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3 nonstandard abbreviations.

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A 24-Year-Old Man with Previously Diagnosed Hemophilia

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Francesca Khani, Mikhail Roshal, A 24-Year-Old Man with Previously Diagnosed Hemophilia, Clinical Chemistry , Volume 58, Issue 7, 1 July 2012, Pages 1086–1089, https://doi.org/10.1373/clinchem.2011.166728

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A 24-year-old Middle Eastern man diagnosed with hemophilia at the age of 4 or 5 years presented to the hematology clinic for follow-up after a recent hospitalization for excessive bleeding from an accidental knife cut. The patient reported a history of prolonged bleeding after teeth extractions, an upper gastrointestinal bleed 3 years previously, and excessive bruising since childhood. He denied hemarthroses but reported chronic pain in his ankles and joints. The patient reported having been treated for episodes of excessive bleeding with fresh frozen plasma (FFP) 3 and factor VIII during past hospitalizations. Because of poor continuity of care, his disease had not been monitored or treated on an ongoing outpatient basis. The patient's family history is noteworthy for consanguineous parents (first cousins) and a sister who also experienced excessive bleeding, although her diagnosis was uncertain. Initial laboratory test results included a normal complete blood count, including platelets, a prolonged activated partial thromboplastin time (aPTT), and a prolonged prothrombin time (PT) ( Table 1 ). Fibrinogen activity was normal. A 1:1 mixture of the patient's plasma with pooled normal plasma demonstrated full correction of the PT and aPTT, a result consistent with factor deficiency.

Patient's laboratory results (citrated plasma).

Additional patient data and differential diagnosis.

Patients with isolated hemophilia A, B, or C (due to deficiencies in factors VIII, IX, and XI, respectively) or factor VIII deficiency due to von Willebrand disease typically have a prolonged aPTT but a normal PT. In the absence of anticoagulation therapy or suspected vitamin K deficiency, a prolonged PT in this patient's initial workup should raise clinical suspicion for a bleeding disorder of a different etiology. Given the patient's clinically notable bleeding symptoms since childhood, a genetic disorder should be considered. The differential diagnosis includes dysfibrinogenemia, prothrombin deficiency, factor V deficiency, combined deficiency of factors V and VIII (F5F8D), factor X deficiency, and hereditary combined deficiency of the vitamin K–dependent clotting factors. All of these conditions feature prolongation of both the PT and the aPTT ( 1 ). Given the results of the mixing studies, we subsequently evaluated factor activities ( Table 1 ).

How do the coagulation studies for this patient differ from those typically seen for patients with hemophilia?

What are possible causes of simultaneous prolonged PT and prolonged aPTT?

What further coagulation studies would you recommend in evaluating this patient?

The results of additional coagulation studies strongly suggested a diagnosis of F5F8D, because activities of factors V and VIII activities were markedly decreased. Also, factor VII activity appeared to be slightly increased, but this finding was considered unlikely to be of clinical consequence. F5F8D is a genetic condition that is often misdiagnosed as a single-factor deficiency condition such as hemophilia A, particularly in institutions with limited diagnostic resources in hematology ( 2 ). The inheritance pattern and pathogenesis of these 2 genetic disorders are distinct and are important for both therapeutic and genetic-counseling purposes. This scenario underscores the importance of further laboratory investigation when initial testing appears to be inconsistent with the patient's supposed diagnosis.

In the coagulation cascade, factors V and VIII are glycoprotein cofactors for the proteolytic activation of prothrombin (factor II) by factor X and of factor X by factor IX, respectively, and thus are essential for clot formation. F5F8D is a rare autosomal recessive disorder in which plasma concentrations of factors V and VIII are both decreased, thus leading to the symptoms of excessive bleeding. The incidence of this condition is approximately 1 in 1 000 000 in the general population but reportedly is more prevalent among Middle Eastern Jewish and non-Jewish Iranian populations, for which the incidence is estimated to be 1 in 100 000. The higher degree of consanguinity in these populations is thought to partially explain the higher prevalence of this autosomal recessive disorder ( 3 ).

F5F8D is genetically distinct from isolated inherited deficiencies of factor VIII (hemophilia A) and factor V (parahemophilia). Although having hemophilia A and a concurrent factor V deficiency is possible, such a combination is much less probable given the distinct inheritance patterns of the 2 conditions. Family history is also important to onsider. Because this patient also has a sister with a similar bleeding disorder, it is unlikely that hemophilia A, which typically affects only males because of its X-linked inheritance, is the etiology ( 3 ). Clinically, patients with hemophilia A present in childhood similarly to those with F5F8D—easy bruising, nosebleeds, and severe bleeding after surgical procedures, dental extractions, and trauma. Menorrhagia and postpartum hemorrhage are common in affected women ( 1 ). Autosomal recessive factor V deficiency, which also presents in childhood and is associated with parental consanguinity, presents with easy bruising, nosebleeds, and mucous membrane bleeding, particularly within the oral cavity ;( 1 ). Hemarthroses, muscle hematomas, and spontaneous bleeding are less likely to be observed in patients with factor V deficiency and in those with F5F8D compared to patients with severe hemophilia A ( 1 ). The bleeding severity in patients with F5F8D is ultimately similar to that experienced by patients with similar deficiency levels of either of these factors alone ( 4 ). The results of the coagulation studies, the clinical presentation, and the family history for the patient described in this case indicate F5F8D as the most likely diagnosis. Molecular genetic testing would be needed to absolutely confirm this diagnosis. For diagnostic and treatment purposes, however, assays of factors V and VIII assays are sufficient ( 2 ).

