Clinical Consults™: A Challenging Case of Acquired Hemophilia A in a Patient with a Malignancy

Introduction

Welcome to the final activity of a 3-part series entitled Clinical Consults™ ─ Challenging Cases in Acquired Hemophilia A: Clinical Issues and Evolving Management Strategies. This Clinical Consults™ activity features a challenging case of AHA in a Patient with a Malignancy, providing the perspectives of AHA experts in oncology and hematology settings. We hope you enjoy part 3 of this series, and please review parts 1 and 2, featuring challenging cases of AHA in the ICU and pregnancy-associated AHA.
Miguel A. Escobar, MD, Chair

Acquired hemophilia A (AHA) is a rare autoimmune disease leading to formation of neutralizing antibodies (inhibitors) against endogenous coagulation factor VIII (FVIII).1 Symptoms include severe and spontaneous bleeding that may prove life-threatening. Although rare, AHA is a condition with high burden of disease. The high morbidity and mortality in patients with AHA are in part attributable to delayed diagnosis, which leads to delayed treatment.2,3 Unfortunately, the rarity of this coagulation disorder often makes it a diagnosis of exclusion, if it is even recognized at all.3

In about half of the cases, FVIII autoantibodies occur in patients lacking any relevant concomitant disease, while the remaining cases may be associated with a clinical condition, including malignancy, autoimmune disease, pregnancy, postpartum, adverse drug reaction, or infection (Table 1).1,3-6 Except for patients affected during pregnancy or postpartum, AHA affects mainly older patients with comorbidities.4

Table 1. Conditions associated with acquired hemophilia A1

Table 1. Conditions associated with acquired hemophilia A

Acquired hemophilia A: a review of recent data and new therapeutic options; Massimo Franchini, Stefania Vaglio, Giuseppe Marano, et al; Hematology, Vol 22, Issue 9, 25 April 2017; reprinted by permission of (Taylor & Francis Ltd, http://www.tandfonline.com).

What is the difference between Acquired Hemophilia A (AHA) and congenital hemophilia?

Escobar

Acquired hemophilia A should be considered if the actively bleeding patient has had recent onset or acute bleeding with no personal or family history of bleeding diatheses, particularly if the patient has cancer, even though bleeding can be the initial manifestation of a malignancy.1,3

Key-points-1v4

Figures 1 and 2. Clinical presentation of acquired hemophilia A3,7

Figures 1 and 2. Clinical presentation of acquired hemophilia A

Figure 1. Miguel A. Escobar; Bleeding in the patient with a malignancy; Cancer, Jun 30, 2011;Copyright © 2011, John Wiley and Sons
Figure 2. P. W. COLLINS; Management of acquired haemophilia A; Journal of Thrombosis and Haemostasis; Jul 22, 2011 Copyright © 2011, John Wiley

Discussion on the coagulopathy workup algorithm

Friedman

Miguel A. Escobar, MD

Escobar

Julie Rowe, MD

Figure 3. Laboratory testing for an acquired anti-FVIII inhibitor3

Figure 3. Laboratory testing for an acquired anti-FVIII inhibitor

Abbreviations: BU, Bethesda units; CBC, complete blood count, FVIII, factor VIII; PT, prothrombin time; PTT, activated partial thromboplastin time; TT, thrombin time.

  • Initial laboratory findings: AHA is characterized by the singular prolongation of activated partial thromboplastin time (PTT) with a normal prothrombin time (PT), thrombin time (TT), and platelet count.3,8 For patients with a malignancy or undergoing chemotherapy, it is not uncommon to sometimes find abnormalities in some or all of these tests.
  • Mixing study: A PTT mixing study is done by obtaining plasma from the patient and mixing it in equal proportion with normal plasma (1:1 mixing) that has all the coagulation factors (Figure 4). Since these antibodies can be time- and temperature-dependent, the PTT should be done at baseline and after at least a 1- to 2-hour incubation at 37°C.1,3 The PTT has an initial partial correction that later prolongs after incubation, which is typical for AHA.1,8
  • AHA is confirmed by documentation of absent or reduced FVIII activity (typically 1%-15% of normal), along with quantification of the FVIII inhibitor by the Bethesda assay.8 Measurement of the inhibitor titer will provide the point of reference upon which initial management of AHA is usually based (ie, high-titer or low-titer). One Bethesda unit is defined as the amount of inhibitor that will inactivate 50% of normal FVIII activity in a mixture of normal plasma and patient plasma after incubation at 37°C for 1 to 2 hours.3

Figure 4. Mixing study

Figure 4. Mixing study

Figure 4 provided by Miguel A. Escobar, MD.

Management

The therapeutic aim for patients with AHA is 2-fold1,3,9:

  1. Control acute bleeding (of variable intensity at presentation)
  2. Long-term eradication of the inhibitor

Therapeutic options are listed in Table 2. In general, successful treatment of an underlying primary disease state, when possible, may lead to inhibitor remission.3 Drug-induced inhibitors should result in spontaneous inhibitor remission within a few months following discontinuation of that drug.

Table 2. Therapeutic optioins for AHA1,3

Table 2. Therapeutic optioins for AHA

Abbreviations: aPCC, activated prothrombin complex concentrate; rFVIIa, recombinant activated factor VII; FVIII, factor VIII; rpFVIII, recombinante porcine FVIII.

Restoration of coagulation is achieved by increasing circulating levels of FVIII or by bypassing the inhibitor in the coagulation cascade. 1,3 Bypassing agents ̶ rFVIIa and pd-aPCC (ie, FEIBA) ̶ are typically used first-line for major bleeds. The main safety concern is the thromboembolic risk, reported for both agents.1

rpFVIII is a newer treatment option that allows a more precise dosing based on FVIII:C measurements. Given that porcine FVIII is similar to human FVIII, some patients develop cross-reactive antibodies to rpFVIII. Assessment of antibodies to rpFVIII may be useful prior to treatment.

