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  1. Bakar MF, Ahmad NE, Karim FA, Saib S
    Antioxidants (Basel), 2014;3(3):516-25.
    PMID: 26785068 DOI: 10.3390/antiox3030516
    Two underutilized indigenous fruits of Borneo, Liposu (Baccaurea lanceolata) and Tampoi (Baccaurea macrocarpa) were investigated for their total phenolic (TPC), flavonoid (TFC), anthocyanin (TAC) and carotenoid (TCC) contents as well as antioxidant properties in vitro. The fruits were separated into three different parts (i.e., pericarp, flesh and seed) and extracted using 80% methanol. Antioxidant activity was determined using DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical scavenging, ABTS decolorization and FRAP (Ferric Reducing Antioxidant Power) assays. The results showed that B. macrocarpa pericarp contained the highest amount of total phenolics, total flavonoid, total anthocyanin and total carotenoid with the values of 60.04 ± 0.53 mg GAE/g, 44.68 ± 0.67 mg CE/g, 1.23 ± 0.20 mg c-3-gE/100 g and 0.81 ± 0.14 mg BCE/g. Results from DPPH, ABTS and FRAP assays also showed that the pericarp of B. macrocarpa displayed the highest antioxidant capacity. The antioxidant activity of the extract was significantly correlated with the total phenolic and flavonoid contents, but not with the carotenoid contents. In conclusion, B. macrocarpa displayed high potential as natural source of phytochemicals with antioxidant properties.
  2. Gul YA, Jabbar MF, Karim FA, Moissinac K
    Acta Chir. Belg., 2002 Jun;102(3):199-200.
    PMID: 12136541
    Dieulafoy's lesion is an uncommon cause of gastrointestinal haemorrhage. It may present with massive and life threatening bleed and although more common in the upper gastrointestinal tract, it is being increasingly reported as affecting the lower gastrointestinal tract. Diagnosis is usually achieved during proctoscopic and endoscopic visualization. In cases where there is profuse and torrential hemorrhage, angiography may help to confirm the diagnosis. There are a few treatment options available, all of which have a varying degree of success. More commonly than not, a combination of treatment is warranted as illustrated by our case. Recurrent bleeding may occur just as in cases of Dieulafoy's lesion affecting the upper gastrointestinal tract. Even though endoscopic visualization of the lower gastrointestinal tract in the presence of profuse lower gastrointestinal haemorrhage may not be possible, this important procedure should not be omitted as the bleeding source may be lying in a low and accessible location for prompt interventional haemorrhage control.
  3. Periayah MH, Halim AS, Saad AZ, Yaacob NS, Karim FA
    Open Access Maced J Med Sci, 2016 Mar 15;4(1):112-7.
    PMID: 27275342 DOI: 10.3889/oamjms.2016.030
    BACKGROUND: Von Willebrand disease (vWD) is an inherited hemostatic disorder that affects the hemostasis pathway. The worldwide prevalence of vWD is estimated to be 1% of the general population but only 0.002% in Malaysia.

    AIM: Our present paper has been written to disclose the statistical counts on the number of vWD cases reported from 2011 to 2013.

    MATERIAL AND METHODS: This article is based on sociodemographic data, diagnoses and laboratory findings of vWD in Malaysia. A total of 92 patients were reported to have vWD in Malaysia from 2011 to 2013.

    RESULTS: Sociodemographic-analysis revealed that 60% were females, 63% were of the Malay ethnicity, 41.3% were in the 19-44 year old age group and 15.2% were from Sabah, with the East region having the highest registered number of vWD cases. In Malaysia, most patients are predominately affected by vWD type 1 (77.2%). Factor 8, von Willebrand factor: Antigen and vWF: Collagen-Binding was the strongest determinants in the laboratory profiles of vWD.

    CONCLUSION: This report has been done with great interest to provide an immense contribution from Malaysia, by revealing the statistical counts on vWD from 2011-2013.