Currently, mutations in either of 2 genes, LMAN1 4 (lectin, mannose-binding, 1) and MCFD2 (multiple coagulation factor deficiency 2), are believed to account for all cases of F5F8D. LMAN1 and MCFD2 encode proteins that form a calcium-dependent complex essential for transporting factors V and VIII from the endoplasmic reticulum to the Golgi apparatus in coat protein II–coated vesicles ( Fig. 1 ). Interestingly, factors V and VIII are the only cargo proteins known to be affected in patients with F5F8D. If the transport of other cargo proteins is affected, the deficiency likely is not large enough to produce a clinical phenotype ( 2 ), ( 5 ).

Illustration of factor V (FV) and factor VIII (FVIII) transport from the endoplasmic reticulum to the Golgi apparatus, facilitated by the calcium-dependent LMAN1–MCFD2 complex.

FV and FVIII leave the endoplasmic reticulum in coat protein II (COPII)-coated vesicles and are further modified in the Golgi apparatus before exiting the cell.

CLINICAL MANAGEMENT

As in most bleeding conditions, the guidelines for the clinical management of F5F8D are dictated by the severity of the disease. In F5F8D, both the nature of the bleeding and the activities of factors V and VIII activities are used to guide therapy. Regular prophylaxis is not usually necessary unless the patient has recurrent severe hematomas and hemarthroses ( 2 ). For minor bleeding episodes, factor VIII activity should be increased to 30%–50% of normal; for more-severe bleeding episodes, factor VIII activity should be increased to 50%–70%. For bleeding episodes in general, factor V activity should be increased to 25% ( 1 ). Sources of both factors are required for adequate hemostasis. Because no factor V concentrates are available at this time, FFP is the only product available for factor V replacement. Although FFP theoretically may be used to replace both factors, it is important to remember that factors V and VIII differ in the recommended concentrations needed for hemostasis and have different plasma half-lives (36 h for factor V and 10–14 h for factor VIII) ( 5 ). Thus, replacing factor VIII with FFP alone would necessitate substantially more exposure to blood products. Factor VIII concentrates can be used to supplement FFP to achieve an adequate factor VIII concentration. Numerous types of factor VIII concentrates are available and are in widespread use for patients with hemophilia A. Desmopressin has been reported to be useful for minor bleeding episodes in F5F8D to further increase the factor VIII concentration ( 6 ). Patients undergoing surgical procedures require appropriate prophylactic therapy: administration of factor VIII concentrates every 12 h to maintain the factor VIII activity at >50% and FFP every 12 h to achieve the factor V activity at >25%, until wound healing occurs ( 1 )

Clinical and family histories pertaining to bleeding abnormalities are extremely important in evaluating hereditary coagulation disorders.

Further laboratory investigation is necessary when supposed diagnoses, family history, and the results of initial laboratory studies are inconsistent.

Although rare, F5F8D should be suspected in patients who claim to have hemophilia and have a prolonged PT and a prolonged aPTT, particularly if they are of Middle Eastern heritage and/or have a family history of consanguinity. It is therefore necessary to include factors V and VIII in testing for unexplained factor deficiencies in the setting of prolongation of both PT and aPTT.

In patients with F5F8D and an acute bleeding episode, both factor V and factor VIII need to be replaced. FFP must be given to replace factor V because no other source of factor V is currently available.

Human genes: LMAN1 , lectin, mannose-binding, 1; MCFD2 , multiple coagulation factor deficiency 2.

fresh frozen plasma

activated partial thromboplastin time

prothrombin time

combined deficiency of factors V and VIII

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

Bolton-Maggs PHB , Perry DJ , Chalmers EA , Parapia LA , Wilde JT , Williams MD et al . The rare coagulation disorders—review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation . Haemophilia 2004 ; 10 : 593 – 628 .

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Zhang B . Recent developments in the understanding of the combined deficiency of FV and FVIII . Br J Haematol 2009 ; 145 : 15 – 23 .

Spreafico M , Peyvandi F . Combined FV and FVIII deficiency . Haemophilia 2008 ; 14 : 1201 – 8 .

Peyvandi F , Tuddenham EG , Akhtari AM , Lak M , Mannucci PM . Bleeding symptoms in 27 Iranian patients with the combined deficiency of factor V and factor VIII . Br J Haematol 1998 ; 100 : 773 – 6 .

Spreafico M , Peyvandi F . Combined factor V and factor VIII deficiency . Semin Thromb Hemost 2009 ; 35 : 390 – 9 .

Mannucci PM , Duga S , Peyvandi F . Recessively inherited coagulation disorders . Blood 2004 ; 104 : 1243 – 52 .

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Treatment Monitoring

New approaches to treatment, competing interests, autoimmune (acquired) hemophilia: updates in diagnosis and therapy.

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Meera Sridharan , Rajiv K. Pruthi; Autoimmune (Acquired) Hemophilia: Updates in Diagnosis and Therapy. The Hematologist 2022; 19 (2): No Pagination Specified. doi: https://doi.org/10.1182/hem.V19.2.2022214

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Acquired hemophilia A (AHA) is an acquired bleeding disorder caused by neutralizing autoantibodies (inhibitors) against coagulation factor VIII (FVIII) with an incidence of 1.5 cases per million persons per year. 1   Most cases occur in older individuals (> 65 years old), of which approximately half have an underlying autoimmune disorder or malignancy; about 1 to 5 percent of cases occur in young females during pregnancy or the postpartum period. 1 - 4  

