[Antithrombotic treatment in acute coronary syndrome and atrial fibrillation]. / Antithrombotische Therapie bei akutem Koronarsyndrom und Vorhofflimmern.

The number of patients with atrial fibrillation (AF) is increasing due to the aging of the population. In addition, the number of patients with AF and indications for oral anticoagulation (OAC) for the prevention of stroke, who need dual antiplatelet treatment (DAPT) with acetylsalicylic acid (ASA) plus a P2Y12 inhibitor because of an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) is also increasing. In the past these patients received a triple therapy (TT) for 3-12 months. This TT has never been studied for efficacy; however, the rate of bleeding complications in comparison to a simple OAC or DAPT is significantly higher. Registries and smaller trials showed that DAPT with an OAC plus a platelet inhibitor may be sufficient to prevent stroke and stent thromboses/myocardial infarctions. These questions were investigated in various prospective and randomized studies involving all four non-vitamin K oral anticoagulants (NOAC) approved for stroke prevention in AF. The NOACs were tested against vitamin K antagonists (VKA) involving single antiplatelet therapy without using DAPT. The trials with rivaroxaban (PIONEER AF-PCI) and dabigatran (RE-DUAL PCI) have already been published but the investigations involving apixaban (AUGUSTUS) and edoxaban (ENTRUST-AF PCI) are still ongoing. The current status is that a NOAC plus a single antiplatelet agent, mostly clopidogrel, is superior to TT with VKA with respect to bleeding complications without any obvious disadvantage due to increases in stroke cases or cardiac ischemia. The international guidelines already permit treatment without TT in cases where the bleeding risk is prevalent. In this situation it is recommended to prescribe a NOAC plus a single antiplatelet therapy. Thus, TT no longer seems to be indicated for most patients with AF and after ACS or PCI.

e-Health-based management of patients receiving oral anticoagulation therapy: results from the observational thrombEVAL study.

Essentials e-Health based health care by an expert centre may advance management of oral anticoagulation. Outcome of patients was compared between an e-health based coagulation service and regular care. Patients in the coagulation service cohort experienced a significantly better clinical outcome. Lower risk for adverse events was related to anticoagulation-specific and non-specific outcome. SUMMARY: Background Management of oral anticoagulation (OAC) therapy is essential to minimize adverse events in patients receiving vitamin K-antagonists (VKAs). Data on the effect of e-health-based anticoagulation management systems on the clinical outcome of OAC patients are limited. Objectives To compare the clinical outcome of OAC patients managed by an e-health-based coagulation service (CS) with that of patients receiving regular medical care (RMC). Methods The prospective multicenter cohort study thrombEVAL (NCT01809015) comprised 1558 individuals receiving RMC and 760 individuals managed by a CS. Independent study monitoring and adjudication of endpoints by an independent review panel were implemented. Results The primary study endpoint (composite of thromboembolism, clinically relevant bleeding and death) occurred in 15.7 per 100 patient-years (py) with RMC and in 7.0 per 100 py with the CS (rate ratio [RR], 2.3; 95% confidence interval [CI], 1.7-3.1). Rates for major and clinically relevant bleeding were higher with RMC than with the CS: 6.8 vs. 2.6 and 10.1 vs. 3.6 per 100 py, respectively. Thromboembolic events showed an RR of 1.5 (95% CI, 0.8-2.6) comparing RMC with the CS. Hospitalization (RR, 2.6; 95% CI, 2.3-3.0) and all-cause mortality (RR, 4.6; 95% CI, 2.8-7.7) were markedly more frequent with RMC. In Cox regression analysis with adjustment for age, sex, cardiovascular risk factors, comorbidities, treatment characteristics and sociodemographic status, hazard ratios (HR) for the primary endpoint (HR, 2.2; 95% CI, 1.5-3.4), clinically relevant bleeding (HR, 3.1; 95% CI, 1.7-5.5), hospitalization (HR, 2.2; 95% CI, 1.8-2.8) and all-cause mortality (HR, 5.6; 95% CI, 2.9-11.0) favored CS treatment. Conclusions In this study, e-health-based management of OAC therapy was associated with a lower frequency of OAC-specific and non-specific adverse events.

