Hendrik Coenraad Hemker

Randomized, placebo-controlled trial of low molecular weight heparin in active ulcerative colitis

Background In several open and 1 controlled trial, unfractionated heparin was effective in the treatment of active ulcerative colitis (UC). Low molecular weight heparin (LMWH) had a similar effect in several open studies. Methods We studied the efficacy, safety, and tolerability of LMWH in mild to moderately active UC in a randomized, double‐blind, placebo‐controlled trial. In all, 29 patients with a mild or moderate recurrence of UC during salicylate treatment were randomized to receive either reviparin 3,436 IU (n = 15) subcutaneously twice daily or placebo (n = 14). The study period was 8 weeks. Treatment was discontinued if there was no improvement at 4 weeks or at any disease progression. Primary outcome measure was clinical improvement at 8 weeks measured by the Colitis Activity Index (CAI) and the Clinical Symptoms Grading (CSG, based on the CAI). Endoscopic and histologic grading and quality of life as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) were secondary outcome measures. Patients were closely monitored for adverse events. Results Twenty of 29 patients finished the 8‐week treatment period (reviparin versus placebo: 11 versus 9; P = 0.70). There was no difference in CSG, CAI, endoscopic and histologic grading, or IBDQ. Treatment was well tolerated and no serious adverse events occurred. Conclusion In this study, treatment with LMWH showed no significant clinical advantage compared to placebo in mild to moderately active UC. (Inflamm Bowel Dis 2007)

Expression of biological activity of draculin, the anticoagulant factor from vampire bat saliva, is strictly dependent on the appropriate glycosylation of the native molecule

Draculin, a glycoprotein isolated from vampire bat (Desmodus rotundus) saliva, is a natural anticoagulant which inhibits activated coagulation factors IX (IXa) and X (Xa). The observation that under captivity conditions, the anticoagulant activity present in vampire bat saliva is dependent upon the salivation protocol, led us to investigate the possible relationship between the expression of biological activity of native draculin and the post-translational glycosylation of the protein backbone. Daily salivation of vampire bats yields a saliva that progressively decreases in anticoagulant activity, without any significant change in overall protein content, or in the amount of protein specifically recognized by a polyclonal anti-draculin antibody. Anticoagulant activity of the saliva is restored after a 4-day period of rest. Besides the marked difference in anticoagulant activity, purified native draculin, obtained from high- and low-activity saliva, shows significant differences in: (a) composition of the carbohydrate moiety, and (b) Glycosylation pattern. Furthermore, controlled chemical deglycosylation of native draculin, under conditions that do not affect the polypeptide backbone, progressively leads to complete loss of the biological activity. Our present results implicate that correct glycosylation of draculin is a seminal event for the expression of the biological activity of this glycoprotein.

Global/integral assays in hemostasis diagnostics : promises, successes, problems and prospects

Laboratory testing in hemostasis is a subject of growing concern among the specialists. To put it plainly, the standard assays that have been in widespread use for more than 40 years (APTT and PT assays for clotting, aggregometry for platelets) are not sensitive and specific for too many major disorders of hemostasis; their parameters can remain within normal ranges when patient is in acute danger of thrombosis or bleeding; even if they do detect some abnormality they do not indicate the severity of the clinical manifestations; in rare cases they are even abnormal in a clinically asymptomatic individual. Admittedly, as already recognized by Virchow in his famous Virchow’s triad, thrombosis can arise from disorders in either vessel wall, blood flow, or blood composition and laboratory diagnostics only concerns the latter. If the origin of a thrombotic or bleeding disorder is not in the blood, as in myocardial infarction caused by atherosclerotic plaque rupture, there is no need for the blood to be in a hyper-coagulable state before the event and laboratory diagnostics of coagulation or platelet function can be completely normal (although some non-hemostatic biomarkers for e.g. atherosclerotic plaque instability do exist [1]). The same holds for hemostasis: the extent of bleeding is determined by the state of the tissue (type and degree of damage, tissue composition at the injury site), physical parameters of the wound and blood flow (geometry of the wound, blood flow patterns there) as well as blood biochemistry. No functional assay of blood clotting is likely to be able to predict hemorragic stroke resulting from aneurism rupture or bleeding in a person with hereditary hemorrhagic telangiectasia or Ehlers–Danlos syndrome, exactly because there is originally nothing wrong with their blood in these cases. Nevertheless, even in a perfectly normal population the function of the clotting system does determine the likelihood and degree of hemostasis and thrombosis. It is for instance well documented that normal persons with blood group O bleed more and have a smaller risk of thrombosis than those with non-O blood groups [2-5]. This is directly related to their having less factor VIII and Von Willebrand factor and higher anti-thrombin activity. Recognizing that the “coagulability” of the blood tells only part of the story cannot justify to acquiesce to the inefficiency of the traditional clotting- and platelet assays. There are too many cases where their results are not correct, even when the origin of the hemostatic abnormality is clearly systemic and is to be found in the blood. A typical example is the hypercoaguable state that results from the presence of circulating coagulation activators in blood (microparticles activating clotting via tissue factor [6] or contact pathway [7], long-lived clotting enzymes like factors IXa, XIa, and XIIa [7-9]). One of the leading Russian hematologists, Andrey Vorobyov, recommended spontaneous clotting of blood in the syringe needle observed during blood collection as one of the typical indicators of the hypercoagulative stage of disseminated intravascular coagulation, usually coinciding with normal APTT [10], and cited this as a regrettable example of why a doctor can hardly rely on the available traditional laboratory diagnostics tools in coagulation.

Thrombin generation in mesalazine refractory ulcerative colitis and the influence of low molecular weight heparin

BackgroundIn ulcerative colitis (UC), a state of hypercoagulation has frequently been observed. Low molecular weight heparin (LMWH) has shown beneficial effects as an adjuvant treatment of steroid refractory UC in open trials. We assessed potential therapeutic effects of the LMWH reviparin in hospitalised patients with mesalazine refractory UC, as well as its influence on haemostasis factors.MethodsTwenty-nine patients with mild-to-moderately active UC were included in a double-blind placebo controlled trial. All patients had a flare-up of disease under mesalazine treatment. Reviparin (Clivarin®) 3,436 IU anti-Xa/0.6 ml or placebo s.c. was added, and self-administered twice daily for 8 weeks. Patients were monitored for possible adverse events and changes in clinical symptoms. Endoscopical, histological, biochemical and haemostasis parameters were analysed.ResultsTolerability and compliance were excellent and no serious adverse events occurred. No significant differences were observed on the clinical, endoscopical and histological outcome, as compared to placebo. A high intrinsic and extrinsic thrombin potential was found before LMWH therapy. However, the significant reduction in the thrombin generation by LMWH was not related to the reduction in disease activity.ConclusionThe LMWH reviparine reduces thrombin generation in patients with mild-to-moderately active, mesalazine refractory UC, but is not associated with a reduction in disease activity.