Human FVIII is usually inadequate as hemostatic treatment, unless the inhibitor titer is low (<5 BU/mL) and is administered at doses able to overwhelm the inhibitor, so that hemostatic levels of FVIII can be achieved.1 Also, desmopressin (alone or in association with FVIII concentrates) may be useful for management of minor bleeds in patients with a low inhibitor titer and measurable FVIII levels.

Eradication of the inhibiting antibody is accomplished with immunosuppressive therapy (IST).1,9Published guidelines recommend IST as early as possible once the diagnosis is made, because these patients remain at risk of severe and fatal hemorrhage until the inhibitor has been eradicated.10 IST reported for AHA includes high-dose steroids, cytotoxics, and anti-CD20 inhibitors, which can be given as a single agent or in combination.1 Clinical and laboratory responses to inhibitor eradication IST may take up to 4 to 20 weeks.3

Common side effects of long-term immunosuppression may include cytopenias, infections, and diabetes, among others.9 Unfortunately, elderly patients with comorbidities, who constitute the largest population with AHA, are at greatest risk of experiencing immunosuppression-related complications.3 

Predictive factors may guide the choice of IST. Residual FVIII activity (≥1 IU/dL) and inhibitor concentration (<20 BU/mL) at baseline were reported to be independent predictors of response to IST.10 This subgroup comprises about one-third of patients who may benefit from less aggressive treatment with a lower rate of adverse events.9

Acquired Hemophilia in Patients with Malignancy
AHA in patients with cancer can cause undue morbidity and mortality, particularly when diagnosis and initiation of appropriate treatment are delayed.3,11 Development of AHA may occur in patients with solid tumors or with hematologic malignancies.3,11-13 In a recent survey of 105 persons with AHA and cancer,12 the most common solid tumors associated with AHA were prostate (25%), lung (16%), and colon (10%) cancers. Other surveys and cases have reported AHA in patients with breast cancer and various other solid malignancies.13,14 Hematologic malignancies associated with AHA included lymphoma (24%), chronic lymphocytic leukemia (22%), plasma cell dyscrasias (20%), acute myeloid leukemia (9%), and myelodysplastic syndrome (9%).12
Pathogenesis of AHA in the setting of an underlying malignancy may involve several mechanisms (Figure 5); among them, regulatory T cells appear to be a promising link.3,12 Development of FVIII inhibitors likely represents an autoimmune response to tumor antigens that resemble FVIII.3 In addition, immune impairment associated with malignancies may lead to spontaneous formation of inhibitory antibodies against FVIII. In some cases, however, the link between AHA and malignancy may be coincidental rather than causal, since most AHA cases occur in elderly persons, among whom cancer is relatively common.

Figure 5. Potential mechanisms of acquired anti-FVIII autoantibodies in the setting of malignancy3

Figure 5. Potential mechanisms of acquired anti-FVIII autoantibodies in the setting of malignancy

Theoretical mechanisms involved in the production of FVIII autoantibodies in patients with hematologic malignancies. The abnormal leukemic clone or neoplastic B cells may mediate the generation of an abnormal FVIII molecule or other similar antigen by unknown mechanisms (1). Alternatively, there may be aberrations in the process of antigen presentation (2) or alterations in the number or function of CD-4+ cells or T-cell receptors (3). Finally, abnormalities in the interaction between T and B cells (4) or in CD-8+ T-suppressor cells (5) may constitute independent or contributory mechanisms in the formation of FVIII autoantibodies. Ag, antigen; APC, antigen-presenting cell; FVIII, factor VIII; MHC, major histocompatibility complex; Th, T helper cell.

Figure 5. Miguel A. Escobar; Bleeding in the patient with a malignancy; Cancer, Jun 30, 2011; Copyright © 2011, John Wiley and Sons

Development of neutralizing antibodies to FVIII may precede the initial diagnosis of a malignancy, or it may occur during the disease course or treatment.3 In fact, a diagnosis of AHA may herald the presence of an undiagnosed malignancy and should prompt age-appropriate cancer screening for an underlying cancer.

Recognizing AHA in a Patient with a Malignancy
Bleeding is a common complication of malignancy, and it may be due to many different etiologies (Figure 6).3 In fact, bleeding is often a presenting sign of many types of cancers. Potential causes include disease- or treatment-related impairment of bone marrow function leading to thrombocytopenia, or trauma to vascularized malignant tissue or adjacent tissues. Treatment-related myelosuppression also predisposes to infection and sepsis, which may trigger disseminated intravascular coagulation (DIC), resulting in diffuse bleeding as platelets and coagulation factors are consumed.3

Figure 6. Potential etiologies of new-onset bleeding in patients with malignancy3

Figure 6. Potential etiologies of  new-onset bleeding in patients with malignancy

What specific challenges do oncologists face when determining the cause of acute bleeding in a patient with a malignancy?

Julie Rowe, MD

Acquired FVIII inhibitors tend to present in the same manner regardless of underlying condition, including malignancy.3 A clinical profile of recent-onset or acute bleeding with no personal or family history of bleeding diatheses and anatomic location of bleeding should raise suspicion of AHA and prompt laboratory testing. Laboratory findings (ie, an isolated PTT with normal PT, thrombin time, and platelet count) can differentiate AHA from other more common causes of bleeding in patients with malignancies.3

In this Clinical Consults™, we consider a challenging case of acquired hemophilia A with a malignancy.

Click "Next" to review this patient case.