Ibrahim C. Haznedaroglu

Acute graft-vs-host disease: Pathobiology and management

Acute graft-vs-host disease (GVHD) is a major obstacle to safe allogeneic hematopoietic stem cell transplantation (HSCT), leading to a significant morbidity and mortality. GVHD occurs when transplanted donor T lymphocytes react to foreign host cells. It causes a wide variety of host tissue injuries. This review focuses on the pathobiological basis, clinical aspects, and current management strategies of acute GVHD. Afferent phase of acute GVHD starts with myeloablative conditioning, i.e., before the infusion of the graft. Total-body irradiation (TBI) or high-dose chemotherapy regimens cause extensive damage and activation in host tissues, which release inflammatory cytokines and enhance recipient major histocompatibility complex (MHC) antigens. Recognition of the foreign host antigens by donor T cells and activation, stimulation, and proliferation of T cells is crucial in the afferent phase. Effector phase of acute GVHD results in direct and indirect damage to host cells. The skin, gastrointestinal tract, and liver are major target organs of acute GVHD. Combination drug prophylaxis in GVHD is essential in all patients undergoing allogeneic HSCT. Steroids have remained the standard for the treatment of acute GVHD. Several clinical trials have evaluated monoclonal antibodies or receptor antagonist therapy for steroid-resistant acute GVHD, with different successes in a variety of settings. There are some newer promising agents like mycophenolate mofetil, glutamic acid-lysine-alanine-tyrosine (GLAT), rapamycin, and trimetrexate currently entering in the clinical studies, and other agents are in development. Future experimental and clinical studies on GVHD will shed further light on the better understanding of the disease pathobiology and generate the tools to treat malignant disorders with allogeneic HSCT with specific graft-vs-tumor effects devoid of GVHD.

Haemostatic actions of the folkloric medicinal plant extract Ankaferd Blood Stopper.

Ankaferd Blood Stopper® (ABS), a standardized mixture of five plants, has been used historically as a haemostatic agent but its mechanism of action remains unknown. This study investigated the in vitro effects of ABS on haemostatic parameters. When added to plasma or serum, ABS induced the very rapid formation of a protein network and erythrocyte aggregation. The levels of coagulation factors II, V, VII, VIII, IX, X, XI, and XIII were not affected by ABS. Plasma fibrinogen activity and antigen levels were decreased following the addition of ABS, in parallel with the prolonged thrombin time. Total protein, albumin, and globulin levels decreased after the addition of ABS. Our findings suggest that ABS stimulates the formation of an encapsulated protein network that provides focal points for erythrocyte aggregation. ABS has the therapeutic potential to be used for the management of haemorrhage and this agent should be investigated further in clinical trials.

Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study

Imatinib mesylate (IM), 400 mg daily, is the standard treatment of Philadelphia-positive (Ph(+)) chronic myeloid leukemia (CML). Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. To investigate whether the systematic use of a higher dose of IM could lead to better results, 216 patients with Ph(+) CML at high risk (HR) according to the Sokal index were randomly assigned to receive IM 800 mg or 400 mg daily, as front-line therapy, for at least 1 year. The CCgR rate at 1 year was 64% and 58% for the high-dose arm and for the standard-dose arm, respectively (P = .435). No differences were detectable in the CgR at 3 and 6 months, in the molecular response rate at any time, as well as in the rate of other events. Twenty-four (94%) of 25 patients who could tolerate the full 800-mg dose achieved a CCgR, and only 4 (23%) of 17 patients who could tolerate less than 350 mg achieved a CCgR. This study does not support the extensive use of high-dose IM (800 mg daily) front-line in all CML HR patients. This trial was registered at www.clinicaltrials.gov as #NCT00514488.

Effects of angiotensin converting enzyme and angiotensin II receptor inhibition on impaired fibrinolysis in systemic hypertension

Abnormalities in fibrinolysis have been reported in hypertension. Angiotensin converting enzyme (ACE) inhibitors have been shown to improve altered fibrinolytic balance in hypertensive patients. It has not been documented, however, whether this is due to a decrease in angiotensin II (Ang-II) generation or is a consequence of elevated local levels of bradykinin. Accordingly, the aim of this study was to determine the effects of an ACE inhibitor (perindopril) and an Ang-II receptor antagonist (losartan) on fibrinolytic kinetics. We have examined the serum levels of the plasminogen activator inhibitor type-1 (PAI-1) antigen and activity, tissue plasminogen activator (t-PA) antigen and activity, soluble thrombomodulin (sTM), and tissue factor pathway inhibitor (TFPI) before and after reaching the target blood pressure (<140/90 mm Hg) in 13 hypertensive patients receiving perindopril (mean age 40+/-11 years, 6 women, 7 men) and in 12 patients receiving losartan (mean age 38+/-9 years, 6 women, 6 men). We also compared the baseline fibrinolytic activity of hypertensive patients with that of 12 normotensive control persons (mean age 40+/-9 years, 6 women, 6 men). The mean basal plasma levels of PAI-1 antigen, PAI-1 activity, and sTM were significantly higher in the hypertensive patients than in normal controls (P<.005). The values of other analytes were similar in both groups. Increased plasma levels of PAI-1 antigen, PAI-1 activity, and sTM were reduced in patients after they were given perindopril and losartan (P<.005); the reductions in losartan-receiving group were more pronounced (P<.05). There were no significant effects on the plasma levels of t-PA antigen, t-PA activity, and TFPI in patients receiving the two therapeutic regimens (P>.05). In conclusion, chronic hypertension is associated with hypofibrinolysis. The beneficial effect of ACE inhibitors on fibrinolysis seems to be related to the blockade of Ang-II, and increased kinin activity does not appear to play a major role.