FVIII is a cofactor for FIXa activation of FX; the inhibitor interferes with this cofactor activity thus preventing thrombin generation and a hemorrhagic tendency. Typical clinical presentation is a new onset of bleeding of variable severity in the absence of previous personal or family history of bleeding. Mucocutaneous bleeding is the most common presentation. Unlike with severe congenital hemophilia A, hemarthrosis is rare. 1 , 2 , 5 - 7   Infrequently, asymptomatic patients may be detected on abnormal routine screening tests of hemostasis. 6 , 8  

Screening hemostatic assays shows a normal prothrombin time (PT) and thrombin time (TT), as well as a prolonged activated partial thromboplastin time (APTT; Figure 1 ). Depending on the sensitivity of the reagents used, APTT typically will be prolonged when FVIII activity (FVIII:C) decreases to 25 to 35 percent of mean normal. Prolongation of the APTT beyond 100 seconds is atypical for FVIII inhibitors and should raise the suspicion for alternative or co-existing causes such as presence of heparin or infrequently a lupus anticoagulant (LA) or deficiency of a coagulation contact factor (e.g., homozygous factor XII deficiency). Mixing studies with an equal volume of normal plasma typically demonstrates immediate inhibition of the APTT. Rarely, with low titer FVIII inhibitors, such inhibition is detectable only after a one- to two-hour incubation at 37°C. 9  

Evaluation of prolonged activated partial thromboplastin time (APTT). *Differential diagnosis: 1) deficiency of coagulation factor(s) (e.g., fVIII, IX, XI, XII, prekallikrein, or high-molecular-weight kininogen); 2) heparin contamination of specimen; 3) inhibitor to a specific coagulation factor (e.g.fVIII); 4) presence of a non-specific inhibitor (e.g.. lupus anticoagulant).

The traditional method of assessing factor VIII inhibitors is the Bethesda assay with Nijmegen modification, which provides the inhibitor titer in Bethesda units (BU). 10 , 11   The Bethesda titer can also be determined using chromogenic assays. 12   Alternative methods for detecting autoantibodies include qualitative enzyme linked immunoassays (ELISA), which are based assays that do not quantify the inhibitor titer (Table 1A; available as online supplement). 11 , 13  

Principles of management of patients with AHA involves a two-tiered approach of optimizing hemostasis and eradicating the inhibitor.

Hemostatic management. Options for hemostatic management include the use of bypassing agents (BPA; activated prothrombin complex concentrates [aPCC] or recombinant FVIIa [rFVIIa]) or recombinant porcine FVIII (rpFVIII: Obizur; Figure 2 ). There are no data to suggest superiority of one option. 14 , 15   For those without access to BPA or rpFVIII and in patients with low-titer inhibitors (<5 BU), initial therapy with human FVIII (hFVIII) is reasonable. 2   This generally results in an increase in inhibitor titer, thus rendering the hFVIII ineffective. However, for patients with high-titer inhibitors (>5 BU), hFVIII is most likely to be ineffective; therefore, every effort to secure BPA or rpFVIII should be made.

Recommendations regarding hemostatic and immunosuppressive therapy in patients with acquired hemophilia A per the 2020 International Recommendations. Adapted with permission from Tiede A et al. International recommendations on the diagnosis and treatment of acquired hemophilia A. Haematologica. 2020;105(7):1791-1801.

rpFVIII is effective in AHA due to differences in the A2 and C2 domains of the pFVIII and hFVIII molecule. 15 , 16   The advantage of U.S. Food and Drug Administration-approved rpFVIII is the ability to measure response to the infused product with FVIII:C. Anti-rpFVIII antibodies may be present for some patients at baseline while some will develop these antibodies after treatment with rpFVIII. The porcine FVIII inhibitor titer should be assessed if rpFVIII is being considered for treatment or if there is a change in treatment response as presence of cross-reacting anti-rpFVIII inhibitors may guide the dose of rpFVIII and identify patients for whom rpFVIII may not be efficacious. 2 , 15  

Inhibitor eradication. Options for eradication of the inhibitor with immunosuppressive (IST) therapy include initial use of glucocorticoids with consideration to add adjunctive agents such as cyclophosphamide or rituximab. The goal of IST is to shorten the time to achieve remission in AHA and decrease bleeding. Spontaneous remission may occur though rare. 2 , 17   Prospective data demonstrated that remission was unlikely within 21 days of steroid therapy if FVIII:C is less than 1 percent or the inhibitor titer was more than 20 BU. 18   Recent guidelines recommend the use of combination therapy with glucocorticoid and either cyclophosphamide or rituximab in the first-line setting for those with FVIII:C less than 1 percent or high inhibitor titer of more than 20 BU. For other patients, first-line monotherapy with glucocorticoids is sufficient ( Figure 2 ). 2  

Hemostatic monitoring. Treatment response is assessed clinically (i.e., control of bleeding) and with laboratory assays for rpFVIII. There are currently no routinely available assays assessing response to BPA (Table 1B; available as online supplement). 19 , 20   If the patient is not responding to treatment with one hemostatic agent, an alternative should be trialed.

Remission. Evidence of eradication of the inhibitor is based on FVIII:C and Bethesda assays. Once remission is achieved, monitoring with FVIII:C should still be performed (monthly for the first 6 months, then every 2-3 months up to 12 months, then every 6 months). 2  

Pending eradication of the inhibitor, patients may experience recurrent hospitalization for bleeding, or some patients may have contraindications to IST. The role of emicizumab, a bispecific FVIII-mimetic antibody, was recently demonstrated for management of AHA. 21   In newly diagnosed patients with AHA with contraindication to IST, short-term use of emicizumab and reduced intensity IST led to hemostatic efficacy with BPA discontinuation after 1.5 (1-4) days of emicizumab initiation. Chromogenic FVIII:C was more than 50 percent after median of 115 (67-185) days and emicizumab was discontinued after a median of 31 (15-79) days. 21  

A caution for FVIII:C monitoring while using emicizumab therapy is that emicizumab falsely elevates the one-stage FVIII:C assay. Chromogenic FVIII:C based on bovine reagents is the optimal assay (Table 2; available as online supplement). 19   Additionally, in clinical trials of congenital hemophilia A using emicizumab, use of high doses of APCC (>100 units/kg/day) for management of breakthrough bleeding resulted in thrombotic microangiopathy. 22   Therefore, the optimal agent for breakthrough bleeds in this situation is rFVIIa. Further prospective studies are needed to confirm these pilot studies and answer many questions regarding duration of therapy and optimal patient with AHA for whom to consider use of emicizumab.