  4. Lentz SR, Rangarajan S, Karim FA, Andersen PD, Arkhammar P, Rosu G, et al.
    Blood Coagul. Fibrinolysis, 2017 Apr;28(3):224-229.
    PMID: 27427786 DOI: 10.1097/MBC.0000000000000584
    : Haemophilia treatment guidelines advocate early home-based treatment of acute bleeds. In the ADEPT2 trial, data were collected on the home treatment of bleeds with recombinant activated factor VII (rFVIIa) in haemophilia patients with inhibitors and self-reported bleeding-related symptoms. A total of 93% of all bleeds, and 91.5% of joint bleeds, were treated successfully with one to three doses of 90 μg/kg rFVIIa. However, some patients self-administered additional haemostatic medication (AHM) up to 48 h after the first rFVIIa treatment. The aim of this trial was to investigate the relationship between patient-reported symptoms, time to treatment initiation, and the use of AHM. A post hoc analysis was conducted on 177 joint bleeds and the patient-reported categorical symptoms of pain, swelling, mobility, tingling, and warmth, and the pain visual analogue scale (VAS) score. Analyses were descriptive and used logistic regression modelling. Complete symptom data were available for 141, 136, and 129 joint bleeds at 0 or 1, 3, and 6 h, respectively. Pain and pain VAS assessments were the best predictors of AHM use. Patients who self-administered AHM had higher mean pain VAS scores at each time point; both pain and pain VAS scores declined over time. Time to treatment initiation was an independent predictor for AHM use. Higher initial pain scores and longer time to treatment were the best predictors for administration of AHM. The observation that some patients chose to self-infuse in the face of declining levels of pain warrants further study to better understand the reasons behind patient decision-making.
  5. Zahari M, Sulaiman SA, Othman Z, Ayob Y, Karim FA, Jamal R
    Mediterr J Hematol Infect Dis, 2018;10(1):e2018056.
    PMID: 30210749 DOI: 10.4084/MJHID.2018.056
    Background: Haemophilia A (HA) and Haemophilia B (HB) are X-linked blood disorders that are caused by various mutations in the factor VIII (F8) and factor IX (F9) genes respectively. Identification of mutations is essential as some of the mutations are associated with the development of inhibitors. This study is the first comprehensive study of the F8 mutational profile in Malaysia.

    Materials and methods: We analysed 100 unrelated HA and 15 unrelated HB patients for genetic alterations in the F8 and F9 genes by using the long-range PCR, DNA sequencing, and the multiplex-ligation-dependent probe amplification assays. The prediction software was used to confirm the effects of these mutations on factor VIII and IX proteins.

    Results: 44 (53%) of the severe HA patients were positive for F8 intron 22 inversion, and three (3.6%) were positive for intron one inversion. There were 22 novel mutations in F8, including missense (8), frameshift (9), splice site (3), large deletion (1) and nonsense (1) mutations. In HB patients, four novel mutations were identified including the splice site (1), small deletion (1), large deletion (1) and missense (1) mutation.

    Discussion: The mutational spectrum of F8 in Malaysian patients is heterogeneous, with a slightly higher frequency of intron 22 inversion in these severe HA patients when compared to other Asian populations. Identification of these mutational profiles in F8 and F9 genes among Malaysian patients will provide a useful reference for the early detection and diagnosis of HA and HB in the Malaysian population.