Massive pulmonary embolism in a young boy with T-cell leukaemia. Successful thrombolytic therapy by recombinant tissue plasminogen activator (rtPA).

Acute pulmonary embolism (PE) is a serious complication in association with malignant diseases. We describe the successful treatment of PE applying a systemic thrombolytic therapy in a 4-year-old boy with acute lymphoblastic leukaemia. The thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) 0.1 mg/kg bodyweight per hour for six hours was continued for six days without important side effects. In particular no bleeding complications were observed. Computed tomography with contrast revealed a remarkable regression of the central PE. Without further delays the chemotherapy was resumed.

Recurrent cerebral ischaemia in a pregnant woman with patent foramen ovale II° and thrombophilia.

This case report concerns a pregnant multipara (age: 27 years) in the 16th gestational week. She developed a sudden onset of paraesthesia in her left lower arm although injecting dalteparin 5000 IU once daily subcutaneously (s. c.) due to a heterozygous factor V Leiden mutation and a prior miscarriage in the first pregnancy and preeclampsia in her third pregnancy. After the miscarriage she delivered two healthy children under prophylactic anticoagulation with low molecular weight heparin (LMWH). Now via magnetic resonance imaging (MRI) she was diagnosed as having multiple cerebral ischaemic lesions. Further workup revealed the presence of a patent foramen ovale (PFO) II° but no venous thrombosis in her legs. She was then treated with dalteparin 5000 IU twice daily by subcutaneous injections. At 19th gestational week she developed paraesthesia in her left lower arm again. The MRI showed a cortical lesion in the territory of the right median cerebral artery. The anticoagulation dose was increased stepwise under surveillance of the anti-FXa-level 3-4 h after subcutaneous injections aiming to achieve the supratherapeutic range of 1.2-1.5 IU/ml anti-Xa-units. No more neurological symptoms appeared under this antithrombotic therapy. The patient delivered by induction of labor at the 38th gestational week.

[Dabigatran therapy--perioperative management and interpretation of coagulation tests]. / Therapie mit Dabigatran. Periinterventionelles Management und Interpretation von Gerinnungstests.

UNLABELLED: Dabigatran, an oral, reversible direct factor IIa inhibitor, is approved in Europe for stroke prevention in atrial fibrillation and for the prevention of venous thromboembolism after elective hip and knee replacement. In contrast to vitamin K antagonists, a routine coagulation monitoring during the treatment with dabigatran etexilate is not necessary. However, in specific clinical situations such as invasive emergency procedures or serious haemorrhage, the actual anticoagulant status of dabigatran may be of importance for the treating clinician and can be assessed by clotting tests (aPTT, TT, ECT). The diluted thrombin time test (Hemoclot®), which is specifically calibrated for dabigatran, is useful for quantitative determination of the dabigatran serum concentration. In general, discontinuation of dabigatran etexilate 24 hours before standard elective surgery is sufficient to normalise the bleeding risk in patients with normal renal function. In patients with renal impairment and/or in the case of a high bleeding risk procedure the recommended duration of discontinuation is prolonged. If a bleeding episode occurs in a patient on dabigatran, further treatment should be based on the severity and localisation of the bleeding. A distinct feature of dabigatran is the possibility of effectively removing dabigatran from the circulation by haemodialysis. RECOMMENDATION: In the case of clinically minor bleedings, a delay in the administration of the next dabigatran etexilate dose is recommended. The length of the delay is based on the patient's individual thromboembolic risk. In minor bleedings the use of prothrombin complex concentrates is not indicated. In the case of moderate or major bleedings the main focus should be on stabilising the circulation by using fluids and blood products and, if a lesion can be identified, the local treatment thereof. If time and infrastructure is available, dialysis offers an effective and fast option to remove dabigatran out of the circulation. In the incidence of severe and life threatening bleedings, an additional, more complex haemostasis management is required. Besides haemodynamic stabilisation of the circulation, administration of prothrombin complex concentrates should not be delayed. It has to be kept in mind that standard laboratory coagulation parameters may not accurately reflect the effect of prothrombin complex concentrates in patients on dabigatran. Hence the effect of the prothrombin complex concentrate should be monitored clinically and adjusted by means of onset of coagulation in vivo.