AHA is a potentially life threatening acquired bleeding disorder. Early recognition and initiation of hemostatic therapy and IST has resulted in a reduction in morbidity and mortality. The role of emicizumab is evolving.

Dr. Sridharan and Dr. Pruthi indicated no relevant conflicts of interest.

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Case Study: Emerging Therapies in Hemophilia

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A 27-year-old man with a history of severe hemophilia A presents for follow-up after a recent hospitalization for a bleeding episode in his knee. His hospitalization was complicated by the presence of a high-titer factor VIII inhibitory antibody measured at 13 Bethesda units (BU), prompting the use of recombinant factor VIIa to control his bleeding.

On examination, his titer remains elevated at 9 BU. Options to best control further bleeding episodes are being considered, including initiation of immune tolerance induction (ITI) to eliminate his inhibitor.The patient asks if there are newer therapies that are on the horizon to prevent bleeding in hemophilia A. Data from the recently published phase III HAVEN 1 Trial report that patients with hemophilia A treated with weekly emicizumab prophylaxis, compared to no prophylaxis, had a lower rate of annualized bleeding events.

What is the mechanism of action of emicizumab?

• A bispecific monoclonal antibody binding activated factor IX and factor X
• Monoclonal antibody that blocks the tissue factor pathway inhibitor (TFPI)
• Monoclonal antibody that inhibits anti-thrombin III by a linked small interference RNA
• Recombinant fusion protein that binds activated factor IX and factor X

Explanation

Emicizumab (answer A) is a bispecific monoclonal antibody binding factor X and activated factor IX, effectively restoring the function of the missing factor VIII. The HAVEN 1 Trial was a phase III open-label, multicenter trial primarily assessing annualized bleeding rates with use of weekly prophylactic emicizumab versus no prophylaxis in hemophilia A patients who were previously receiving episodic factor VIII bypassing agents. At 24 weeks, annualized bleeding rate in the emicizumab prophylaxis group was 2.9 events compared to 23.3 events in the no prophylaxis group( p<0.001). This represents an 87 percent decrease in annualized bleeding rates with use of emicizumab. Quality of life scores were also significantly higher in the emicizumab group. However, approximately 47 percent of subjects on emicizumab prophylaxis required activated prothrombin complex concentrate (aPCC) and/or recombinant factor VIIa.

Conicizumab (answer B) is a monoclonal antibody that blocks TFPI. TFPI helps regulate initiation of thrombin generation and has three separate domains that bind to tissue factor-factor VIIa, bind and inhibit factor Xa, and interact with protein S, respectively. Conicizumab interferes with factor Xa binding domain, and patients are currently being enrolled in a phase II trial.

Fitusiran is an investigational small RNA interference (RNAi) agent that targets antithrombin messenger RNA to improve thrombin generation and promote hemostasis in patients with hemophilia. It is not a monoclonal antibody (answer C). In a phase I dose escalation trial, once-monthly subcutaneous fitusiran injections resulted in increased thrombin generation. Of note, the population studied did not have inhibitory antibodies. Fitusiran resulted in decreased bleeding episodes and appeared to be well tolerated. Further enrollment of subjects onto this study has been put on hold due to the death of a subject, related to cerebral sinus venous thrombosis.

Recombinant factor VIII Fc fusion protein (answer D) has a half-life that is 1.5 times longer than standard recombinant factor VIII (18.8 hours vs. 11 hours). The efficacy of recombinant factor VIII Fc fusion protein was demonstrated in two phase III studies: A-LONG in adults and Kids A-LONG in children. It is dosed prophylactically one to two times a week, with 30 percent of patients in the trial achieving a five-day dosing interval. 1-6

References 

• Arruda VR, Doshi BS, Samelson-Jones BJ. Novel approaches to hemophilia therapy: successes and challenges . Blood. 2017;doi: 10.1182/blood-2017-08-742312. [Epub ahead of print].
• Chowdary P, Lethagen S, Friedrich U, et al. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial . J Thromb Haemost. 2015;13:743-754.
• Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A . Blood. 2014;123:317-325.
• Nolan B, Mahlangu J, Perry D, et al. Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with hemophilia A . Haemophilia. 2016;22:72-80.
• Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors . N Engl J Med. 2017;377:809-818.
• Pasi KJ, Rangarajan S, Georgiev P, et al. Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy . N Engl J Med. 2017;377:819-828.

Case study submitted by Gemlyn George, MD, and Arun K Singavi, MD, of Medical College of Wisconsin, Milwaukee, WI.

American Society of Hematology. (1). Case Study: Emerging Therapies in Hemophilia. Retrieved from https://www.hematology.org/education/trainees/fellows/case-studies/emerging-therapies-hemophilia .

American Society of Hematology. "Case Study: Emerging Therapies in Hemophilia." Hematology.org. https://www.hematology.org/education/trainees/fellows/case-studies/emerging-therapies-hemophilia (label-accessed May 21, 2024).

