Incidence of thrombotic complications and overall survival in hospitalized patients with COVID-19 in the second and first wave.

INTRODUCTION: In the first wave, thrombotic complications were common in COVID-19 patients. It is unknown whether state-of-the-art treatment has resulted in less thrombotic complications in the second wave. METHODS: We assessed the incidence of thrombotic complications and overall mortality in COVID-19 patients admitted to eight Dutch hospitals between September 1st and November 30th 2020. Follow-up ended at discharge, transfer to another hospital, when they died, or on November 30th 2020, whichever came first. Cumulative incidences were estimated, adjusted for competing risk of death. These were compared to those observed in 579 patients admitted in the first wave, between February 24th and April 26th 2020, by means of Cox regression techniques adjusted for age, sex and weight. RESULTS: In total 947 patients with COVID-19 were included in this analysis, of whom 358 patients were admitted to the ICU; 144 patients died (15%). The adjusted cumulative incidence of all thrombotic complications after 10, 20 and 30 days was 12% (95% confidence interval (CI) 9.8-15%), 16% (13-19%) and 21% (17-25%), respectively. Patient characteristics between the first and second wave were comparable. The adjusted hazard ratio (HR) for overall mortality in the second wave versus the first wave was 0.53 (95%CI 0.41-0.70). The adjusted HR for any thrombotic complication in the second versus the first wave was 0.89 (95%CI 0.65-1.2). CONCLUSIONS: Mortality was reduced by 47% in the second wave, but the thrombotic complication rate remained high, and comparable to the first wave. Careful attention to provision of adequate thromboprophylaxis is invariably warranted.

[Normoglycaemic ketoacidosis in pregnant patients with diabetes; early recognition is critical]. / Normoglykemische ketoacidose bij zwangere diabetici.

Diabetic ketoacidosis (DKA) during pregnancy is a rare but very serious complication that requires early recognition and treatment to prevent severe complications. Here we present three cases in which DKA occurred during normoglycaemia, demonstrating the importance of early recognition. In pregnancy, DKA can occur at lower blood glucose levels than usual due to several pregnancy-related factors, such as altered metabolism, increased insulin resistance, lower buffering capacity related to chronic hyperventilation and hunger. Symptoms that are common during pregnancy, such as vomiting, may be missed as a first sign of DKA. In patients with type 1 diabetes mellitus (especially those on continuous subcutaneous insulin infusion) insulin administration must never be discontinued, as this prevents lipolysis and ketone formation. Physicians and patients need to be aware of the risks and management of DKA in pregnancy.

Plasma adiponectin concentration has an inverse and a non linear association with estimated glomerular filtration rate in patients with K/DOQI 3 - 5 chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased incidence of cardiovascular disease (CVD). A few studies have demonstrated elevated plasma adiponectin and leptin levels in CKD. The aims of this study were to assess whether 1) estimated glomerular filtration rate (eGFR) is associated with plasma leptin and adiponectin; and 2) adiponectin and leptin (partly) explain associations of CKD with endothelial dysfunction, insulin resistance, and low-grade inflammation in patients with K/DOQI Stage 3 - 5 CKD. METHODS: Baseline data from 91 patients with Stage 3 - 4 CKD in the anti-oxidant therapy in chronic renal insufficiency study, a randomized, double-blind, placebo-controlled trial, in which the effects of oxidative stress-lowering treatment on vascular function and structure were studied, and from 50 dialysis naïve patients, who took part in an open-label, randomized study that compared two peritoneal dialysis regimens, used in the analysis. All subjects for both the studies were recruited in the same centres. RESULTS: The association between eGFR and adiponectin was non-linear. In multivariate analysis, log-eGFR (unstandardized beta = 8.303 microg/ml, p < 0.0001) was the strongest determinant of adiponectin, and body mass index the strongest determinant of leptin (beta = 2.477 ng/ml, p < 0.0001). Plasma adiponectin and leptin did not modify the associations between eGFR and plasma von Willebrand factor or soluble vascular adhesion molecule-1. Plasma leptin had the strongest association with the homeostatic model assessment (HOMA-IR) index. Plasma C-reactive protein had no association with adiponectin or leptin. CONCLUSIONS: In patients with K/DOQI Stage 3 - 5 CKD, renal function had a significant non-linear inverse association with and was the strongest predictor of adiponectin. BMI was the strongest predictor of plasma leptin. Plasma adiponectin and leptin did not explain, and thus presumably are not involved in, the association between eGFR and some markers of endothelial dysfunction.

