Clinical Consults™: A Challenging Case of Pregnancy-Associated Acquired Hemophilia A

Introduction

Welcome to the second of a 3-part series entitled Clinical Consults™ ─ A Challenging Case of Pregnancy-Associated Acquired Hemophilia A. This Clinical Consults™ activity features a challenging case of pregnancy-associated acquired hemophilia A, providing the perspectives of AHA experts in OB-GYN settings. We hope you enjoy part 1 and 2 of this series, and we look forward to presenting part 3, featuring a challenging case of a patient with a malignancy.
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, respiratory diseases (eg, chronic obstructive pulmonary disease, asthma), 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 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 is elderly or postpartum.1,3

Key-points-1v4

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

Table 1. Conditions associated with acquired hemophilia A

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

Can you walk us through the coagulopathy workup algorithm?

Escobar

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
  • 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 37⁰C.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.

  • Control acute bleeding (of variable intensity at presentation)
  • 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) but may be considered to avoid delays in appropriate treatment for serious hemorrhage.1 Desmopressin should only be used for minor bleeds, not for true hemorrhage.

Eradication of the inhibiting antibody is accomplished with immunosuppressive therapy (IST).1,9 Published 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.11 This subgroup comprises about one-third of patients who may benefit from less aggressive treatment with a lower rate of adverse events.9

PREGNANCY-ASSOCIATED AHA
AHA is a very rare hemorrhagic complication of pregnancy, but it accounts for most AHA cases in people under the age of 40 years.7 The timing of presentation is variable, as women may present with bleeding due to AHA in their third trimester of pregnancy, at delivery, or postpartum.12 Combined, pregnancy-associated AHA constitutes up to 21% of all confirmed cases.13 The etiology of AHA in women postpartum is unknown.12

If AHA is not immediately recognized and treated appropriately, consequences can be catastrophic, including the need for hysterectomy, debilitating morbidity, or death.14 Due to its rarity, much of our clinical knowledge about pregnancy-associated AHA comes from case studies, the European Acquired Hemophilia (EACH2) registry,15 and other registry studies.12,13,16

EACH2 is a large, prospective database tracking the characteristics, diagnosis, treatment, and outcomes of patients (n = 501, males and females, included between 2003 and 2008) with bleeding due to an acquired FVIII inhibitor. Forty-two AHA cases (8.4%) from EACH2 were associated with the peripartum period.15 The survival of women with pregnancy-associated AHA was significantly better than for women in the EACH2 cohort with other underlying etiologies (P < 0.001) (Figure 5).15

Figure 5. Overall survival of women with pregnancy-associated AHA is superior than for AHA associated with other etiologies (EACH2)15

Figure 5. Overall survival of women with pregnancy-associated AHA is superior than for AHA associated with other etiologies (EACH2)

Figure 5 reproduced with permission of L Tengborn, F Baudo, A Huth‐Kühne, et al; Pregnancy‐associated acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) registry; BJOG: An International Journal of Obstetrics and Gynaecology; Aug 20, 2012; Copyright © 2012, John Wiley and Sons

Due to a lack of controlled clinical trials, treatment recommendations are based on expert opinion rather than evidence-based guidelines. Immediate collaboration between obstetrician/gynecologists and experienced hematology specialists is crucial to optimize diagnostic evaluation, treatment, and long-term management of women who experience pregnancy-associated AHA.

In this Clinical Consults™, we consider a challenging case of pregnancy- associated acquired hemophilia A.

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