"American Society of Hematology." Case Study: Emerging Therapies in Hemophilia, 21 May. 2024 , https://www.hematology.org/education/trainees/fellows/case-studies/emerging-therapies-hemophilia .

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• Published: 27 January 2023

A case report of haemophilia: a review of haemophilia and oral health implications

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British Dental Journal volume  234 ,  pages 92–95 ( 2023 ) Cite this article

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Haemophilia is an inherited haematological disorder that can result in prolonged bleeding in patients. Dental procedures such as extractions and periodontal surgery can be associated with post-operative bleeding; therefore, patients with the diagnosis of haemophilia must have proper medical management. In this article, we aim to illustrate the importance of: having the appropriate knowledge to manage a patient with haemophilia suspected by the dental team; the need for proper medical management; and referral of patients with symptoms of a bleeding disorder.

In mild form, haemophilia can remain undiagnosed until a procedure, such as dental extraction or periodontal therapy, is required. At that time, the first treatment provider might encounter prolonged bleeding.

Although haemophilia is a rare condition, it is likely that at some stage, a dental practitioner may need to manage a patient and knowledge of heritable bleeding disorders and their management is essential.

People with haemophilia require close liaison with their clinician and team regarding management and augmentation of the clotting factor deficiency to prevent delayed and prolonged bleeding.

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Acknowledgements

The authors would like to thank Dr. Gita Massey MD, Associate Professor at Virginia Commonwealth University, Department of Haematology and Oncology, for her edits to the manuscript.

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Paediatric Dental Resident, Bon Secours St Mary´s Hospital Program for Advanced Paediatric Dental Education, 6900 Forest Ave, Suite 110, Richmond, Virginia, 23230, USA

Shreya Desai

Research Course Director, Bon Secours St Mary´s Hospital Program for Advanced Paediatric Dental Education, 6900 Forest Ave, Suite 110, Richmond, Virginia, 23230, USA

Elizabeth J. Berry

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John H. Unkel

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Desai, S., Berry, E., Unkel, J. et al. A case report of haemophilia: a review of haemophilia and oral health implications. Br Dent J 234 , 92–95 (2023). https://doi.org/10.1038/s41415-023-5448-y

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• Published: 25 January 2022

Acquired hemophilia A (AHA): underreported, underdiagnosed, undertreated medical condition

• Doaa M. El Demerdash   ORCID: orcid.org/0000-0002-5061-9536 1 ,
• Alia Ayad 1 &
• Noha Tawfik 1  

The Egyptian Journal of Internal Medicine volume  34 , Article number:  12 ( 2022 ) Cite this article

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Acquired hemophilia A (AHA) is a rare acquired bleeding disorder occurred due to the formation of inhibitory antibodies neutralizing endogenous factor VIII.

About half the cases are idiopathic. Symptoms include severe and unexpected bleeding that could be life-threatening. High index of suspicion should be raised when unexplained subcutaneous or post-surgical bleeding with isolated prolonged APTT.

Conclusions

Acquired hemophilia A is a rare underdiagnosed underreported acquired hemostatic disorder that presents with sudden usually life-threatening bleeding; it is crucial to raise awareness and suspicion index of clinicians for early diagnosis and treatment to avoid morbidity and mortality.

Acquired hemophilia A (AHA) is a rare bleeding disorder; it is an underreported condition because of the severity of AHA at presentation with life-threatening bleeding especially in the elderly in whom other bleeding conditions may coexist; also, it is underdiagnosed due to rarity and the unawareness of the condition which sometimes presented to surgical wards, and this may lead to delayed diagnosis hence worse outcome [ 1 ]. Our aim in this review article is to raise the awareness of the underreported acquired cause of bleeding.

Acquired hemophilia recurrent scenario

To clarify this recurrent scenario here, one of our cases, a female patient, 32 years old, G2P1, presented to the obstetric department for normal vaginal delivery without any previous known medical problems. She had hemoglobin (Hb%) of 11 g/dl with a normal baseline coagulation profile. Her puerperium was complicated by excessive vaginal bleeding with a drop in her hemoglobin from 11 to 6.8 g/dl. Hysterectomy was performed for the persistent vaginal bleeding that was complicated by intra-abdominal hemorrhage. Her condition continued to deteriorate; the gynecologist feels that something was wrong with no obvious obstetric cause of bleeding, and she was referred to ICU with a diagnosis of DIC. Her labs on admission are summarized in Table 1 ; the striking result noticed was an isolated prolonged APTT. The striking result noticed was an isolated prolonged aPTT, with normal platelets count, normal PT, and slightly elevated d-dimer and FDP, and that is why the diagnosis of DIC was not convincing

Acquired hemophilia A (AHA) which is a severe acquired rare bleeding disorder. It is a rare bleeding disorder; in the reported cases, only 1–1.5 per million persons are affected yearly [ 2 ], AHA characterized by suddenly appearing autoantibodies (inhibitors) that partially or completely neutralize the activation or function or accelerate the clearance of factor VIII [ 3 ].

Although it is like well-known congenital hemophilia in lacking factor VIII activity and hence bleeding tendency, but it is totally different from the well-known congenital hemophilia as It affects both males and females without previous family or personal history of bleeding while congenital hemophilia affects only males with a long history or family history of bleeding [ 4 ].

AHA incidence is typically observed in old age (> 60 years old) but another peak is noticed in middle age females especially with reported postpartum AHA cases [ 5 ].

Etiology is unknown in half of the reported cases but reported associated conditions (Table 2 ) in the other half were solid and hematological malignancies, autoimmune conditions such as SLE, dermatological conditions as pymphygus, drug-induced, pregnancy, and recently reported with COVID-19 and post COVID vaccines [ 11 , 12 ].