The additive value of N-terminal pro-B-type natriuretic peptide testing at the emergency department in patients with acute dyspnoea.

BACKGROUND: B-type natriuretic peptide (BNP) and its inactive counterpart NT-proBNP can help to identify or rule out heart failure in patients presenting with acute dyspnoea. It is not well known whether measurement of these peptides can be omitted in certain patient groups. METHODS: We conducted a prospective observational study of 221 patients presenting with acute dyspnoea at the emergency department. The attending physicians estimated the probability of heart failure by clinical judgement. NT-proBNP was measured, but not reported. An independent panel made a final diagnosis of all available data including NT-proBNP level and judged whether and how NT-proBNP would have altered patient management. RESULTS: NT-proBNP levels were highest in patients with heart failure, alone or in combination with pulmonary failure. Additive value of NT-proBNP was present in 40 of 221 (18%) of the patients, and it mostly indicated that a more intensive treatment for heart failure would have been needed. Clinical judgement was an independent predictor of additive value of NT-proBNP with a maximum at a clinical probability of heart failure of 36%. CONCLUSION: NT-proBNP measurement has additive value in a substantial number of patients presenting with acute dyspnoea, but can possibly be omitted in patients with a clinical probability of heart failure of >70%.

Mild-to-moderate renal impairment is associated with platelet activation: a cross-sectional study.

The high incidence of cardiovascular disease in patients with moderate renal impairment is not fully explained by traditional atherothrombotic risk factors. Independently from these factors, blood platelet activation may increase the cardiovascular disease risk of patients with mild-to-moderate renal impairment. Blood platelet activation has not been studied in nondiabetic patients with mild-to-moderate renal impairment. Therefore, we measured the extent of platelet activation by means of fluorescence cytometry in 93 nondiabetic patients with MDRD-estimated creatinine clearance ranging from 13 - 63 ml/min/1.73 m2. As platelet activation parameters we used the expression of CD62P (P-selectin), CD 63 (glycoprotein 53), PAC-1 (activated fibrinogen receptor), CD42b (von Willebrand factor receptor) and CD41 (fibrinogen receptor) on the platelet surface membrane. The expression of CD62p, CD63 and PAC-1 was statistically significantly inversely related to the estimated glomerular filtration rate in these patients (standardized b -0.28, -0.32 and -0.39, respectively). We conclude that nondiabetic mild-to-moderate renal impairment is associated with blood platelet activation. Whether this contributes to the increased cardiovascular risk in these patients needs further study.

Two rare complications of glioblastoma multiforme: persistent hiccup and acquired haemophilia A.

A 69-year-old man was admitted to the hospital with persistent hiccups. Computed tomography and magnetic resonance imaging of the brain were performed and revealed a glioblastoma multiforme localised in the right temporal lobe. After resection, the hiccups disappeared, suggesting that temporal areas are involved in control mechanisms of hiccups. A month later, the patient was readmitted because of skin, mucosal and soft tissue bleedings. Laboratory findings showed a prolonged aPTT, a low factor VIII activity and a factor VIII inhibitor, leading to the diagnosis of acquired haemophilia A. Acquired haemophilia A is a potentially life-threatening haemorrhagic disorder resulting from the presence of antibodies against factor VIII. We believe that this disorder developed due to exposure of factor VIII(-like) tumour antigens to the immune system. This case illustrates two yet unknown complications of a glioblastoma multiforme: persistent hiccups and acquired haemophilia A.

