Clinical Consults™: A Challenging Case of Acquired Hemophilia in the ICU

Introduction

Welcome to the first 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 acquired hemophilia A (AHA) in the ICU, providing the perspectives of AHA experts in critical care and hematology settings. We hope you enjoy part 1 of this series, and we look forward to presenting parts 2 and 3, featuring challenging cases of pregnancy-associated AHA and AHA in 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, 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

Adapted from Franchini M, et al. Hematology. 2017;22:514-520.

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 Escobar MA. Cancer. 2012;118:312-320.
Figure 2 reproduced with permission of Collins PW. J Thromb Haemost. 2011;9(Suppl 1):226-235.

Can you walk us through the coagulopathy workup algorithm?

Escobar

Is there anything else or different in the workup coagulopathy algorithm for a patient in the ICU?

Shander

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 acutely ill patients in the ICU, it is not uncommon to 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 1-2 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 37oC 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 options for AHA1,3

Table 2. Therapeutic options for AHA

Abbreviations: aPCC, activated prothrombin complex concentrate; rFVIIa, recombinant activated factor VII; FVIII, factor VIII; rpFVIII, recombinant 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.11 This subgroup comprises about one-third of patients who may benefit from less aggressive treatment with a lower rate of adverse events.9

AHA IN THE ICU
AHA is a rare condition with high burden of disease. Although it is not often seen, nearly two-thirds of patients with AHA will present with a major bleeding event, making them likely to be admitted to the emergency department or ICU.2,8,12 Severe bleeding occurs in up to 90% of patients with AHA, and the mortality rate is substantial.

Disorders of coagulation are frequently encountered initially in the ICU setting.13 AHA is one many etiologies of major bleeds requiring critical care (Table 3).8 Due to the high risk of morbidity and mortality associated with AHA, prompt diagnosis and management are crucial.8,12

Table 3. Potential etiologies of new-onset bleeding encountered in the intensive care unit8

Table 3. Potential etiologies of new-onset bleeding encountered in the intensive care unit

Abbreviations: DIC, disseminated intravascular coagulation.
Adapted from Shander A, et al. Intensive Care Med. 2011;37:1240-1249.

What specific challenges do ICU clinicians face when managing severe bleeding in a patient?

Shander

In this Clinical Consults™, we consider a challenging case of acute bleeding in a patient admitted to the intensive care. Click "Next" to review this patient case.