Superficial thrombophlebitis in varicose vein disease: the particular role of methylenetetrahydrofolate reductase.

BACKGROUND: The purpose of this study was to compare the genetic background of superficial (SVT) and deep vein thrombosis (DVT). METHODS: Factor V (FV)-Leiden (G16891A)-, factor II(G20210A)-mutations, protein C- and S, as well as methylenetetrahydrofolate reductase (MTHFR) polymorphisms at C677T and A1298C, and serum homocysteine levels (hcy) were determined in 29 patients with SVT and 26 with DVT. Findings FV- and -II-mutations were less frequent in patients with SVT (2/3) compared with DVT (9/5), respectively (P < 0.002 in case of FV). However, the frequency of the MTHFR C677T polymorphism was significantly higher in patients with SVT compared with DVT (CT 12 versus 10, and TT 7 versus 1, respectively, P << 0.001). The distribution of the MTHFR A1298C genotype and serum hcy levels was similar in both patient groups. Protein S-deficiency was recorded once (SVT). Interpretation These results suggest that the MTHFR C677T-mutant genetically predisposes its carriers to SVT which may contribute to hypercoagulation in pre-existing varicose vein disease.

[Haemostatic testing prior to elective surgery? Yes!]. / Laboranalytischer Ausschluss einer hämorrhagischen Diathese vor elektiven Eingriffen? Ja!

Haemorrhagic disorders must be excluded prior to any operation or other invasive procedure that has the potential to involve serious bleeding. When assessing the individual risk of bleeding, screening tests of hemostasis must be combined with the patient's clinical history and symptoms, and any history of bleeding must be explored under direct medical supervision using a standardized questionnaire. However, this bleeding history is neither very specific, nor is it particularly sensitive. Screening tests that have been found to be useful include platelet count, activated partial thrombo plastin time (aPTT), prothrombin time (PT) and clottable fibrinogen. No reliable, sensitive and specific screening test is however available today to screen for platelet dysfunction or von Willebrand disease. A specialized coagulation laboratory should be involved when the bleeding history or laboratory screening indicate a potential haemorrhagic disorder.

[Low molecular heparin for treatment of venous thrombosis in two very low-birth-weight pre-term infants with genetic risk factors]. / Niedermolekulares Heparin bei Frühgeborenen mit hereditären Risikofaktoren und venösen Thrombosen.

We describe the use of low molecular weight heparin to treat venous thrombosis in two very low-birth-weight pre-term infants (GA: 30 and 27 weeks) both with genetic and acquired prothrombotic risk factors. Initially both infants were treated with unfractionated heparin. Since in one infant no effect on the thrombus size was observed and in the other infant there was an increase in size, the anticoagulation therapy was switched to subcutaneously injected low molecular heparin (Enoxaparin). During enoxaparin therapy the anti-Xa-level was carefully monitored and dosages were adjusted accordingly. Partial resolution of the thrombosis was achieved in both infants during enoxaparin therapy. No clot extension or recurrence of thrombosis occurred. An accidental overdose of Enoxaparin (100 times the required dosage) was administered to one infant without any consequences. Our data suggest that the use of low molecular weight heparin (Enoxaparin) for treatment of venous thrombosis in our two preterm infants was practical, safe and effective.

Antidiabetic medications in overdose: a comparison of the inquiries made to a regional poisons unit regarding original sulfonylureas, biguanides and insulin.