  6. Noordin SS, Karim FA, Mohammad WMZBW, Hussein AR
    PMID: 30127563 DOI: 10.1007/s12288-017-0879-8
    Thawed plasma is fresh frozen plasma (FFP) that has been stored for 5 days at 1-6 °C. Duration of storage and different storage temperatures might affect the coagulation factor activity in thawed FFP. This study measured the changes of coagulation factor activities over 5 days in thawed FFP and stored at two different initial storage temperatures. Thirty-six units of FFP, which consisted of nine units each from blood groups A, B, AB, and O, were thawed at 37 °C. Each unit was divided into two separate groups (Group A and Group B) based on initial storage temperature. The first group was stored at 2-6 °C for 5 days (Group A). The second group was stored at 20-24 °C for initial 6 h followed by 2-6 °C for 5 days (Group B). Prothrombin time (PT), activated partial thromboplastin time (APTT), coagulation factor activities of fibrinogen, factor (F) II, FV, FVII, FVIII, FIX, FX, and von Willebrand factor antigen (vWF Ag) were assessed at baseline after thawing, at 6 h, and on days 1, 3, and 5 of storage for both groups. All coagulation factors mean activities in both storage groups decreased significantly over 5 days of storage. The mean FVIII activity at day 5 of storage was 36.9% in Group A and 39.8% in Group B. The other coagulation factors mean activities were > 50% on day 5 of storage in both groups. The coagulation factor activities of thawed FFP stored for 5 consecutive days were reduced in the two storage groups but most of the activities were still above 30%. This study suggests that thawed FFP stored for 5 days has the potential to ameliorate coagulation factor deficiencies in affected patients.
  7. Curtin J, Santagostino E, Karim FA, Li Y, Seifert W, Négrier C
    Thromb. Res., 2020 04;188:85-89.
    PMID: 32109773 DOI: 10.1016/j.thromres.2020.02.011
    INTRODUCTION: Long-acting recombinant factor IX (FIX) products may simplify the surgical treatment of haemophilia B patients. The impact of rIX-FP, a recombinant FIX fused to recombinant albumin, on FIX consumption and surgical management was assessed in patients with haemophilia B.

    MATERIALS AND METHODS: Male patients, ≤65 years old with severe haemophilia B (FIX activity ≤2%) requiring non-emergency surgery were enrolled in the surgical substudy of PROLONG-9FP. Dosing was based on World Federation of Hemophilia guidelines and patients' pharmacokinetics. Haemostatic efficacy was assessed on a 4-point scale. rIX-FP consumption and safety were monitored throughout the perioperative period.

    RESULTS: This updated dataset reports on thirty (8 minor and 22 major) surgeries conducted in 21 patients. A single preoperative bolus was used in 96.7% (n = 29) of surgeries. After minor surgery, patients received a median (range) of 0 (0-3) infusions with a median (range) consumption of 0 (0-178.89) IU/kg in the 14-day postoperative period. In patients who underwent major surgery (including 15 patients undergoing joint replacement surgery), the median (range) number of infusions in the 14-day postoperative period was 5 (0-11) and median consumption was 221.7 (0-444.07) IU/kg. Haemostatic efficacy was rated as excellent or good in 87.5% (7/8) of minor surgeries and 95.5% (21/22) of major surgeries.

    CONCLUSION: Surgical procedures can be performed using a single preoperative bolus of rIX-FP in nearly all patients. During postoperative care, use of rIX-FP necessitated infrequent infusions and low FIX consumption. Overall, data suggest rIX-FP simplifies perioperative care in patients with haemophilia B.