Erectile dysfunction as the presenting symptom of a pheochromocytoma.

We report the case of a 59-year-old man with a pheochromocytoma in which erectile dysfunction was the main symptom. Erectile function was related to the amount of noradrenaline secreted by the tumor, as was determined when recurrence of the malignancy was diagnosed twice. Erectile function could be restored by lowering the level of noradrenaline excretion, either by removal of the noradrenaline-producing tumor or by treatment with doxazosin. By stimulating alpha-1-adrenoceptors, high levels of noradrenaline are likely to result in excessive contraction of the corpus cavernosum and penile vessels and, thereby, cause erectile dysfunction.

[Anejaculation caused by haemosiderosis: male infertility in hereditary haemochromatosis]. / Zaadloos door ijzerstapeling: mannelijke infertiliteit bij hereditaire hemochromatose.

A couple was investigated for subfertility. Haemochromatosis was suspected when the 36-year-old man had failure of ejaculation, fatigue and limited facial hair growth. Haemochromatosis was confirmed by an iron saturation of 102% (normal range: 20-45), a highly elevated serum ferritin concentration of 5468 mg/1l (normal range: 18-280) and highly elevated liver enzymes. Molecular genetics showed homozygous C282Y mutation of the HFE gene. Due to consequent venesection therapy, levels of ferritin and transferrin decreased and liver enzymes normalized. However luteinizing hormone and follicle stimulating hormone failed to increase to normal levels. Treatment with gonadotropins was then applied, which corrected ejaculation and semen characteristics. His partner failed to become pregnant with ovulation stimulation and intrauterine inseminations. After two unsuccessful IVF procedures she became pregnant in the third procedure. Haemochromatosis should be considered and iron studies performed if subfertility due to an endocrine disorder is being investigated. Deposition in the pituitary or the gonads of the HFE-mutated patients leads to hypogonadism. Most of the patients with C282Y mutation are homozygous (85-90%), but the majority of the carriers will not develop the disease. Deficiency of hepcidin, an important regulator for the iron metabolism, was suspected in our patient, based on the early onset of his disease and the low serum levels of hepcidin. The age at diagnosis and the start of venesections is critical for reversal of organ damage. Aggressive venesection can restore hypothalamic-pituitary-gonadal function, preventing further organ damage. But with increasing disease progression venesection will not restore azoospermia or the failure to ejaculate.

Non invasive treatment of peri-aortic inflammation after endovascular graft.

INTRODUCTION: Peri-aortitis is a rare and severe complication of endovascular treatment. REPORT: Two cases of peri-aortic inflammation are reported after receiving an abdominal endoprosthesis as treatment for abdominal aneurysm. Both patients were successfully treated with high doses of prednisone and the grafts were left in situ. DISCUSSION: High doses of prednisone may be the treatment of choice for post endovascular peri-aortitis.

Epidemiology of homocysteine as a risk factor in diabetes.

Patients with diabetes mellitus are prone to cardiovascular disease, and risk factors presumably unrelated to diabetes, such as hyperhomocysteinemia, may be involved in the atherothrombotic process in these subjects. Plasma homocysteine levels are usually normal in diabetes, although both lower and higher levels have been reported. This has been ascribed to hyperfiltration and renal dysfunction or low folate status, respectively. Insulin resistance does not appear to be a major determinant of plasma homocysteine level. Hyperhomocysteinemia has been associated with microalbuminuria and retinopathy in type 1 and type 2 diabetes. In patients with type 2 diabetes, plasma homocysteine concentration has also been shown to be related to macrovascular disease and death. This relation seems to be stronger in subjects with diabetes than without. The underlying pathophysiological mechanism of this increased vascular risk remains unexplained, but may relate to worsening of endothelial dysfunction or structural vessel properties. Because homocysteine and diabetes have an apparent synergistic detrimental vascular effect, patients with diabetes are good candidates for screening and treatment with folic acid until the results of ongoing clinical trials are available.

