The diagnosis and Management of HIV Associated Acquired Hemophilia A: A Case Series From Durban,South Africa

Abstract

Introduction:

In acquired hemophilia A (AHA), the body produces auto-antibodies against Factor VIII. Although AHA is rare, with an incidence of 1.5 patients/1 million population/year, there is a strong association with human immunodeficiency virus (HIV) infection. The accurate interpretation of screening coagulation tests is critical to identify patients with AHA, as the mortality rate secondary to bleeding is high.

Methods:

This was a retrospective case series which included all newly diagnosed AHA patients that were referred to Hemophilia care unit at King Edward VIII Hospital, Durban, South Africa from January 2011 to December 2021. The clinical presentation and laboratory results were documented.

Results:

Five patients were included in this case series. All patients were females aged between 28 and 64 years of age and they were HIV seropositive. They presented with spontaneous cutaneous and intramuscular bleeding. Four patients were virologically suppressed on anti-retroviral therapy, and no patient had a family history of congenital bleeding diathesis. Laboratory investigations confirmed AHA with high Factor VIII inhibitor titers, which ranged from 41 to 900 Bethesda Units (BU). All patients were managed with bypassing agents and oral corticosteroids. The monitoring of patients after the initiation of treatment was difficult as they all defaulted treatment.

Conclusion:

In view of the prevalence of HIV in sub-Saharan Africa, there is a possibility that AHA is under-diagnosed in our setting. The clinician and the laboratory have a combined critical role in identifying patients with AHA as the investigation of a prolonged APTT is mandatory. There are challenges in managing AHA patients in a resource-constrained setting.

Introduction

Acquired hemophilia A (AHA) is a rare auto-immune condition characterized by the production of autoantibodies that neutralize coagulation factor VIII. AHA has a bimodal age distribution with a peak in younger pregnant females (median age of 33.5 years) and another peak in adults who are more than 60 years old.^{1 -3}

Patients with AHA usually present with mucocutaneous, intramuscular, postpartum, or surgical bleeding and if untreated, the mortality rate is high. The diagnosis is confirmed by investigation of an unexplained prolonged activated partial thromboplastin time (APTT). The management includes the use of bypassing replacement therapy and immunosuppressive therapy to reduce the antibody titer.

Most cases of AHA are idiopathic. Auto-immune disease, human immunodeficiency virus (HIV), pregnancy, malignancy, and drugs (e.g., interferon alpha) are well-known precipitating causes of AHA. ⁴ Pediatric cases of AHA are rarer with less than 45 cases reported.^5,6 In South Africa (SA), the prevalence of HIV-associated AHA is expected to be higher because the HIV prevalence in SA is higher at 18.1% when compared to the global HIV statistics. ⁷

Our retrospective review at our academic center over a 10-year period (from January 2011 to December 2021) confirmed the diagnosis of AHA in only 5 adult patients that were referred to the King Edward Hospital (KEH) VIII Hemophilia treatment center KwaZulu-Natal (KZN) from district and regional health care facilities. The academic center laboratory performs all specialized coagulation testing for the public sector in the KZN province, and KEH is the main hemophilia treatment center in the province. The finding of only 5 patients in this setting is unexpected in view of the prevalence of HIV in SA, and it raises the possibility of undiagnosed patients in the peripheral hospitals and laboratories. The aim of discussing these 5 cases is to raise awareness of this rare disease so that patients are diagnosed and managed timeously. We also highlight the challenges experienced in a resource-constrained health sector and review the available literature on HIV-associated AHA.

Methods

In this retrospective descriptive study, the clinical records from the Kwa-Zulu Natal Hemophilia care center were reviewed to identify the cases of AHA that were referred to the unit for further management from January 2011 to December 2021. Ethics approval for this study was obtained from the Biomedical Research Ethics Committee (BREC), University of KwaZulu Natal (ethics number: BCA608/17). The authors certify that patient consent was obtained prior to any investigation and management as per institutional policy. As the study is retrospective and descriptive, no study-specific consent was obtained. To protect patient confidentiality, patients’ personal details are not disclosed in this report. The demographic data, clinical presentation, laboratory results, and clinical management of each patient diagnosed with AHA were recorded.

Results

A diagnosis of AHA was suspected in all 5 adult patients when they presented with a history of bleeding and an isolated prolonged activated partial thromboplastin (APTT) which did not correct on mixing studies. The factor VIII level was reduced and factor VIII inhibitors were detected in all patients.

The age of our patients ranged from 28 to 64 years of age (median = 56). All of the patients were female, of African ethnicity, and they were HIV seropositive. The patient characteristics and the clinical presentation of each patient are summarized in Table 1. At the time of diagnosis, all patients were on HIV anti-retroviral therapy and the viral loads were lower than the detectable limit in 4 patients, in keeping with an optimal response to highly active antiretroviral therapy. On clinical examination, there was no lymphadenopathy and no hepatosplenomegaly in any of the patients.

Table 1.

Clinical Characteristics of the Patients With Acquired Hemophilia A.