OBJECTIVE: The drugs most commonly used to treat diabetes mellitus are sulfonylureas, biguanides and insulin. The most serious effects seen in overdose with these agents are hypoglycemia or lactic acidosis which may be fatal or cause cerebral defects. The present investigation analyzes inquiries made to a regional poisons unit involving overdoses with sulfonylureas, biguanides and insulin. PATIENTS AND METHODS: A total of 218,070 made inquiries between 1995 and 2004 were evaluated. The inquiries were received by telephone and a standardized questionnaire was sent subsequently to the physicians calling for follow-up information. The cases were analyzed with regard to gender, age, etiology, symptoms and clinical outcome. RESULTS: 263 inquiries concerning sulfonylureas (48.3% female, 49.4% male, 2.3% sex unknown, average age 39.1 +/- 26.8 years), 172 concerning biguanides (60.5% female, 37.2% male, 2.3% sex unknown, average age 41.5 +/- 24.1 years), and 191 concerning insulin (53.9% female, 41.9% male, 4.2% sex unknown, average age 44.6 +/- 16.7) were made. In cases involving sulfonylureas, the etiology was deliberate self-poisoning in 62.7% and accidental in 31.9% (biguanides 60.5% and 29.1%, insulin 85.3% and 9.4%). Using the Poisoning Severity Score, no symptoms were observed in 41.4% of the patients with sulfonylurea overdose (biguanides 40.1%, insulin 22.5%), minor symptoms in 37.6% (biguanides 32.6%, insulin 33.5%), major symptoms in 14.4% (biguanides 13.4%, insulin 26.2%) and serious symptoms in 4.6% (biguanides 12.2%, insulin 14.7%). Returned questionnaires reporting clinical outcomes showed that a full recovery occurred in most patients (sulfonylureas 97.4%, biguanides 93.0%, insulin 94.4%), cerebral defects persisted in 1.8% of the cases involving sulfonylureas (biguanides 1.5%, insulin 2.4%), and that 0.9% of the patients with sulfonylurea overdose died (biguanides 6.1%, insulin 3.6%). CONCLUSIONS: Sulfonylureas were the most frequently observed medication in cases of overdose with antidiabetic agents. Insulin overdose caused the highest number of major and serious symptoms. Overdose with biguanides led to the most deaths.

Arterial embolism to the upper extremity in a patient with factor V Leiden mutation (APC resistance)--a case report and review of the literature.

Factor V Leiden mutation has emerged as one of the leading abnormalities in inherited blood coagulation disorders, resulting in a markedly increased risk for deep leg vein thrombosis. A 24-year-old woman presented with acute onset of critical ischemia of her left thumb and index finger. Intraarterial angiography revealed an embolus in the distal radial artery and a thrombotic occlusion of the digital artery of the thumb and index finger. Immediate therapy encompassed a selective surgical embolectomy of the distal radial artery followed by a local intraarterial lysis that was continued for 3 days. Additionally, therapeutic anticoagulation and vasodilating drugs (prostaglandin E) were administered. Within 2 days, capillary refill reappeared and the initial loss of sensory function at the tip of the thumb and index finger diminished. A screening test for thrombophilic disorders led to the diagnosis of a heterozygous mutation of factor V (Leiden mutation). Arterial thromboembolic events of factor V Leiden mutation are rare and have to date been described only in the supraaortic and coronary circulation. Therefore, the arterial embolism to the left hand presented in this report constitutes a rarity that could be successfully salvaged by the combined use of a vascular surgical procedure and intensified medical management.

[Anticoagulation of pregnant women with mechanical heart valve prostheses]. / Antikoagulation in der Schwangerschaft bei mechanischem Herzklappenersatz.