[Sudden death following a single oral administration of haloperidol]. / Plotseling overlijden na eenmalige orale toediening van haloperidol.

A 39-year-old man was admitted with myasthenia, alcoholic hepatitis and electrolyte abnormalities due to an inadequate nutritional state. On admission the ECG showed a prolonged QTc interval (0.46 s). The patient was treated with intravenous fluid and supplementary vitamins and minerals. On the third day of admission the patient developed a delirium, partly due to alcohol withdrawal, and was therefore treated with oxazepam 50 mg 3 times daily and a single dose of haloperidol 5 mg. One hour after ingesting haloperidol, the patient suddenly succumbed and resuscitation was not successful. The autopsy revealed a cardiomyopathy but no explanation for the sudden death. Due to the temporal relationship between the ingestion of haloperidol and this sudden death, we assume that haloperidol induced a fatal arrhythmia in the presence of a preexisting prolonged repolarisation time. To the best of our knowledge, sudden death after a single oral therapeutic dose of haloperidol has not previously been described.

Homocysteine-lowering treatment: an overview.

Elevated fasting plasma concentrations of homocysteine have a high prevalence in subjects with cardiovascular disease and have also been associated with an increased risk of atherothrombosis in most, but not all, prospective studies. The most frequent causes of hyperhomocysteinaemia are genetic defects, such as cystathionine-beta-synthase (CBS) deficiency, deficiencies of folic acid and/or vitamin B12, renal failure and interference in homocysteine metabolism by drugs or metabolic alterations. In most cases, no underlying cause can be established. Subjects with CBS deficiency are treated with pyridoxine with additional folic acid and betaine if necessary. Folic acid and vitamin B12 deficiencies should be corrected by supplementation. Increases in folate intake by dietary changes or fortification can also lower plasma homocysteine in vitamin-replete subjects with normal plasma homocysteine levels. In renal failure, folic acid treatment (1-5 mg/day) ameliorates the plasma homocysteine level in most cases but hyperhomocysteinaemia persists in the majority of patients. Primary (fasting) hyperhomocysteinaemia can be treated with folic acid (0.5-5 mg/day). An abnormal methionine-loading test identifies additional patients at risk and postmethionine-loading hyperhomocysteinaemia should be treated with a combination of pyridoxine and folic acid. In the absence of dose-effect studies, a combination of pyridoxine (50 mg) and folic acid (5 mg) is advised. Large clinical trials are currently underway to establish the role of homocysteine-lowering therapy in the secondary prevention of atherothrombotic disease. In view of the effective, cheap and safe character of therapy with folic acid and pyridoxine, a policy can be accepted to screen and treat high-risk patients until these trials have been concluded.

Intravascular hemolysis by IgA red cell autoantibodies.

A 66-year-old male patient with severe intravascular hemolysis is presented. Laboratory investigation revealed initially a negative direct antiglobulin test (DAT), suggesting a Coombs-negative hemolytic anemia. Additional testing with monospecific anti-IgA was strongly positive. IgA autoantibodies with anti-e specificity and nonspecific IgA autoantibodies were identified. A diagnosis of IgA-only-associated warm AIHA was made. Treatment included transfusion of multiple e-negative typed red cell concentrates and administration of high-dose prednisone. The pathophysiologic mechanism of the rare IgA-induced warm AIHA is discussed.

Homocysteine metabolism in renal failure.

