Heng Joo Ng

Acquired factor V inhibitor - A problem-based systematic review

Acquired factor V(FV) inhibitors as a rare bleeding disorder, poses a formidable challenge to treating physicians with limited evidence to guide its management. We systematically reviewed our experience in Singapore and the published literature to determine possible answers to clinical questions formulated on the manifestation and best management of non-bovine thrombin and non-congenital acquired FV inhibitors. The incidence in Singapore was 0.09 cases per million person years (3 cases over 10 years). Seventy-three other cases meeting pre-defined search criteria were found in the published literature. Bleeding occurred in 68.4% of these patients, with mucous membranes being the most common site. Intracranial and retroperitoneal bleeds carried the highest mortality. The mortality rate from bleeding was 12%. There was a tendency for FV levels and PT/aPTT prolongation to predict bleeding but not the inhibitor level. No consistently effective haemostatic agent could be determined, but platelet transfusion should probably be the first line therapy. Among bleeding patients, inhibitors tended to disappear faster with inhibitor elimination therapy (IET) compared to without IET (60 vs. 150 days, p=0.299). IET made no significant difference among non-bleeding patients (p=0.511) and is thus recommended for bleeding patients or those with high bleeding risk. Steroids as single agent IET was effective in the majority of patients. Logical management approaches may be drawn but are limited by small sample size, heterogeneity of reports, and potential publication bias. The inception of a comprehensive registry will provide more reliable data that may verify our findings.

Treatment and outcome of acquired haemophilia A with a standard conventional regimen in a cohort without associated conditions

Summary.  Acquired haemophilia A (AH) is a rare bleeding disorder with significant risk of mortality. We conducted a study on the treatment and outcomes of patients with AH diagnosed between 1998 and 2004 in our institution. Fourteen patients (age range 17–89, median 64) were followed‐up from between 10–64 months (average 32 months). Inhibitor levels ranged from 5 to 450 BU. Ten patients required either recombinant activated factor VIIa or prothrombin complexes for control of bleeding. All patients received a standard immunosuppressive regimen of prednisolone 1 mg kg day−1 and oral cyclophosphamide 50–100 mg day−1. In addition, nine patients received intravenous immunoglobulin. Complete remission (CR) was achieved in 88% (eight of nine evaluable patients) over durations ranging from 5–78 days (average 35 days). There were three mortality; from bleeding, sepsis and cerebral infarct. Two patients were lost to follow‐up. There were no relapses among patients achieving CR. Conditions associated with AH were not identified at diagnosis or subsequent follow‐up in all patients. This series represent one of the largest aetiologically and treatment‐wise, uniformed cohort of AH patients. Despite toxicity concerns, the combination of prednisolone and cyclophosphamide remain an effective regimen and should be among the first line of treatment choices, with careful patient selection.

Hereditary thrombophilia in an unselected cohort of venous thrombosis patients in Singapore

Aim Hereditary thrombophilic markers are commonly screened among patients diagnosed as having venous thromboembolism, but optimal patient selection and the goals of screening may differ between populations. Determining the patterns of hereditary thrombophilia may improve screening strategies. Method An unselected cohort of venous thromboembolism patients in three tertiary institutions in Singapore was prospectively tested for the prevalence of deficiencies of protein C, protein S, antithrombin III, factor V Leiden and prothrombin 20210 gene mutations. Results Among 384 patients screened, the prevalences of protein S, protein C and antithrombin III were 9.20%, 1.18% and 4.19% respectively. Only one patient was positive for the factor V Leiden mutation and none tested positive for the prothrombin 20210 gene mutation. At least 1 in 9 patients (11.52%, 95% CI 8.20 to 15.93) will test positive for one of the above markers in an unselected group of 269 patients who completed all tests. The exclusion of patients with clinical risk factors did not improve the detection rates, in comparison with those with obvious provoking clinical risk factors (11.72%, 95% CI 7.36 to 18.06 vs 11.29%, 95% CI 6.73 to 18.18). When upper age limits were set for thrombophilia screening by decades, a statistical difference in the likelihood of a positive thrombophilia screen between younger and older patient was seen for patients below 40 (p<0.001). Conclusion In Singapore and countries with similar demographics, hereditary thrombophilia screening should be confined to testing for protein C, protein S and antithrombin III.

