Unexpected bleeding following eyelid tumor resection leading to the rare diagnosis of acquired haemophilia.

BACKGROUND: Our goal is to report for the first time in the literature a case of uncontrolled bleeding after an oculoplastic surgical procedure leading to the diagnosis of acquired haemophilia. HISTORY AND SIGNS: An 82-year-old patient underwent tumor excision and reconstruction of his right lower eyelid. On the same day, uncontrolled bleeding occurred that resisted optimal blood pressure control, external compression, surgical haemostasis and wound revision. Usual coagulation screening tests were normal, except for a slightly prolonged activated partial thromboplastin time. THERAPY AND OUTCOME: Extensive coagulation check was performed, which showed a severely reduced factor VIII due to the presence of an inhibitor. The bleeding was immediately stopped after administration of recombinant factor VIIa. After healing of the wound, factor VIIa treatment was replaced by immunosuppressive therapy. The factor VIII inhibitor became unmeasurable and remained so for three months after stopping the immunosuppressive therapy. CONCLUSIONS: Ophthalmologists confronted with unexpected uncontrolled bleeding should think about the possibility of blood dyscrasia, in particular acquired haemophilia.

[Heparins]. / Heparine.

Unfractionated heparin (UH) and low-molecular-weight heparins (LMWH) are antithrombotic drugs covering virtually all indications requiring immediately effective anticoagulation. For prevention and treatment of venous thromboembolism (VTE) UH have mainly been replaced by LMWH due to their practical usefulness (one or two subcutaneous daily doses without laboratory test for dose adjustment) and their more favourable risk-benefit profile. With respect to arterial occlusions this statement is also valid for unstable angina pectoris. The risk to develop heparin-induced thrombocytopenia (HIT) appears to be ten times lower with LMWH. In hospitals the use of UH is reserved for complex cases with high bleeding risk and the necessity to interrupt heparin effects rapidly. Therapeutic doses of UH are monitored by the classical coagulation assays, activated partial thromboplastin time (aPTT) and thrombin time (TT), but also by automated chromogenic tests of anti-factor Xa activity. There are no prospective studies directly comparing the efficiency of these three approaches. Disagreements between tests are not rare in individual cases. However, dosing recommendations for UH treatment of VTE (intravenous bolus of 80 IU/kg, followed by 18 IU/kg/h infusion) and average doses used are concordant. 0.30-0.70 anti-Xa IU/ml are considered as therapeutic range for UF infusion. Higher UH activities required during extracorporeal circulation in heart surgery or during coronary angioplasty are usually guided by bedside ACT (activated clotting time). For LMWH tests of anti-Xa activities may only be necessary during weight adjusted treatment of pregnant women, children, or cases with reduced kidney function (glomerular filtration rate < 30 ml/min.) or increased bleeding risk. Expected anti-Xa activities are 0.5-1.1 IU/ml and 1.0-2.0 IU/ml 4 hours after subcutaneous LMWH for dosing intervals of 12 hours and 24 hours respectively.

[Factor XIII in man: a review]. / Der Faktor XIII des Menschen: eine Ubersicht.

Activated by calcium and thrombin, factor XIII (FXIIIa) cross-links fibrin, thus increasing the stability of the fibrin clot. Furthermore, the hemostatic and reparative function of factor XIIIa is mediated by cross-linking other proteins like alpha(2)-plasmin-inhibitor, fibronectin, and collagen. The FXIII Val34Leu polymorphism plays a role in athero- and thrombogenesis. FXIII deficiency is an autosomal recessive disorder. The most common symptom is the bleeding tendency of the umbilical cord some days after birth. The diagnosis is confirmed by a solubility clot test in urea (5 mol/l) and then differentiated with an incorporation assay and immuno-electrophoresis. The bleeding tendency typically becomes obvious when FXIIIa activity is <1-2%. Severe bleeding episodes, however, may even occur with FXIIIa activities of 30-50%, especially in heterozygous persons. The sometimes life-threatening bleeding tendency of the inherited FXIII deficiency can be treated with FXIII concentrates. Acquired FXIII deficiency occurs in several internal diseases and after major surgery. The clinical significance is not completely clear. Moreover, FXIII is applied locally as a component of fibrin glues.

Platelets and cytokines in concert with endothelial activation in patients with peripheral arterial occlusive disease.