The cause of bleeding tendency is the same in both classic and AHA which decrease in the factor VIII activity. However, the clinical manifestation is not identical; in classic congenital hemophilia, usually, spontaneous bleeding into joints is typical, while in AHA, type of bleeding is different which is massive subcutaneous blood extravasations and mucosal hemorrhages [ 13 ].

The bleeding phenotype in AHA is variable ranging from mild to life-threatening bleeding, and there is poor correlation between FVIII level and inhibitor titer at presentation with bleeding severity unlike the congenital hemophilia bleeding phenotype [ 14 ].

The mortality rate is 41% if AHA patients are not treated: within the 1st week of presentation, mortality occurs due to GIT and lung bleeding Later, mortalities are usually from intracranial and retroperitoneal hemorrhages [ 15 ].

It is worth to be noted that 10% of patients do not present with bleeding and accidentally discovered with laboratory workup; therefore, a prolonged APTT should never be ignored prior to invasive procedures [ 16 ].

Post-partum acquired hemophilia A

We must focus on the entity which is postpartum acquired hemophilia in which there is spontaneous development of autoantibodies (inhibitors) against factor VIII during the peripartum period; it is reported in 7–21% of AHA cases [ 10 ]. Documented cases of postpartum AHA in EACH2 registry which included 501 AHA cases from 117 hemophilia centers in 13 European countries was 42 (8.4%). Mortality due to hemorrhage in these cases varies between 12 & 22% [ 17 ]. It Should be suspected in postpartum or pregnant patients who hemorrhage for no apparent cause and who have no previous history of bleeding disorders. Post-partum AHA usually appear after the 1st pregnancy in 80% of the cases. Most reported cases arise from 1 to 4 months after delivery, but some cases presented up to 1 year after delivery [ 18 ].

It commonly presents as severe ecchymosis, soft tissue hematomas, and severe life-threatening hemorrhage. Vaginal bleeding could be the presenting symptom if the inhibitor appears early in the course, so it is usually misdiagnosed by an obstetrician especially with no previous bleeding or family history in presented females with postpartum unexplained bleeding. Intraplacental transfer of antibodies and intracerebral hemorrhage in neonates are reported in few cases [ 19 ].

AHA laboratory workup

Laboratory workup of a suspected case of AHA especially in the setting of unexplained bleeding associate with an isolated prolonged aPTT without previous medical or family history of bleeding should include measuring factor VIII activity and its inhibitor in those patients.

Initial workup

Individuals present with new-onset bleeding without previous history of bleeding disorders. Labs will show an isolated increase in aPTT with a normal PT, platelet count, and thrombin time. This points to either a deficient factor VIII or the presence of a factor VIII Inhibitor.

Therefore, a mixing study must be ordered to determine the cause. If there is a factor deficiency, the results will show a correction of PTT. If there is a factor inhibitor present, the PTT will remain elevated and uncorrected or partially corrected [ 2 ].

Confirmation test

Factor VIII activity test to exclude the presence of antiphospholipid antibodies and Bethesda assay to measure the strength of the inhibitors in the plasma, expressed in Bethesda units [ 20 ]. Workup of a case with AHA is summarized in Fig. 1 .

Workup of a case of AHA

Why acquired hemophilia A is undermanaged?

AHA is a rare but potentially lethal disease this make it underreported, no comparative clinical studies are available in AHA, the severity of the clinical condition of patients at presentation, and the decisions are often based on the clinical experience of treating physicians, all these factors lead to undermanagement of AHA [ 21 ].

Management of AHA is representing a medical challenge from its diagnosis to its treatment, the early initiation of Therapy results in higher efficacy. The only parameter that differed between patients who responded to treatment and those who did not was a delay in time to treatment [ 22 ].

Optimal management included the use of “bypass” agents when active bleeding presents, altogether with active inhibitor eradication through immunosuppressant drugs, the 2 lines of treatment should be started aside with most importantly treatment of any underlying condition, e.g., autoimmune disease. Further recommendations should include avoidance of invasive procedures that may induce bleeds even sampling of blood or inserting IV cannula [ 23 ].

Control bleeding if present

Lines to control the acute bleeding includes:

Bypassing agents: Recombinant Factor VIla (rFVIIa) or FEIBA, activated prothrombin complex concentrate (APCC)

Recombinant porcine factor VIII rpFVIII (susoctocog alfa)

Registries data did not show a clear efficacy or safety benefit of one drug over the others.

Recombinant Factor VIla (rFVIIa)

It is given as 90 μg/kg bolus at every 2 h, Cases of mild bleeding, one or two doses of rFVIIa may be sufficient. Once hemostasis has been achieved, the dose interval can be increased successively to every 4, 6, 8, or 12 h when indicated. rFVIIa controls bleeding at the site of vascular injury only. Its safety profile includes that thrombotic events of rFVIIa <1% with an ~800,000 doses, it is not contraindicated for use with anti-fibrinolytics, it is a pure FVII, with no risk of anamnesis, and also it is a recombinant product with no risk of viral transmission [ 24 ].

FEIBA, an activated prothrombin complex concentrate (aPCC)

It includes factor II, VII, IX, X, and small amount of factor VIIIa. Also, it includes natural anticoagulant (protein C and S) in physiological balance. aPCC doses in the range of 50–100/kg units every 8–12 h are given by intravenous infusion. it is important not to exceed a total of 200 units/kg within a 24-h period as this may be associated with a risk of VTE or DIC. We must point out that tranexamic acid should not be given together with this agent [ 25 , 26 ].