Patients with a mechanical heart valve prosthesis (MHVP) are usually anticoagulated with oral anticoagulants (OAC) to prevent thromboembolic complications. Considering the paucity of published data, the management of women with MHVP of childbearing age, who wish to become pregnant, still remains difficult and complicated. OAC may cause embryopathy during the first trimester, while neurologic complications, stillbirth and fetal death may appear during the second and third trimester. While the application of unfractionated heparin (UFH) in pregnant patients with MHVP may fail to prevent thromboembolic complications even with therapeutic dosage, only little is known about the application of body weight adjusted therapeutic dosages of low molecular weight heparin (LMWH). We report on 8 female patients, 7 with MHVP, one with atrial fibrillation, who were treated with LMWH during the whole pregnancy. No malformations or major bleeding complications were observed, no valve thrombosis or thromboembolic complications occurred. Three patients developed moderate heart failure during the third trimester, which resolved after treatment. In three patients, cesarean section was necessary, while the other five patients delivered spontaneously. Therefore, anticoagulation with body weight adjusted LMWH seems to be an alternative, safe and efficient treatment for pregnant women with MHVP. Prospective, randomized studies are needed to further evaluate this new therapeutic approach. The underlying heart disease represents a serious comorbid condition that requires continuous interdisciplinary monitoring.

[Anticoagulation of pregnant women with a mechanical heart valve prosthesis]. / Antikoagulation in der Schwangerschaft bei mechanischem Herzklappenersatz.

Patients with a mechanical heart valve prosthesis (MHVP) are usually anticoagulated with oral anticoagulants (OAC) to prevent thromboembolic complications. Considering the paucity of published data, the management of women with MHVP of childbearing age, who wish to become pregnant, still remains difficult and complicated. OAC may cause embryopathy during the first trimester, while neurologic complications, stillbirth and fetal death may appear during the second and third trimester. While the application of unfractionated heparin (UFH) in pregnant patients with MHVP may fail to prevent thromboembolic complications even with therapeutic dosage, only little is known about the application of body weight adjusted therapeutic dosages of low molecular weight heparin (LMWH). We report on 8 female patients, 7 with MHVP, one with atrial fibrillation, who were treated with LMWH during the whole pregnancy. No malformations or major bleeding complications were observed, no valve thrombosis or thromboembolic complications occurred. Three patients developed moderate heart failure during the third trimester, which resolved after treatment. In three patients, cesarean section was necessary, while the other five patients delivered spontaneously.Therefore, anticoagulation with body weight adjusted LMWH seems to be an alternative, safe and efficient treatment for pregnant women with MHVP. Prospective, randomized studies are needed to further evaluate this new therapeutic approach. The underlying heart disease represents a serious comorbid condition that requires continuous interdisciplinary monitoring.

[Diagnosis and therapy of leg and pelvic deep vein thrombosis in pregnancy]. / Diagnostik und Therapie der tiefen Becken-Beinvenenthrombose in der Schwangerschaft.

OBJECTIVE: To establish differences in the management of acute thrombosis in the deep venous system associated with pregnancy in patients undergoing thrombectomy and in patients receiving heparin therapy. MATERIALS AND METHODS: From 1984 to 1995 the course of pregnancy was assessed retrospectively in 26 patients with acute deep vein thrombosis. Thirteen patients underwent thrombectomy with establishment of an arteriovenous fistula and 13 patients received conservative treatment with heparin therapy. In addition to the assessment of clinical symptoms, signs of thrombosis, diagnoses established with imaging techniques and of laboratory parameters, early complications and obstetric data obtained in surgically and conservatively treated patients were compared. RESULTS: The incidence of deep vein thrombosis in the 26 patients (median age 28 years) was 0.21%. In 53.8% of the cases the occurrence of thrombosis was observed in the second trimester (median: 27.5 weeks of gestation). The presence of risk factors was demonstrated in 58% of cases. The most frequently reported symptoms were swelling of the affected leg (88.5%) and pain (61.5%). A marked predilection for the left leg was recorded in 88% of cases. In contrast to phlebography, twice the number of sonographic studies were performed. The comparison of both therapeutic regimes showed a three-fold increase in the rate of early complications in patients after thrombectomy. The rate of recurrent thrombosis in these patients was 58.3% compared to a recurrence rate of 15.4% in patients undergoing heparin therapy. CONCLUSIONS: Recurrent thrombosis and pulmonary embolism represent the most frequent complications associated with thrombosis in the deep venous system during pregnancy. Although currently there is a lack of conclusive data on the development of postthrombotic syndrome, heparin therapy appears to be associated with fewer maternal risks. Interdisciplinary cooperation is urgently needed.