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Age (years)	28	56	64	62	50
Gender	Female	Female	Female	Female	Female
Year of diagnosis	2011	2015	2018	2020	2021
HIV status	Positive	Positive	Positive	Positive	Positive
CD4 count (×106/l)	543	197	315	350	462
Antiretroviral therapy	Yes	Yes,	Yes	Yes	Yes
HIV viral load (copies/ml)	Lower than detectable limit	Not documented a	Lower than detectable limit	Lower than detectable limit	Lower than detectable limit
Relevant clinical history	No family history of inherited bleeding disorder.	No family history of inherited bleeding disorder.	No family history of inherited bleeding disorder.	No family history of inherited bleeding disorder. Chronic alcohol ingestion	No family history of inherited bleeding disorder.
Clinical presentation	Spontaneous hematoma left thigh	Spontaneous hematomas bilateral upper and lower limbs	Spontaneous swelling of bilateral knees, elbows. Bleeding gums and ecchymoses.	Spontaneous left thigh hematoma	Spontaneous general ecchymoses

Abbreviations: CD, cluster of differentiation; HIV, human immunodeficiency virus.

a

The laboratory rejected the sample submitted for viral load owing to suboptimal preanalytical requirements. Patient 2 defaulted treatment prior to repeat phlebotomy.

Table 2 summarizes the laboratory results of each patient. All of the patients had a high Factor VIII inhibitor titer level of greater than 20 Bethesda Units (BU)/ml. On peripheral blood smear morphology, there were no features of a clonal lymphoproliferative disorder. A limited auto-immune screen was performed in 4 of the patients and a bone marrow investigation was performed in 2 of the patients. Patient 1 was clinically stable with a Factor VIII inhibitor level of 41 BU/ml and testing for lupus anticoagulant on a Dilute Russel Viper Venom-based assay (DRVVT) was positive. She had no other clinical signs and symptoms of antiphospholipid syndrome.

Table 2.

Laboratory Results of Acquired Hemophilia A patients in Durban, South Africa.

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Laboratory assays
Hemoglobin (g/dl)	8.7	6.3	10.1	8.3	10.7
White cell count (×109/l)	5.3	6.6	5.5	5.3	18
Platelets (×109/l)	326	256	748	320	577
Activated Partial thromboplastin Time (s) Control: 38 s	76.2	43	91	80	75.9
Factor VIII (%)	<1	<1	<1	<1	<1
Factor VIII inhibitor titer (BU/ml)	41	66	215	900	132
Bone marrow investigation	Not done	Not done	Not done	No infiltrate	No infiltrate
Auto-immune screen	ANF negative, LAC negative, Anti-cardiolipin antibodies positive	Not done	ANF negative Anti-proteinase antibody negative	Increased TSH, Reduced Free T4. Insufficient sample for thyroid antibody testing	Negative

Abbreviations: BU, Bethesda units; TSH, thyroid stimulating hormone; ANF, anti-nuclear factor; LAC, Lupus anti-coagulant.

The inhibitor screen for patient 4 confirmed an extremely high inhibitor titer of 900 BU. This is the highest Factor VIII inhibitor titer recorded in our academic laboratory (for both congenital and acquired hemophilia A). Patient 4 defaulted further investigation and returned to the hospital 1 year later in June 2021 with a spontaneous hematoma of the left hand. Her thyroid stimulating hormone (TSH) level was markedly elevated at 138.7 mIU/ L (0.35-5.50mIU/ L).

Patient 4 had a history of chronic alcohol ingestion, and this was an additional challenge in the management and follow-up.

At diagnosis, all of the patients were counseled about their diagnosis and the acute bleed was managed with bypassing agents which included recombinant factor VIIa (Novoseven^®) and/or activated prothrombin complex concentrates (FEIBA^®). The patients were also started on Prednisone 1 mg/kg/day for inhibitor eradication.

Unfortunately, all of the patients defaulted treatment and we were unable to follow up on the responses to eradication of the inhibitor. The attempted telephonic follow-up by the Haemophilia health care nursing staff yielded no responses from the patients.

Discussion

Incidence

AHA is a rare bleeding disorder and patients present with bleeding and a prolonged APTT which does not correct with prolonged incubation with normal plasma. The reported incidence of AHA is 1.5 patients per million per year. ⁸ South Africa has the largest adult population living with HIV, representing 18% of the global population. ⁹ KZN, a province in South Africa has a population of 11.1 million and the province has the highest HIV prevalence, 18%.^9,10 It is therefore expected that KZN would be diagnosing at least 10 patients with AHA annually. However, over a study period of 10 years, our laboratory, which is the diagnostic laboratory for all state or government patients with suspected inhibitors in KZN, South Africa has only diagnosed these 5 patients with AHA. This highlights that AHA is an underdiagnosed condition in our setting, with potential missed diagnoses in some of our patients, and the need for education and raised awareness.