Clinical utility of anti-Xa monitoring and differential sensitivity of prothrombin time assays: an illustrated case report

Novel oral anticoagulants (NOACs) are designed to avoid the need for monitoring of drug levels in routine clinical use. This has not impeded the development of laboratory tests for monitoring drug levels, but their place in routine clinical use of NOACs is currently contentious. Laboratory kits are now commercially available for measuring anti-Xa activity in patients given rivaroxaban (Bayer Healthcare AG, Leverkusen, Germany), an anti-Xa inhibitor. Besides such specific assays, rivaroxaban also affects routine coagulation tests such as the prothrombin time (PT). This effect is however dependent on the type of thromboplastin used.1 We describe our experience recently where access to anti-Xa monitoring and the differential sensitivity of two prothrombin assays were used to manage a difficult situation. A middle-aged woman with end-stage renal failure presented with deep vein thrombosis of the right lower limb. This occurred as a complication of heparin-induced thrombocytopenia (HIT) which developed 9 days after exposure to heparin used in haemodialysis and maintenance of patency of an internal jugular venous access catheter. HIT was suspected because of a precipitous drop in her platelet count from 177×109/L 3 days earlier to 61×109/L, together with the new onset of thrombosis. This was supported by a positive test result from the Asserachrom HPIA polyspecific antibody assay …

Mycophenolate in the remission induction of a patient with acquired haemophilia A.

joint damage have been the predominant recipients of FEIBA prophylaxis, often commencing years after the appearance of inhibitor. Whether arthropathy in inhibitor patients, especially the most problematic cases with persistent inhibitors, can be minimized with early prophylaxis remains a pressing clinical question. In one long-term study of early FEIBA prophylaxis in seven patients, no patient developed major joint damage during prophylaxis [5]. As individual patients can respond more fully to one bypassing agent than the other, both FEIBA and rFVIIa have earned a place in the armamentarium of the haemophilia treater. Nevertheless, as a prophylactic modality, FEIBA has been more extensively characterized. Data accumulated over the past decade have demonstrated encouraging effects of FEIBA prophylaxis on bleeding incidence, quality of life and joint function [5–8], and clinical research on this form of treatment remains active, as exemplified by two ongoing prospective trials. The PRO-FEIBA Study (ClinicalTrials.gov Identifier NCT00221195), a randomized crossover trial of patients with haemophilia A and high-titer inhibitors, is evaluating the effectiveness of FEIBA prophylaxis in reducing the incidence of bleeds. Additionally, bleeding frequency over a 12-month period of FEIBA prophylaxis will be compared with that of on-demand FEIBA treatment in a multinational parallel-group randomized trial (ClinicalTrials.gov Identifier NCT00851721).

