National survey of patients with hemophilia and other congenital bleeding disorders in Thailand

A national survey of patients with hemophilia and other congenital bleeding disorders in Thailand was conducted in the years 2000 to 2002. Questionnaires were sent to physicians working at hospitals throughout the country. Although the overall response rate to the questionnaires was 19%, the two highest rates of 80% and 73.7% were found at university and regional hospitals, respectively, where most of the patients received their diagnosis and treatment. A total of 1,450 patients comprised of hemophilia 1,325 cases, von Willebrand disease, 69 cases, congenital factor VII deficiency, 15 cases, hereditary platelet dysfunction, 22 cases, and undefined causes of congenital bleeding disorders, 19 cases. Most were pediatric patients <15 years of age. Treatment was mainly given on demand for a bleeding episode, while only 8.6% received additional home treatment for early bleeding episodes. Replacement therapy primarily relied on fresh frozen plasma, cryoprecipitate and cryo-removed plasma. Factor concentrate was seldom used because of the high price. As a result, hemophilia care services in Thailand should be strengthened by providing comprehensive education for medical personnel, making available simple laboratory kits to determine hemophilia A and B, ensuring an adequate supply of blood components and affordable factor concentrate, and establishing home care treatment.     

Prevalence of monoclonal gammopathy of undetermined significance in Thailand

Individuals with monoclonal gammopathy of undetermined significance (MGUS) develop multiple myeloma and related malignancies at the rate of 1% per year. Given differences in ethnicity, data on prevalence and risk factors of MGUS in Thai population will be helpful in understanding the pathogenesis of plasma cell disorders and designing an early cancer detection strategy. Subjects of 50 years or older were included. Demographic data and suspected risk factors were collected. Monoclonal proteins were detected using serum protein electrophoresis. Serum was obtained from 3,260 participants; 1,104 males (33.9%) and 2,156 females (66.1%). The median age was 57 years (range 50–93 years). Monoclonal proteins were detectable in 2.3% (95% confidence interval [CI] 1.8–2.8). M spikes were found in gamma- and beta-globulin regions in 50 (1.5%) and 25 (0.8%) subjects, respectively. The prevalence of MGUS in subjects 50–59, 60–69, and 70 years or older was 2.0% (41/1,975), 2.6% (22/851), and 2.8% (12/434), respectively. By multivariate analysis, MGUS was associated with living outside Bangkok (odds ratio 2.25, 95% CI 1.11–4.58). The overall prevalence of MGUS in the Thai population was 2.3%, which was lower than that in Western countries, but comparable to that in Japan.     

Rituximab-CHOP-ESHAP vs CHOP-ESHAP-high-dose therapy vs conventional CHOP chemotherapy in high-intermediate and high-risk aggressive non-Hodgkin's lymphoma

With currently available combination chemotherapy regimens, the outcome of the patients newly diagnosed with aggressive non-Hodgkin's lymphoma (NHL) identified as 'high' and 'high-intermediate' risk groups according to the international prognostic index (IPI) is still unsatisfactory and a more innovative therapy is urgently required to improve the survival of the patients. The purpose of this study was to compare the efficacy of rituximab given in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and ESHAP (etoposide, methylprednisolone, high-dose Ara-C, cisplatin) vs CHOP-ESHAP and upfront high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) vs standard CHOP in patients aged < or = 65 years old newly diagnosed with 'high' and 'high-intermediate' risk aggressive lymphoma enrolled onto two consecutive treatment trials at the institute. Between May 1995 - July 2002, 84 patients, aged 15 - 65 years old, with newly diagnosed aggressive NHL and an age-adjusted IPI of 2 or 3 were enrolled. The median age of the patients was 38 years (range 15 - 65). The baseline demographic features, in particular the major prognostic variables, were similar between the treatment groups. Patients treated with rituximab-CHOP-ESHAP received eight cycles of rituximab (375 mg m(-2) on day 1 of cycles 1 - 6 and days 21 and 28 of cycle 7) plus CHOP (day 3 of cycles 1, 3 and 5) and ESHAP (day 3 of cycles 2, 4 and 6 and day 1 of cycle 7) at 21-day intervals. Patients enrolled onto the CHOP-ESHAP-HDT arm (n = 23) were treated with three courses of CHOP and then switched to two or four cycles of ESHAP followed by HDT. Patients treated with CHOP alone (n = 25) were treated with the standard eight cycles of CHOP. The rate of complete remission was significantly improved with rituximab-CHOP-ESHAP compared with either CHOP-ESHAP-HDT or CHOP alone (67% compared with 44% and 36%, respectively; p = 0.043). With a median follow-up time of 53 months, the 5-year overall survival (OS) was improved by the addition of rituximab-61% with rituximab-CHOP-ESHAP, compared with 43% for CHOP-ESHAP-HDT and 24% for CHOP alone (p = 0.088). Significant increases in failure-free survival (FFS) and disease-free survival (DFS) (61% and 96%), compared with CHOP-ESHAP-HDT (34% and 90%) and CHOP (16% and 44%; p = 0.002 and p < 0.001, respectively) were observed. Compared to CHOP, rituximab-CHOP-ESHAP yielded significantly superior OS (p = 0.014), FFS (p < 0.001) and DFS (p < 0.001). The survivals, however, were not significantly different from patients treated with CHOP-ESHAP-HDT. It is concluded that rituximab-ESHAP-CHOP is superior over standard CHOP and fares comparably to upfront HDT/ASCT in previously untreated patients with aggressive lymphoma. A prospective randomized controlled trial is warranted to confirm these results.     