We tested the hypothesis whether circulating oncostatin-M (OSM), a cytokine that in vitro promotes fibrinogen biosynthesis and smooth muscle cell proliferation, or soluble CD40 ligand (CD40L; CD154), a leukocyte and platelet surface marker that stimulates endothelial cells, were associated: (a) with fibrinogen and other soluble cell adhesion molecules, such as P-selectin, vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 and platelet-endothelial cell adhesion molecule-1; or (b) with restenosis and platelet activation in 71 patients with peripheral arterial occlusive disease undergoing peripheral angioplasty (PTA). Platelet membrane activation markers (CD62P, CD63, activated GPIIb/IIIa) were immunologically measured at 0, 1, 24 and 48 h, and 3 and 6 months after PTA. Soluble cell adhesion molecules, endothelial markers and various hemostatic variables were measured before PTA. Of the patients, 42.3% developed restenosis within 6 months, defined as a >50% reduction of the lumen at the site of balloon dilatation. Soluble CD40L was not higher in the restenosis group. Interestingly, patients with high CD40L showed significantly higher soluble VCAM-1 (P < 0.01) and thrombomodulin (P < 0.01), as well as trends for higher soluble P- and E-selectin. Platelet activation was found uniformly increased mostly at 1 and 24 h, as well as at 3 and 6 months. OSM was measurable in 53.5% (6.9 +/- 9.4 pg/ml) of the patients and undetectable in the others. No differences in the rate of restenosis was found in these two groups, which did not differ with respect to fibrinogen (3.14 +/- 1.00 versus 3.21 +/- 0.70 g/l), or the other parameters. In conclusion, soluble CD40L is associated with higher endothelial biological markers that might implicate its involvement in endothelial activation. Platelet activation, probably intermittent, might play a significant role through the expression of CD40L as a source of activation signals to the endothelial cells. Free circulating OSM does not seem to correlate directly with fibrinogen or with other acute phase reaction proteins, the synthesis of which it could influence in vitro. This might well not mean, however, that OSM lacks this activity in vivo.

Continuous infusion of von Willebrand factor and factor VIII after elective heart surgery in a 12-year-old girl with von Willebrand disease type 3.

The continuous infusion of von Willebrand factor (VWF) in a 12-year-old girl with type 3 von Willebrand disease is described. The patient had elective heart surgery with cardiopulmonary bypass for closure of her atrial septum defect. The surgical procedure lasted 3 h. A presurgical bolus followed by a postoperative continuous infusion of factor VIII/VWF concentrates was administered. During the continuous infusion of clotting factors, stable plasma levels of hemostasis and avoidance of dangerously low levels of factor concentrates were achieved. No peri- or postsurgical complications occurred. Continuous infusion of clotting factors allows constant and hemostatic factor concentrations to be maintained with the possibility of dose titration and adjustment.

The effect of nimesulide versus placebo on hemostasis in healthy volunteers.

OBJECTIVE: The primary objective was to evaluate the effect of 7 days treatment with nimesulide on bleeding time. Blood coagulation, von Willebrand factor and platelet aggregation ex vivo were investigated as a secondary objective. METHOD: A randomised, double-blind, placebo-controlled, parallel group, single centre study performed on 20 healthy male volunteers who received either placebo or nimesulide 100 mg twice daily for 7 days. Bleeding time, platelet count and platelet aggregation, thromboplastin time (prothrombin time), activated partial thromboplastin time, fibrinogen, Factor VIII:C, vWF:Ag, vWF:RCof and platelet-rich plasma aggregation following stimulation with adenosine 5'-diphosphate, collagen, arachidonic acid, ristocetin, thrombin and thrombin receptor-activating peptide were measured at baseline (day 0), and then 3 h after the first (day 1) and last (day 7) treatment. RESULTS: The bleeding times for all subjects remained within the normal range throughout the study period, with no significant differences between the two treatment groups. There were no significant changes from baseline in platelet aggregation studies or in any of the other haemostasis tests, with no significant differences between the two groups. No clinically significant adverse events were reported or observed. CONCLUSIONS: Daily administration of 200 mg nimesulide for 7 days neither prolongs bleeding time nor modifies any of the other haemostasis variables measured. The lack of interactions with important haemostatic mechanisms suggests that nimesulide may also be used in patients with bleeding problems. This expectation has still to be confirmed by clinical experience.

Role of hemostatic risk factors for restenosis in peripheral arterial occlusive disease after transluminal angioplasty.