  8. Pan-Petesch B, Nagao A, Karim FA, Tosetto A, Roman MTA, Seifert W, et al.
    Thromb. Res., 2020 Sep;193:139-141.
    PMID: 32559570 DOI: 10.1016/j.thromres.2020.05.046
  9. Mahlangu JN, Weldingh KN, Lentz SR, Kaicker S, Karim FA, Matsushita T, et al.
    J Thromb Haemost, 2015 Nov;13(11):1989-98.
    PMID: 26362483 DOI: 10.1111/jth.13141
    Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept(™) 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa.
  10. Periayah MH, Halim AS, Saad AZ, Yaacob NS, Hussein AR, Karim FA, et al.
    Int J Clin Exp Med, 2015;8(9):15611-20.
    PMID: 26629055
    Chitosan-derived biomaterials have been reported to adhere when in contact with blood by encouraging platelets to adhere, activate and aggregate at the sites of vascular injury, thus enhanced wound healing capacity. This study investigated platelet morphology changes and the expression level of transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor-AB (PDGF-AB) in the adherence of two different types of chitosans in von Willebrand disease (vWD): N,O-carboxymethylchitosan (NO-CMC) and oligo-chitosan (O-C). Fourteen vWD voluntary subjects were recruited, and they provided written informed consent. Scanning electron microscopy and enzyme-linked immunosorbent assay test procedures were employed to achieve the objective of the study. The results suggest that the O-C group showed dramatic changes in the platelet's behaviors. Platelets extended filopodia and generated lamellipodia, leading to the formation of grape-like shaped aggregation. The platelet aggregation occurred depending on the severity of vWD. O-C was bound to platelets on approximately 90% of the surface membrane in vWD type 1; there was 70% and 50% coverage in vWD type II and III, respectively. The O-C chitosan group showed an elevated expression level of TGF-β1 and PDGF-AB. This finding suggests that O-C stimulates these mediators from the activated platelets to the early stage of restoring the damaged cells and tissues. This study demonstrated that the greater expression level of O-C assists in mediating the cytokine complex networks of TGF-β1 and PDGF-AB and induces platelet activities towards wound healing in vWD. With a better understanding of chitosan's mechanisms of action, researchers are able to accurately develop novel therapies to prevent hemorrhage.
  11. Escobar MA, Tehranchi R, Karim FA, Caliskan U, Chowdary P, Colberg T, et al.
    Haemophilia, 2017 Jan;23(1):67-76.
    PMID: 27480487 DOI: 10.1111/hae.13041
    INTRODUCTION: Surgery in patients with haemophilia B carries a high risk of excessive bleeding and requires adequate haemostatic control until wound healing. Nonacog beta pegol, a long-acting recombinant glycoPEGylated factor IX (FIX), was used in the perioperative management of patients undergoing major surgery.
    AIM: To evaluate the efficacy and safety of nonacog beta pegol in patients with haemophilia B who undergo major surgery.
    METHODS: This was an open-label, multicentre, non-controlled surgery trial aimed at assessing peri- and postoperative efficacy and safety of nonacog beta pegol in 13 previously treated patients with haemophilia B. All patients received a preoperative nonacog beta pegol bolus injection of 80 IU kg-1 . Postoperatively, the patients received fixed nonacog beta pegol doses of 40 IU kg-1 , repeated at the investigator's discretion. Safety assessments included monitoring of immunogenicity and adverse events.
    RESULTS: Intraoperative haemostatic effect was rated 'excellent' or 'good' in all 13 cases. Apart from the preoperative injection, none of the patients needed additional doses of nonacog beta pegol on the day of surgery. The median number of postoperative doses of nonacog beta pegol was 2.0 from days 1 to 6 and 1.5 from days 7 to 13. No unexpected intra- or postoperative complications were observed including deaths or thromboembolic events. No patients developed inhibitors.
    CONCLUSIONS: These results indicated that nonacog beta pegol was safe and effective in the perioperative setting, allowing major surgical interventions in patients with haemophilia B with minimal peri- and postoperative concentrate consumption and infrequent injections as reported with standard FIX products.
    KEYWORDS: Phase III; factor IX; haemophilia B; long-acting recombinant factor IX; nonacog beta pegol; surgery
  12. Collins PW, Young G, Knobe K, Karim FA, Angchaisuksiri P, Banner C, et al.
    Blood, 2014 Dec 18;124(26):3880-6.
    PMID: 25261199 DOI: 10.1182/blood-2014-05-573055
    This multinational, randomized, single-blind trial investigated the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in 74 previously treated patients with hemophilia B (FIX activity ≤2 IU/dL). Patients received prophylaxis for 52 weeks, randomized to either 10 IU/kg or 40 IU/kg once weekly or to on-demand treatment of 28 weeks. No patients developed inhibitors, and no safety concerns were identified. Three hundred forty-five bleeding episodes were treated, with an estimated success rate of 92.2%. The median annualized bleeding rates (ABRs) were 1.04 in the 40 IU/kg prophylaxis group, 2.93 in the 10 IU/kg prophylaxis group, and 15.58 in the on-demand treatment group. In the 40 IU/kg group, 10 (66.7%) of 15 patients experienced no bleeding episodes into target joints compared with 1 (7.7%) of 13 patients in the 10 IU/kg group. Health-related quality of life (HR-QoL) assessed with the EuroQoL-5 Dimensions visual analog scale score improved from a median of 75 to 90 in the 40 IU/kg prophylaxis group. Nonacog beta pegol was well tolerated and efficacious for the treatment of bleeding episodes and was associated with low ABRs in patients receiving prophylaxis. Once-weekly prophylaxis with 40 IU/kg resolved target joint bleeds in 66.7% of the affected patients and improved HR-QoL. This trial was registered at www.clinicaltrials.gov as #NCT01333111.
  13. Gill HK, Ten SK, Dhaliwal JS, Moore S, Hassan R, Karim FA, et al.
    Malays J Pathol, 2004 Dec;26(2):105-10.
    PMID: 16329562
    An RT-PCR assay detected the t(4;11) translocation in two infants with acute lymphoblastic leukemia (ALL). Case P76 was a 10-month-old, female infant, who presented with a WBC of 137.4 x 10(9)/l and a pre-pre-B ALL immunophenotype. Case P120 was a 6-month-old female infant, with a WBC > 615 x 10(9)/l and a pre-pre-B ALL immunophenotype. RT-PCR of cDNA from both these cases generated a 656 bp and a 542 bp respectively, which sequencing confirmed as t(4;11) fusion transcripts. The primers and conditions selected for this assay are compatible with a one-step multiplex PCR for the main translocations in childhood ALL.
  14. Gill HK, Keoh TS, Dhaliwal JS, Moore S, Kim TS, Hassan R, et al.
    Cancer Genet. Cytogenet., 2005 Jan 15;156(2):129-33.
    PMID: 15642392
    Eighty-eight multi-ethnic Malaysian pediatric acute lymphoblastic leukemia (ALL) patients were screened for the TEL-AML1 rearrangement by reverse transcription-polymerase chain reaction (RT-PCR). Fluorescence in situ hybridization (FISH) was used as an independent screen for 30 cases and to confirm RT-PCR positive cases. Seventeen patients, or 19%, were found to be t(12;21) positive. Ethnically the group comprised 12 Malays, 4 Chinese, and 1 Indian. All patients, including 1 with an unusual blast cell morphology who suffered an early relapse and death, were characteristic TEL-AML1 cases in cell count, age, ALL subset classification, and fusion transcript expressed. This study shows that in Malaysia, TEL-AML1 is found in the same distinct ALL subset and at a similar frequency as in other diverse childhood ALL cohorts.
  15. Young G, Collins PW, Colberg T, Chuansumrit A, Hanabusa H, Lentz SR, et al.
    Thromb. Res., 2016 May;141:69-76.
    PMID: 26970716 DOI: 10.1016/j.thromres.2016.02.030
    INTRODUCTION: Paradigm™4 was an international extension trial investigating the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in haemophilia B patients (FIX activity ≤2%; aged 13-70years) who had previously participated in phase III pivotal (paradigm™2) or surgery (paradigm™3) trials.