A comprehensive study of current haemophilia care and outcomes in Singapore

As an island nation, Singapore has a small haemophilia population. Through a hybrid health care model which taps on state-funding, medical insurance, the national retirement savings fund and co-payment by patients, our haemophiliacs receive on-demand therapy as standard of care with opportunities for prophylactic treatment if indicated. Recently, we embarked on a comprehensive crosssectional review of our haemophilia A and B populations to determine their current demographic profile and clinical status in order to gauge the performance of our management model and permit forward planning. This study was conducted in 2013 at the three haemophilia treatment centres in Singapore: Singapore General Hospital (SGH), National University Hospital (NUH) and Kandang Kerbau Women’s and Children’s Hospital (KKH). SGH houses a Comprehensive Haemophilia Treatment Centre (CHTC) and maintains the National Haemophilia Registry. The Registry provided the baseline demographic information on our haemophiliacs while population and health care statistics on Singapore were obtained from the Department of Statistics, Singapore [1]. All haemophiliacs listed in the Registry were invited to participate in this study. Consenting participants answered a set of questionnaires that explores further details of their treatment, complications and socio-economic data. Participants above the age of 4 were also assessed by a site investigator for the status of their joints using the Haemophilia Joint Health Scores (HJHS) version 2.1 [2]. Joint assessments were only conducted in the absence of recent joint bleed or other acute joint symptoms. Data on factor concentrates usage in 2013 were obtained from units dispensing clotting factors at the respective hospitals. Singapore has 195 identified people living with haemophilia A and another 40 people with haemophilia B among a resident population of 3.85 million [2]. The prevalence of haemophilia A and B is 10.31 per 100 000 males and 2.11 per 100 000 males respectively. Demographic and clinical characteristics of these individuals are shown in Table 1. Inhibitors developed in 17.9% of our haemophilia A population [8.2% persistent, 5.6% high responders]. Only one haemophilia B individual had inhibitors. Immune tolerance induction (ITI) therapy was successfully given to two haemophilia A adults with inhibitors using a dose regimen of 100 IU kg 1 day 1 without additional immunosuppressive therapy. One third (30.2%) of our haemophilia A and 20% of our haemophilia B population had no family history of haemophilia. Ninety-two individuals with haemophilia A and 16 with haemophilia B from the ages of 1–79 consented to contributing further socio-economic and clinical data. They represented 19.4%, 56.2% and 67.2% of the mild, moderate and severe haemophilia A population respectively and 40% of the haemophilia B population. The bleeding profile and bleeding-related complications of participating individuals as well as their current mode of treatment, type of product used and access to home treatment is shown in Table 2. One third of the study population are hepatitis C carriers (35 of 108 individuals, youngest 29 years). Eight patients have been treated with interferon and ribavirin. There are no cases of HIV infection linked to the use of factor concentrates. A fifth of people with moderate to severe haemophilia A and B (n = 18) are unemployed. Three quarters of our participants (n = 70) did not have any health insurance coverage. As a result, about half of them (n = 43) receive additional financial assistance from the government for their factor concentrates. Eighty-five haemophilia A and 14 haemophilia B participants also had their latest HJHS score assessed. Scores generally correlate with disease severity and increasing age. Mild haemophilia A scores range from 0 to 8 (average 2.85, median 3.0). Moderate haemophilia A scores range from 0 to 77 (average 13.0, median 9.0). In severe haemophilia A, the range of the score was 0–38 (average 13.79, median 11). In severe haemophilia A, the average HJHS score for those Correspondence: Heng Joo Ng, Department of Haematology, Singapore General Hospital, 20 College Road, Singapore 169856. Tel.: (65) 63266604; fax: (65) 62260237; e-mail: ng.heng.joo@sgh.com.sg

Utility of global hemostatic assays in the management of anticoagulation in a haemophilia patient

1 . UK Haemophilia Centre Doctors Organisation database annual report ; 2017 . www.ukhcdo.org last. Accessed December 28, 2017. 2 . Klaassen RJ , Blanchette VS , Barnard D , et al. Validity, reliability, and responsiveness of a new measure of healthrelated quality of life in children with immune thrombocytopenic purpura: the Kids’ ITP Tools . J Pediatr . 2007 ; 150 ( 5 ): 510 515 . 3 . Klaassen RJ , Blanchette V , Burke TA , et al. Quality of life in childhood immune thrombocytopenia: international validation of the kids’ ITP tools . Pediatr Blood Cancer . 2013 ; 60 ( 1 ): 95 100 .