In a prospective study, the role of various hemostatic factors known to be associated with thrombotic risk was investigated in 71 patients with peripheral arterial occlusive disease (PAOD, stages II through IV, Fontaine; aged 68 +/- 13 years). Laboratory investigations were done before; 1, 24, and 48 hours after; and 3 and 6 months after percutaneous transluminal angioplasty (PTA). Thirty of 71 (42.3%) patients developed restenosis (> 50% reduction of the lumen diameter) at the site of PTA within 6 months, verified by color-coded duplex sonography. Significantly increased levels of thrombin-antithrombin III complexes (P < .01), prothrombin fragments 1 + 2 (P < .01), and D-dimers (P < .01) were found 1 hour, as well as 24 to 48 hours, after PTA. Fibrinogen (P < .01) and von Willebrand factor (P < .01) were significantly higher 48 hours after PTA. Restenotic patients as a whole had higher plasma fibrinogen (3.46 +/- 1.12 versus 2.95 +/- 0.62 g/L, P < .01) and C-reactive protein (25.4 +/- 46.7 versus 7.9 +/- 6.9 mg/L, P < .05) at baseline, as well as higher fibrinogen (P < .05) and prothrombin fragments 1 + 2 (P < .01) during months 3 to 6 after PTA. There was a nonsignificant tendency for higher values of von Willebrand factor (206 +/- 98% versus 184 +/- 100%, P = .2) at baseline in patients with restenosis, whereas tissue plasminogen activator, plasminogen activator inhibitor, coagulation screening tests, blood cell counts, and serum lipids showed no significant difference between the two groups. The relative risk for developing restenosis within 6 months while having high fibrinogen (> 2.8 g/L) or C-reactive protein at baseline was 2.80 (95% CI: 1.30-6.02, P < .01) and 1.96 (95% CI: 1.07-3.58, P < .05), respectively. Patients with critical limb ischemia (stage III/IV, Fontaine) had significantly higher fibrinogen and von Willebrand factor at repeated points of time, as well as significantly higher C-reactive protein and lower creatinine clearance at entry. In the logistic regression risk factor analysis, baseline plasma fibrinogen, C-reactive protein concentration, and the severity of the arterial disease were significantly predictive of restenosis. Our results indicate that high procoagulant factors and persistent thrombin generation of the hemostatic system might promote restenosis, particularly in patients with extended atherosclerosis. This finding suggests that new treatment strategies should be taken under consideration for patients with PAOD and PTA.

[Activation of endothelium-dependent hemostatic factors following bone marrow transplantation]. / Aktivierung Endothel-abhängiger hämostatischer Faktoren nach Knochenmarktransplantation.

Changes in hemostatic factors after bone marrow transplantation (BMT), with or without thrombotic complications, have already been described. The endothelium seems to be actively involved in such processes. Over a period of 2 years we evaluated various hemostatic factors, associated or not with endothelial stimulation, in 44 patients with BMT (40 leukemias and 4 aplastic anemias). Factor VIII activity (VIII:C), von Willebrand factor antigen (vWF:Ag), tissue plasminogen activator antigen (tPA), plasminogen activator inhibitor activity (PAI-1), antithrombin III, protein C and protein S were assayed before and 1, 3, 6, 12, 18, and 24 months after BMT. Factor VIII:C, vWF and tPA were found to be significantly increased 1-6 months after BMT, returning to normal later. Patients with acute graft versus host disease, fever or cyclosporin treatment had significantly higher VIII:C, vWF and tPA. The increase in these factors implies lasting stimulation of their release and/or synthesis from endothelial cells that is enhanced by some complications of BMT. The degree and character of these changes could favor activation of thrombotic processes.

Weak allergenicity of recombinant hirudin CGP 39393 (REVASC) in immunocompetent volunteers. The European Hirudin in Thrombosis Group (HIT Group).