Patient Profile

All of our patients were female and they were HIV seropositive, unlike the literature which observes an equal male and female ratio. Four of the patients were more than 50 years of age supporting the peak that is observed in older men and women. ² However, our patients were younger compared to the reported peak age of more than 60 years of age. ¹¹ Female patients presenting with AHA are generally younger and pregnant. Our patients were female, with a background history of HIV, spontaneously bleeding, had prolonged APTT’s and no correction on the APTT after 50:50 mixing studies. These findings, together with the bleeding pattern were suggestive of AHA. All of patients presented with subcutaneous bleeding and/or mucosal bleeding which is similar to the most common type of bleeding observed in AHA. ² Our patients had a severe coagulation Factor VIII deficiency of less than 1% in keeping with a diagnosis of AHA. It is strongly recommended that clinicians have a high index of suspicion to investigate an unexplained prolonged APTT. This clinical approach is potentially life-saving as the mortality rate of AHA secondary to bleeding is between 7.9% and 22%. ¹ It is suspected that in our setting patients are not timeously diagnosed in the peripheral clinics or hospitals as APTTs are not routinely requested pre-operatively and/or there is limited investigation of a prolonged APTT.

Prolonged APTT Investigation

The causes of a prolonged APTT indicate a coagulation factor deficiency of the intrinsic and/or common pathways of the coagulation cascade or the presence of a circulating inhibitor. In resource-constrained settings where a Factor VIII level is not available timeously, a 50:50 mixing study with normal plasma assists in quickly differentiating the two considerations. The absence of correction of the APTT indicates an inhibitor that could be secondary to drugs, for example, heparin or dabigatran therapy, a circulating auto-antibody to factors VIII, IX, XI, XII or the presence of a lupus anticoagulant. A prolonged thrombin time which does not correct on 50:50 mixing studies suggests the effects of heparin or dabigatran. ¹² Correlation with the clinical and drug history is mandatory to determine which patients will require further investigation. ³ All of our cases were referred from peripheral hospitals and this emphasizes the dual roles of the clinical team and the laboratory staff to investigate a prolonged APTT (Figure 1).

Figure 1.

Diagnostic algorithm to investigate a prolonged APTT with a normal PT.

Pathogenesis of AHA

At diagnosis, all of the patients were on antiretroviral therapy and the majority of our patients were started on ART therapy more than 2 years preceding the diagnosis of AHA which makes immune reconstitution inflammatory syndrome (IRIS) an unlikely contributory factor. ¹³

Shein et al ¹⁴ from Cape Town, SA compared two HIV-positive patients with AHA to two HIV-negative patients with AHA and compared their small case series to the known patients reported in the literature. The Factor VIII inhibitor titer was higher in the HIV-positive patients and the Factor VIII level was usually <1%. These findings are similar to our group of HIV seropositive patients.

Patient 1 had antibodies to anti-cardiolipin, and Patient 4 had a reduced free T4, increased TSH and the consideration was autoimmune thyroiditis. Further testing for anti-thyroid antibodies would have been requested if the patient returned for follow-up visit. This stresses the importance of investigating for an underlying cause of AHA.

Management of Acute Bleed

The management of AHA includes the prevention of bleeding, obtaining hemostasis timeously, eliminating the autoantibodies with immunosuppressive therapy, and treating the underlying cause. The treatment modalities available internationally include recombinant porcine Factor VIII (rpFVIII), recombinant factor VIIa (rFVIIa), activated prothrombin complex concentrates (APCC), and desmopressin in patients with low inhibitor titers. Antifibrinolytic agents, for example, tranexamic acid may be used as adjunctive therapy however caution is advised in patients receiving bypassing agents (APCC), as there is an increased risk of thrombosis.^3,15,16 In our setting, all patients diagnosed with AHA are transferred to the Hemophilia care unit in KEH for definitive management of the acute bleed as bypassing agents are not easily available in the district hospitals.

The management of our patients included immediate hemostatic management with recombinant FVIIa and/or APCC and corticosteroids. When patients present with an acute bleed, the cost of therapy escalates with the combination of hospital admission costs, supportive treatment, and the use of bypassing agents. All of our patients defaulted treatment.

Our center’s experiences highlight the difficulties of managing AHA in a resource-constrained setting, where the use of recombinant therapy and monoclonal antibodies has to be strategic: considering cost of treatment and the availability of the treatment. Prompt referral of patients to a clinical hematology unit is mandatory for expert advice and management. The summary of our patients reinforces the importance of investigating an isolated prolonged APTT and raises awareness of a rare and potentially fatal disease. It is a concern that only 5 patients were diagnosed and referred to the hemophilia care unit over our ten-year retrospective review, and in view of the HIV prevalence in our province the findings suggest that patients are not diagnosed timeously and may demise prior to investigations and management at a health care facility.

Conclusion

AHA is a rare auto-immune condition and there is an association with HIV infection which was seen in all of our patients. The combined KZN population statistics and the HIV prevalence suggest that AHA is under-diagnosed in our setting. The mortality rate of AHA is high owing to lack of awareness and late recognition of the disease. Prompt investigation of an unexplained APTT and timeous referral to a hematology unit may help to improve patient outcome. All 5 of our patients defaulted treatment and this reinforces the difficulty of managing this rare condition with expensive bypassing agents in the public healthcare sector.