Antithrombin substitution therapy.

Antithrombin (AT) is the most important inhibitor of the coagulation system. Due to the high cost of AT treatment, there must be rational arguments to justify its use. Established indications for AT substitution include hereditary homozygous AT deficiency in newborn babies and hereditary AT deficiency before or during certain situations, for example, surgery and pregnancy. AT substitution therapy can also be justified in the treatment of complex coagulation disorders, sepsis with disseminated intravascular coagulation and acute thromboembolic events with reduced AT activity. Administration of AT concentrates to patients with nephrotic syndrome or stable hepatopathy is not justified. To achieve an anti-inflammatory effect in patients with sepsis, it is thought that above-normal levels of AT activity (> 140% of the normal level) are probably needed. Although currently available data on the effect of AT in the treatment of sepsis are insufficient, results from controlled studies will soon become available and will show whether sepsis is an indication for AT substitution.

[Goodpasture syndrome: treatment initiation with plasmapheresis before histologic diagnostic verification]. / Goodpasture-Syndrom (GPS): Behandlungsbeginn mit Plasmapherese vor histologischer Diagnosesicherung.

A 28 years old male patient presented, after a history of previous recurrent hemoptysis, with diffuse bilateral air space consolidation at chest radiography (CXR). Within 48 hours, partial respiratory insufficiency developed and required intubation. On a clinical and roentgenographic basis, the diagnosis of a Goodpasture syndrome was suspected. Plasmapheresis and immunosuppressive therapy with prednisone and cyclophosphamide were started immediately. Three days after admission, macrohematuria developed and serum creatinine began to rise to a maximum of 3.9 mg/dl. Totally, 13 plasmaphereses were performed within 27 days. Clinical, laboratory and radiological findings improved markedly. 30 days after admission, the patient was discharged and followed on an outpatient basis. Serum creatinine eventually decreased to 1.1 mg/dl. Initially, circulating antibodies against glomerular basement membrane (GBM) were positive, controls remained negative. Renal biopsy was performed after the acute phase and showed glomerulonephritis and linear immunoglobulin deposition along the GBM. Radiologic findings at CXR and high resolution computed tomography are demonstrated.

[The use of low-molecular heparin for anticoagulation in pregnancy]. / Einsatz von niedermolekularem Heparin zur Antikoagulation in der Schwangerschaft.

A 26-year-old woman, on bedrest since the 6th week of pregnancy because of threatened abortion, developed thrombosis in the left iliac, superficial femoral and common femoral veins with small pulmonary emboli in the 11th week. Inhibitor deficiency was excluded. The thrombosis was only partially recanalized by unfractionated heparin at therapeutic dosage (38,400 IU per 24 h). As thrombolysis treatment and oral anticoagulation were contraindicated because of the threatened abortion, coagulation with low molecular weight heparin (LMWH) was started in the 18th week (5000 anti-Xa units daily subcutaneously). Maximal anti-Xa activity in plasma never exceeded 0.3 U/ml and there were no complications. The patient was delivered of a healthy girl (2,660 g, 48 cm) by caesarean section in the 37th week. Immediately post-partum LMWH was demonstrated with an anti-Xa activity of 0.3 U/ml in maternal blood, but none in simultaneously obtained cord venous blood. This case suggests that treatment of phlebothrombosis with LMWH is a reasonable measure even during pregnancy.