BACKGROUND: As a result of their polypeptidic nature, hirudins could theoretically elicit an immunologic response in humans. METHODS: The present open survey evaluates the allergenic potential of recombinant hirudin CGP 39393 (REVASC) after repeated intravenous or subcutaneous exposures in immunocompetent volunteers with no known previous exposure to hirudins. Clinical signs and symptoms of allergic manifestations and surrogate markers of allergy (i.e. response to skin tests) were collected before and after each administration of CGP 39393. Hirudin-specific immunoglobulin (Ig)G or IgE antibodies were measured. RESULTS: Two hundred and sixty-three healthy volunteers were eligible, of whom 12.2% had a history of allergy and 18.3% had a high level of total IgE. No signs or symptoms of allergy directly attributable to CGP 39393 were reported, either during or immediately after a first challenge. Irritative skin reactions, to either the prick or the intradermal skin test, were observed in eight volunteers 28-56 days after the challenge. Three out of 200 volunteers exposed to a second course of CGP 39393 showed signs and symptoms of an allergic reaction. In all but one subject with a pruritic erythema it was possible to rule out a causative role for CGP 39393 (0.50%, 95% confidence limits [CL] 0.01-2.75). Three other volunteers displayed a suspect or a positive immediate-type skin reaction to the follow-up intradermal skin test without any signs or symptoms of allergy. Another asymptomatic volunteer (0.80%, 95% CL: 0.02-4.41) developed a low [i.e. 1+ on the radio-allergosorbent test (RAST) scale] but measurable titre of hirudin-specific IgE antibodies after the second exposure to CGP 39393. A third exposure in five volunteers was clinically uneventful. A positive reaction to the prick test and to the intradermal skin test was observed in one individual. CONCLUSIONS: Recombinant hirudin CGP 39393 appears to be a weak allergen. Repeated exposures are safe in fully immunocompetent subjects, including those with a history of previous allergies and high levels of total IgE. Type I allergic reactions are rare (i.e. less than 1%) after a second exposure and are limited to the skin. Routine skin tests are not needed to identify patients at risk of developing type I allergic reactions. Hirudin-specific IgE antibodies are rarely seen and then at very low titres.

[Low molecular weight heparin: favorable effect profile for prevention and therapy of venous thrombosis]. / Niedermolekulare Heparine: vorteilhaftes Wirkungsprofil für Prophylaxe und Therapie venöser Thrombosen.

This short review addresses the use of low molecular weight heparins (LMWH) for prevention and treatment of venous thromboembolism. In general surgery, the once daily subcutaneous (sc) administration of LMWH provides at least as much protection against thrombosis as 2 to 3 times 5000 IU sc of unfractionated heparin (UFH). In high-risk orthopedic surgery LMWH prophylaxis is definitely more efficient than conventional regimens with UFH or dextran. Several studies convincingly demonstrate that LMWH may be at least as good as UFH for the treatment of deep venous thrombosis.

[Tendency to thrombosis following bone marrow transplantation?]. / Thromboseneigung nach Knochenmarktransplantation?

Various thrombosis related parameters of the hemostatic system were evaluated in 11 patients who had had bone marrow transplantation (BMT). At 0, 1, 3 and 6 months after BMT, antithrombin III, heparin cofactor II, protein S (PS), factor VIII:C, von Willebrand factor (vWF:Ag, vWF:RiCof), tissue plasminogen activator (tPA), plasminogen activator inhibitor, thrombin antithrombin III complexes (TAT), d-dimers (DD) and antiphospholipid antibodies (APA) were determined. A statistically significant rise in the levels of vWF was observed after BMT, with a similar trend for tPA. High TAT and/or DD were detected in 10/11 patients and positive APA only in 5/11. Of the other parameters only free PS was permanently low, with normal total PS and C4bBP. These findings suggest persistent thrombin generation peri- and post-BMT. The significantly high vWF and the low free PS could foster a procoagulant state.

[Factor VIII (coagulation activity VIII:C, antigen concentration VIIIR:Ag and von Willebrand factor) in patients with clinically expected intravascular coagulation]. / Faktor VIII (Gerinnungsaktivität VIII:C, Antigenkonzentration VIIIR:Ag und von-Willebrand-Faktor) bei Patienten mit klinisch erwarteter intravasaler Gerinnung.

Factor VIII procoagulant activity, antigen concentration and von Willebrand activity as ristocetin cofactor were determined several times in 10 patients with DIC. These is a significant negative correlation between the DIC-score and the VIII:C/von Willebrand activity ratio.

[The determination of plasma proteolytic activity]. / Bestimmung der proteolytischen Aktivität im Plasma.

Experience with different peptide substrates for coagulation and fibrinolysis is reported. As the specifity of these substrates is relative, appropriate characterization of the proteolytic activity of defibrination syndromes is only achieved by simultaneous assays with various substrates. The influence of contact activation on blood sampling must be strictly defined.