    METHODS: Patients chose to continue treatment with nonacog beta pegol in either one of two once-weekly prophylaxis arms (10IU/kg or 40IU/kg), or an on-demand arm (40IU/kg for mild/moderate bleeds; 80IU/kg for severe bleeds). The primary objective was to evaluate immunogenicity; key secondary objectives included assessing safety and haemostatic efficacy in the treatment and prevention of bleeds.

    RESULTS: Seventy-one patients received prophylaxis or on-demand treatment. No patient developed an inhibitor and no safety concerns were identified. The success rate for the treatment of reported bleeds was 94.6%; most (87.9%) resolved with one injection. The median annualised bleeding rate for patients on prophylaxis was 1.36 (interquartile range [IQR] 0.00-2.23) and 1.00 (IQR 0.00-2.03) for the 10 and 40IU/kg treatment arms, respectively. The mean FIX activity trough achieved for 10 and 40IU once weekly was 9.8% and 21.3%, respectively. Fourteen patients on prophylaxis underwent 23 minor surgical procedures; haemostatic perioperative outcomes for all of those evaluated were 'excellent' or 'good'.

    CONCLUSIONS: Nonacog beta pegol showed a favourable tolerability profile (with no safety issues identified) with good prophylactic protection and control of bleeding in previously treated adult and adolescent haemophilia B patients.

  16. Mahlangu J, Kuliczkowski K, Karim FA, Stasyshyn O, Kosinova MV, Lepatan LM, et al.
    Blood, 2016 Aug 04;128(5):630-7.
    PMID: 27330001 DOI: 10.1182/blood-2016-01-687434
    Recombinant VIII (rVIII)-SingleChain is a novel B-domain-truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927.
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