It could be given in cases of AHA as human anti-FVIII autoantibodies have low cross-reactivity with porcine FVIII, it could be given in Patients with AHA with a serious bleed but it should be excluded if they had an anti-rpFVIII inhibitor titer >20 BU.

rpFVIII dose of 200 U/kg, followed by further doses to maintain trough levels of factor VIII >50% .close monitoring of FVIII activity during therapy is recommended to avoid the theoretical risk of thrombosis while there were no thromboembolic events reported [ 27 ].

Eradications of inhibitors by immunosuppressants

In all patients with AHA, they should receive immunosuppressants to eradicate inhibitors in form of corticosteroids alone or plus either rituximab or cytotoxic agents, while speaking about steroid therapy mentions that oral prednisone is the preferred one [ 28 ]. If FVIII ≥1 IU/dL and inhibitor titer ≤20 BU at baseline receive 1st line treatment with corticosteroids alone for 3–4 weeks is recommended, but If FVIII <1 IU/dL or inhibitor titer >20 BU it is suggested combining corticosteroids with rituximab or a cytotoxic agent for 1st line therapy. If no response to 1 st line therapy 2nd line therapy with rituximab or a cytotoxic agent, whichever was not used during first-line therapy is suggested, immune tolerance induction in AHA. Or high-dose intravenous immunoglobulins for inhibitor eradication in patients with AHA are not recommended [ 21 ].

Because relapse has been reported in approximately 1 in 5 patients after immunosuppressive therapy is discontinued. The assessment of the response requires follow-up of factor VIII activity and inhibitors assay. It is recommended of using FVIII:C monitoring monthly during the first 6 months, every 2–3 months up to 12 months, and every 6 months during the second year and beyond, if possible [ 21 ] (Table 3 ).

Table 2 summarizes 2020 International recommendations of immunosuppressive therapy in the treatment of acquired hemophilia A.

Back to presented scenario

workup of the patient was continued as a case presented with isolated prolonged aPTT. Laboratory results confirm the diagnosis of postpartum AHA as demonstrated below.

Diagnosis of postpartum AHA was confirmed by doing mixing studies for aPTT which was not corrected by adding normal plasma which confirm the presence with of inhibitor, absence of antibodies for antiphospholipid altogether with a reduced level of factor VIII, and presence of FVIII antibodies in our case confirm the final diagnosis of postpartum AHA (Table 4 ).

Her bleeding was life-threatening and massive due to late diagnosis and management, also it was aggravated by the surgical intervention (hysterectomy), as we must point out that any surgical intervention may aggravate antibodies formation and hence the severe bleeding [ 28 ].

To stop bleeding, rFVIIa was given 90 mic/kg every 2 h then gradually spaced to be every 6 h, 12 h, and 24 h (12 doses were needed till regression), prednisone 1mg/kg/day was added (4 weeks duration) to eradicate inhibitor, her course was stable apart from intermittent symptoms and prolongation of APTT which mean persistent inhibitor rituximab was added in a dose of 375 mg/m 2 for 4 doses, and resolution of inhibitors was achieved after 3 weeks of initiation of added rituximab.

Acquired hemophilia A is a rare underdiagnosed underreported acquired hemostatic disorder that presents with sudden usually life-threatening bleeding, it is crucial to raise awareness and suspicion index of clinicians for early diagnosis and treatment to avoid morbidity and mortality.

Availability of data and materials

Not applicable

Abbreviations

Acquired hemophilia A

Activated prothrombin complex concentrate

Activated partial thromboplastin time

Bacille Calmette-Guerin

Bethesda unit

Coronavirus sisease

Disseminated intravascular coagulation

European Acquired Hemophilia Registry

Fibrin degradation products

Factor eight inhibitor bypass activity

Gastrointestinal tract

Intensive care unit

Recombinant porcine factor VIII

Systemic lupus erythematosus

Venous thromboembolism

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Doaa M. El Demerdash, Alia Ayad & Noha Tawfik

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El Demerdash, D.M., Ayad, A. & Tawfik, N. Acquired hemophilia A (AHA): underreported, underdiagnosed, undertreated medical condition. Egypt J Intern Med 34 , 12 (2022). https://doi.org/10.1186/s43162-021-00074-9

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DOI : https://doi.org/10.1186/s43162-021-00074-9

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The 'Royal Disease'

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This case deals with the genetics of the hemophilic condition that afflicted the royal families of Europe.  Students trace the pedigrees of the descendants of Queen Victoria and the passage of the recessive X-linked trait from ancestor to ancestor. The case is suitable for courses in general biology at either the high school or college level.

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• Provide a real example of pedigree analysis of a sex-linked trait.
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Hemophilia; haemophilia; hemophiliac; recessive disorder; genetic disease; sex-linked trait; blood; hemoglobin; Queen Victoria; Tsarevich Alexei Nikolaevich; Romanovs

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A Case of Hemophilia A Presenting in a Neonate and a Review of the Literature

Esther kisseih.

1 Children’s Hospital of Michigan, Detroit, MI, USA

Neeraja Yerrapotu

Deepak yadav, melissa february, introduction.

