pathophysiology that constitutes acquired hemophilia, making it hard for them to recognize the condition. Given the survey findings reflecting the infrequency with which most physicians have encountered these conditions, consultation with a hematologist may facilitate the diagnostic evaluation and proper management of a hemorrhaging patient suspected of having an underlying bleeding diathesis, particularly acquired hemophilia.
The consulting hematologist can provide specific guidance, leading to the prompt diagnosis and optimal management of an actively bleeding patient with acquired hemophilia, including initiation of immunosuppression, which is usually necessary to eradicate the inhibitor and to prevent additional bleeding episodes. However, this requires a level of familiarity and expertise in treating acquired hemophilia and other rare bleeding disorders that is not often seen outside of an academic hematology practice. This represents yet another barrier to the effective diagnosis and management of this rare yet serious bleeding diathesis.