Endoscopic Application of Ankaferd Blood Stopper as a Novel Experimental Treatment Modality for Upper Gastrointestinal Bleeding: A Case Report

Endoscopic Application of Ankaferd Blood Stopper as a Novel Experimental Treatment Modality for Upper Gastrointestinal Bleeding: A Case Report

Impaired haemostatic kinetics and endothelial function in Behçet's disease

Objectives. This study was planned to explore the alterations of endothelial functions in the prethrombotic state of Behçets disease (BD) patients.

Ankaferd Blood Stopper as an effective adjunctive hemostatic agent for the management of life-threatening arterial bleeding of the digestive tract

latory failure, morbidity, and mortality are still important life-threatening prob- lems in this clinical setting. ABS may be useful as an adjunctive agent to mechan- ical intervention in cases of serious arte- rial bleeding. Neither any local adverse effect nor systemic toxicity was observed following the topical application of ABS.

In vivo hemostatic effect of the medicinal plant extract Ankaferd Blood Stopper in rats pretreated with warfarin.

Aim: Ankaferd comprises a mixture of Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum and Urtica dioica. Ankaferd Blood Stopper (ABS) has been approved in the management of bleedings. This study aimed to evaluate in vivo hemostatic effect of ABS in rats pretreated with warfarin. Materials and methods: Wistar rats (210-270 g) were treated either with warfarin (2 mg/kg) or vehicle (0.9% NaCl) orally before bilateral hind leg amputation. ABS was administered topically to one of the amputed legs. The duration of bleeding and the amount of bleeding were measured to evaluate the hemostatic effect of ABS. Results: Topical ABS administration to amputed leg shortened the duration of bleeding markedly in both untreated and warfarin-treated rats by 31.9% [1.42 min (95% CI: 0.35-2.49)] and 43.5% [5.12 min (95% CI: 2.16-8.07)] respectively. The amount of bleeding in ABS-administered amputed leg showed a decrease by 53.8% in warfarin-treated group. Conclusions: ABS has in vivo hemostatic actions that may provide a therapeutic potential for the management of patients with deficient primary hemostasis in clinical medicine.

Hemostatic Efficacy of Ankaferd Blood Stopper® in a Swine Bleeding Model

Objective: The purpose of this study was to show the hemostatic effect of spray, solution and tampon forms of Ankaferd Blood Stopper® (ABS), a unique medicinal plant extract historically used as a hemostatic agent in Turkish folklore medicine, in a porcine bleeding model. Materials and Methods: Two 1-year-old pigs were used as bleeding models for superficial and deep skin lacerations, grade II liver and spleen injuries, grade II saphenous vein injury and grade IV saphenous artery injury. Spray, solution or tampon forms of ABS were applied after continuing bleeding was confirmed. The primary outcome was time to hemostasis. Volume of blood loss was not measured. The pigs were euthanized at the end of the experiment. Results: Spray or direct application of ABS solution resulted in instant control of bleeding in superficial and deep skin lacerations as well as puncture wounds of the liver. A 40-second application of ABS tampon was sufficient to stop bleeding of skin lacerations, while 1.5- and 3.5-min applications were used to control hemorrhage from the saphenous vein and artery, respectively. No rebleeding was observed once hemostasis was achieved. However, repeated applications of ABS solution and tampon were only temporarily effective in the hemostasis of spleen injury. Conclusions: The data showed that ABS was an effective hemostatic agent for superficial and deep skin lacerations and minor/moderate trauma injuries in a porcine bleeding model.

Endoscopic topical application of Ankaferd Blood Stopper for neoplastic gastrointestinal bleeding: A retrospective analysis

AIM The aim of this study was to retrospectively assess the haemostatic efficacy of the endoscopic topical use of Ankaferd Blood Stopper (ABS) in the setting of neoplastic GI bleeding. METHODS The records of 10 patients with neoplastic GI bleeding (7 gastric, 3 rectal) were evaluated retrospectively. Written informed consent regarding the off-label use of ABS as a means of attaining haemostasis had been obtained from all of the patients prior to the procedure. In all patients, ABS was applied topically. Rates of bleeding control and post-procedural complications were documented. RESULTS Haemostasis was achieved in all patients within seconds of endoscopic application of ABS, with no immediate complications. Seven patients underwent subsequent cancer surgery after a bleeding-free post-procedural period. CONCLUSIONS ABS as a novel haemostatic agent could have a potential benefit in controlling bleeding from GI tumours. Prospective controlled studies are needed to help establish its efficacy, and perhaps offer a comparison to conventional haemostatic interventions.