Hemophilia A is an X-linked hereditary condition caused by decreased factor VIII activity, which predominately occurs in males. 1 Severe hemophilia occurs when circulating levels of a factor are less than 1% of normal activity in the blood and is typically diagnosed in the first 2 years of life. 2 Early identification of these patients is essential since they are at risk for spontaneous life- or limb-threatening bleeding and disability resulting from repeated joint bleeding. 3 Hemophilia A and B are X-linked recessive disorders, which explains their preponderance in males. Genetic studies reveal that majority of hemophilia A cases are due to an inversion of the long arm of chromosome X. 4 Hemophilia A, which is the deficiency of factor VIII, occurs with an incidence of 1 in 500 to 10 000 males. 5 Diagnostic criteria for hemophilia include confirmation of a factor activity level below 40% of normal (below 0.40 IU/mL), or a hemophilia gene mutation. A normal von Willebrand factor antigen should also be documented in patients with reduced factor VIII activity levels, to eliminate the possibility of von Willebrand disease. Severe hemophilia is a relatively uncommon condition in the newborn period and usually manifests within the first year to 1½ years of life with easy bruising, hemarthrosis, bleeding due to oral injury, or after an invasive procedure. 6 Hemophilia can also be diagnosed in the absence of a family history with the initial presentation of bleeding in the neonatal period. Moderate and mild hemophilia, on the other hand, are defined as factor 8 levels >1% to <5% and >5% to <40%, respectively. 7 , 8

Final Diagnosis

We report a case of severe hemophilia presenting in a newborn after circumcision.

Hospital Course

An African American male infant born via vaginal delivery to a 23-year-old gravida 3 para 1 woman at 40 weeks gestation. Pregnancy was unremarkable.

The infant’s APGARs were 9 at 1 and 5 minutes, with no complications.

Birth parameters were birth weight of 2.94 kg, the birth length of 50 cm, and head circumference of 34 cm. Examination revealed a small for gestational age (SGA) baby with caput succedaneum and an extra digit on the right hand. The neonate was monitored in the newborn nursery. Baby received 1 mg of vitamin K with no feeding issues noted. Blood was drawn for complete blood count (due to SGA status) as well as blood typing.

Laboratory workup on day 1 revealed a white cell count of 11.5 k/mm 3 , hemoglobin of 21.7 gm/dL, hematocrit of 61.3%, with a platelet count of 32 k/mm 3 ; on repeat, platelets were 183 k/mm 3 . The infant’s blood type was B positive, and the antibody screen was negative.

On the second day of life, the patient was circumcised after which there was bleeding noted from postcircumcision frenulum tears. Pressure dressing was applied. Over the next 5 hours, the bleeding worsened with staff having to change 3 soaked pressure dressings. During that time the patient was also noted to have prolonged bleeding from prior heel sticks. The patient was transferred to the neonatal intensive care unit, and due to concerns of bleeding diathesis labs were sent for coagulation studies: factor VIII activity, factor IX activity, factor XIII activity, von Willebrand factor antigen/activity, platelet function assays along with a complete blood count. Hematology and urology were consulted.

Results were significant for a partial thromboplastin time of >200 seconds (23.1-33.1), D-dimer of >35.2 mg/L, and a fibrinogen level of 103 mg/dL (186-486 mg/dL). The patient was given cryoprecipitate for the presumed diagnosis of hemophilia as well as due to low fibrinogen while awaiting the remaining test results.

Remaining lab work showed factor VIII level <1%, factor IX activity 9%, von Willebrand factor activity level 134% (43% to 138%), and von Willebrand antigen of 102% (60% to 153%). Platelet function testing with screening epinephrine was 119 seconds (100-163), and a platelet factor ADP of 78 seconds (57-114).

Once factor VIII deficiency was established, recombinant factor VIII was provided to the baby and bleeding subsided after replacement. Due to an increased risk of intracranial hemorrhage in patients with hemophilia, an ultrasound of the head was performed, which did not show any evidence of intracranial hemorrhage.

The clinical care team went back and elicited further history from the family. On further questioning of the family, it became apparent that the maternal grandfather had hemophilia, which the mother was unaware.

In any child with bleeding symptoms, initial evaluation should include a complete blood count, prothrombin time, and activated partial thromboplastin time. Testing factor levels, platelet function, and fibrinogen can also be considered based on the initial lab testing. Consultation with a hematologist should occur with the slightest concern for an inheritable coagulation defect. While interpreting the test results during the newborn period, it is important to remember that normal ranges for newborns vary from adult values. The exception to this is factor VIII, which is at the normal adult range or mildly increased at birth. 9 Adult levels are also achieved in preterm infants, thusit is therefore possible to diagnose most cases of hemophilia A at birth. 10 Prenatal diagnosis of hemophilia via chorionic villus sampling is the most widely used method, 11 but amniotic fluid, fetal blood, and pre-implantation genetic diagnostics can also be used in selected cases. Prenatal diagnosis must be preceded by adequate genetic counseling and risk assessment of the potential carrier and subsequent support during the diagnostic process.

As per the United Kingdom Hemophilia Centre Doctors’ Organization Guideline approved by the British Committee for Standards in Hematology, the treatment of choice for both hemophilia A and B are recombinant factor VIII and recombinant factor IX concentrates, which carry the lowest risk of transmitting viral infection. 12 In a neonate with clinically significant ongoing hemorrhage, where hemophilia is suspected based on a prolonged activated partial thromboplastin time, it may be appropriate to administer fresh frozen plasma while the results of appropriate factor assays are awaited. In the event of a low fibrinogen level, as in this case, cryoprecipitate is considered the best choice.

In newborns with hemophilia, intracranial hemorrhage is the most life-threatening complication. 13 The cranial ultrasound should be undertaken before discharge in all neonates with severe or moderate hemophilia. 14

Severe hemophilia is not an absolute contraindication to circumcision. However, there is a wide range of variation in approaching this clinical scenario among pediatric hematologist with the major concern of inhibitor development. 15 Circumcision has to be deferred in a male neonate of carrier mother until hemophilia A is confirmed or ruled out.

Author Contributions

Esther Kisseih contributed to conception, design and drafting of the manuscript. Neeraja Yerrapotu contributed to data acquisition and drafting of the manuscript. Deepak Yadav and Melissa February reviewed and critically appraised the manuscript.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.