The effects of green pit viper (Trimeresurus albolabris and Trimeresurus macrops) venom on the fibrinolytic system in human.

Green pit viper (Trimeresurus albolabris and Trimeresurus macrops) venom was found to have a thrombin-like effect in vitro but cause a defibrination syndrome in vivo. The effects of venom on fibrinolytic system have not been well characterized. This knowledge can help to define the roles of antifibrinolytic therapy, give insights in fibrinolytic system regulation and potentially lead to identification of a new profibrinolytic agent from this venom. Forty-six cases of green pit viper bites were studied for various coagulation and fibrinolytic parameters and correlated with serum venom levels measured by ELISA. Fibrinolytic system activation is very common as indicated by low plasminogen (50%), low antiplasmin (56.5%) and elevated fibrin-fibrinogen degradation products (FDPs, 97.4%) levels. FDP test is very sensitive and a normal level is useful for exclusion of systemic envenomation. In contrast to some other models of defibrination syndrome, such as Russell viper (Daboia russelli siamensis), elevation of plasminogen activator activity (PA) was found indicating a hyperfibrinolytic state. Definite increase in tissue-type plasminogen activator (t-PA) antigen (p = 0.00075) with a modest elevation of its inhibitor plasminogen activator inhibitor-1 (PAI-1) (p = 0.27) probably contributes to this effect. This supports the idea that the balance between plasminogen activators and inhibitors can determine fibrinolytic responses in pathologic states. Fibrinopeptide A levels were markedly elevated (68.43 +/- 51.57 ng/ml in cases and 2.83 +/- 3.80 ng/ml in control, p < 0.0001) and correlated well with clinical severity suggesting that the fibrin deposition from the thrombin-like effect is the main mechanism of fibrinolysis. Therefore, antifibrinolytic agents probably have no role in treatment. However, the components of green pit viper venom that have these profibrinolytic effects in human are interesting and should be further identified.     

Brownian dynamics simulations of protein folding: Access to milliseconds time scale and beyond

Protein folding occurs on a time scale ranging from milliseconds to minutes for a majority of proteins. Computer simulation of protein folding, from a random configuration to the native structure, is nontrivial owing to the large disparity between the simulation and folding time scales. As an effort to overcome this limitation, simple models with idealized protein subdomains, e.g., the diffusion–collision model of Karplus and Weaver, have gained some popularity. We present here new results for the folding of a four-helix bundle within the framework of the diffusion–collision model. Even with such simplifying assumptions, a direct application of standard Brownian dynamics methods would consume 10,000 processor-years on current supercomputers. We circumvent this difficulty by invoking a special Brownian dynamics simulation. The method features the calculation of the mean passage time of an event from the flux overpopulation method and the sampling of events that lead to productive collisions even if their probability is extremely small (because of large free-energy barriers that separate them from the higher probability events). Using these developments, we demonstrate that a coarse-grained model of the four-helix bundle can be simulated in several days on current supercomputers. Furthermore, such simulations yield folding times that are in the range of time scales observed in experiments.     

Megakaryocytes require thrombospondin-2 for normal platelet formation and function

Mice that lack the matricellular angiogenesis inhibitor, thrombospondin-2 (TSP2), display a bleeding diathesis, despite normal blood coagulation and the lack of thrombocytopenia. Although platelets do not contain detectable levels of TSP2, TSP2-null platelets are compromised in their ability to aggregate in vivo in response to denudation of the carotid artery endothelium, and in vitro following exposure to adenosine diphosphate (ADP). Megakaryocytes (MKs) show high levels of TSP2 by immunohistochemical analysis of bone marrow. However, when cultured in vitro, MKs contain little TSP2 protein or mRNA. These findings suggest that most TSP2 is acquired from the bone marrow microenvironment. Consistent with this hypothesis, MKs take up recombinant TSP2 in an integrin-dependent manner when it is supplied in the culture medium. Furthermore, uptake of TSP2 in vitro affects MK differentiation and proplatelet formation. The functional significance of this process is supported by the presence of ultrastructural abnormalities in TSP2-null bone marrow, including extensive fragmentation of the peripheral zone in MKs and failure of this zone to form close associations with vascular sinuses. We conclude that the uptake of TSP2 by MKs from the marrow milieu is required for proper MK function and the release of functionally competent platelets.     

Utilization review of concomitant use of potentially interacting drugs in Thai patients using warfarin therapy

PURPOSE: In Thailand, there has been no study determining the concomitant use of medications, known to potentially interact with warfarin, in patients receiving warfarin therapy. This paper examined the frequency of which specific interacting drugs were concomitantly used in warfarin users. METHODS: We retrospectively examined the database of warfarin outpatient medical records from a regional 756-bed hospital located in the north of Thailand. All patients receiving warfarin from 10 June 1999 to 4 August 2004 were reviewed to identify all drugs possessing interaction potential with warfarin. The potential of significant interactions were divided into high, moderate and low, according to the extent of evidence documented in textbooks and literature. RESULTS: Among 1093 patients receiving warfarin therapy, 914 (84%) patients received at least one potentially interacting drug and half of them (457 patients) received at least one drug with high potential for interaction. The most frequently concomitant drug that increased INR was acetaminophen (63%, 316/457). Propylthiouracil was the most frequently concomitant drug that decreased INR response (4%, 19/457), while diclofenac was the most frequently concomitant drug that increased bleeding risk (16%, 73/457). CONCLUSIONS: About a half of patients receiving warfarin therapy was prescribed concomitant drug(s) that has a high potential of interactions with warfarin. These patients should be closely monitored and counselled to watch for signs and symptoms of bleeding and thrombosis to avoid adverse events associated with drug interactions.