A difficult case of acquired haemophilia with concomitant Evan's Syndrome presenting with acute subdural haematoma

Acquired haemophilia (AH) is a rare bleeding disorder with an incidence of approximately 1.5 per million people per year [1] and characterized by autoantibodies directed against circulating coagulation factor VIII. The condition causes severe and often life-threatening bleeding, with a high mortality rate of up to 22% [1]. Evan’s syndrome describes the simultaneous or sequential development of autoimmune thrombocytopenic purpura (ITP) and autoimmune haemolytic anaemia (AIHA) or autoimmune neutropenia in the absence of other underlying cause [2]. The co-existence of these two conditions compounds bleeding risk and has not been previously reported. We report our experience managing a patient having these two conditions simultaneously with potentially catastrophic bleeding.

Extensive subcutaneous haematoma associated with transdermal analgesic patch in a haemophilia A patient with inhibitor

PL carried out the literature study, organized and conducted the focus groups, led data analysis and drafted the manuscript. MP conceived the study, supervised data analysis and critically revised the manuscript. EG contributed in drafting the manuscript. MC and CV contributed in organizing the focus groups and critically revised the manuscript for intellectual content. MG conceived the study, supervised data collection and critically revised the manuscript for intellectual content. LH supervised data collection and data analysis, and critically revised the manuscript. All authors read and approved the final manuscript.

Delayed recurrent bleeding from central venous catheter track after catheter removal in a haemophilia patient

Dear Editor Temporary percutaneous central venous catheters are occasionally inserted in haemophilia patients for various indications such as central venous pressure monitoring, drug delivery or haemodialysis. For the latter indication, catheter sizes tend to be bigger resulting in wider formed tracks following removal of the catheter. The consequences of mature wide bore catheter tracks and whether there is requirement for prolonged and increased prophylactic factor administration following catheter removal is not known. We report our experience following removal of such a catheter in one haemophiliac. A 44-year-old man with severe haemophilia A was on renal replacement therapy for end stage renal failure with peritoneal dialysis. He received prophylactic factor VIII replacement of 25 IU kg 1 3 times weekly and did not have inhibitors. In July 2012, he was admitted for bacterial peritonitis and as a result, his Tenckhoff peritoneal dialysis catheter had to be removed. Haemodialysis was then performed with a right internal jugular vein tunnelled dialysis catheter. He also required an additional left internal jugular vein tunnelled double lumen Hickman catheter (7F, Bard Access Systems, Salt Lake City, UT, USA) for total parenteral nutrition. This second catheter was placed for 7 weeks before it was removed. Following catheter removal, he was given his usual low-dose prophylactic FVIII replacement of 25 IU kg 1 thrice weekly with no initial visible bleeding from the exit site which was located below the left clavicle. Previous trough measurements of FVIII had demonstrated levels of up to 4% prior to infusion. On the 28th day postcatheter removal, he presented to our clinic with a nodular mass on his left upper chest wall which corresponded to the previous catheter insertion site. Mild oozing was noticeable on the surface of this mass. His prophylactic factor replacement was increased from 25 IU kg 1 to 40 IU kg 1 thrice weekly which stopped the bleeding. After 1 week, the factor replacement was reduced to 25 IU kg 1 thrice weekly. Bleeding, however, recurred from the same site requiring his hospitalization during which FVIII replacement was increased to 50 IU kg 1 twice daily. The bleeding was controlled after 2 days of increased dose. Factor replacement was again reduced to the prophylactic dose of 25 IU kg 1 thrice weekly and continued for 1 week. An excisional biopsy of the exit site mass was then performed under FVIII replacement of 50 IU kg 1 for 2 days and was uneventful. He was discharged and his factor replacement was reduced to 40 IU kg 1 thrice weekly. After 10 days of increased dose, the factor replacement was reduced to 25 IU kg 1 thrice weekly as the wound had healed. Histology of the mass showed a large ovoid red brown material and represented a portion of hardened blood clot. A haematoma mimicking a nodular mass, however, reappeared 10 days later (Fig. 1) and FVIII replacement had to be increased to 40 IU kg 1 thrice weekly. The lesion subsequently decreased in size and attained complete resolution after 10 days of the increased dose. The increased dosage was extended for a total period of 5 weeks before it was reduced to the