Of the many amino acid abnormalities that are present in chronic renal failure, hyperhomocysteinemia has drawn increasing attention because of its proposed role in the development and/or progression of atherothrombotic disease. Renal function is a major determinant of fasting plasma homocysteine level, and the inverse relationship between the glomerular filtration rate (GFR) and plasma homocysteine level is present throughout the whole range of renal function. Although this suggests an active renal homocysteine metabolism, no important urinary excretion or active homocysteine extraction has been demonstrated in the human kidney. Analysis of plasma concentrations of the various cofactors and substrates of homocysteine metabolism, and the effects of different therapies indicate that an abnormal folate metabolism may be the cause of hyperhomocysteinemia in uremia. This is further supported by the finding that homocysteine remethylation, as assessed by stable isotope techniques, is impaired in dialysis patients. It is unclear whether decreased remethylation is also responsible for other abnormalities of homocysteine metabolism in renal failure such as the exaggerated rise and the impaired decline of plasma homocysteine concentration after methionine or homocysteine loading. More studies are necessary to pinpoint the precise mechanisms that lead to hyperhomocysteinemia in renal failure. This should lead to optimal treatment and, ultimately, to the prevention of cardiovascular complications in this vulnerable patient group.

Long-term reduction of plasma homocysteine levels by super-flux dialyzers in hemodialysis patients.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for cardiovascular disease in chronic hemodialysis (CHD) patients. Treatment with folic acid normalizes total homocysteine (tHcy) in only a minority of the patients. The present investigation has been conducted to study the influence of various dialyzers with different flux characteristics on the reduction of tHcy in the long term. METHODS: Total Hcy, folate, vitamin B6, vitamin B12, and albumin levels were assessed prospectively in 10 patients undergoing HD with high-flux polysulfon (PS; F 60) and 20 patients with super-flux dialyzers (N = 10 PS, F 500S; N = 10 CTA, Tricea 150G). Blood samples were collected before hemodialysis both at the beginning of the study and after 12 weeks. RESULTS: At baseline, all the groups showed similar tHcy levels. During high-flux dialysis, tHcy remained stable. In contrast, during dialysis with both super-flux modalities, tHcy decreased significantly (F 500S week 1, 29.6 +/- 9.9 micromol/L, and week 12, 21.5 +/- 8.5 micromol/L, P = 0.007; Tricea 150G week 1, 24.4 +/- 8.7 micromol/L, and week 12, 15.3 +/- 3.7 micromol/L, P = 0.008). The difference between high-flux and super-flux dialyzers was highly significant (mean: high-flux increase 15.6%, super-flux decrease 33. 3%, P = 0.001). Multivariate analysis showed a significant effect of super-flux dialysis on tHcy (P = 0.001), independently of the previously mentioned variables. CONCLUSIONS: Our findings clearly show that both types of super-flux dialyzers reduced tHcy significantly. As the molecular weight of free homocysteine is less than 268 D, the most likely explanation seems to be the removal of uremic toxins with inhibitory activities against enzymes involved in the extrarenal homocysteine metabolism.

Hyperhomocysteinemia, vascular pathology, and endothelial dysfunction.

Hyperhomocysteinemia has been associated with premature atherothrombotic vascular disease. It is not known whether hyperhomocysteinemia induces a distinct type of vascular disease. Its interaction, if any, with traditional risk factors also remains unclear. The pathophysiological mechanisms linking hyperhomocysteinemia to vascular disease have been extensively studied in vitro and in animals. From these studies, it has been suggested that homocysteine limits the bioavailability of nitric oxide (NO), increases oxidative stress, stimulates smooth cell proliferation, and alters elastic wall properties. The relevance of these proposed mechanisms in vivo is unclear, because clinical studies have yielded controversial results with regard to the relation between plasma homocysteine levels and indices of endothelial function, such as brachial artery flow-mediated vasodilatation and plasma levels of endothelium-derived marker proteins. Up till now, there have been no controlled data on the effects of homocysteine-lowering treatment on vascular function or clinical end points. The precise mechanisms (if any) by which homocysteine mediates its adverse vascular effects are in fact unknown but may relate to impaired endothelial and smooth muscle cell function.

Homocysteine and renal disease.

Hyperhomocysteinemia refers to an elevated circulating level of the sulfur-containing amino acid homocysteine and has been shown to be a risk factor for vascular disease in the general population. In patients with renal failure, hyperhomocysteinemia is a common feature. The underlying pathophysiological mechanism for this phenomenon is unknown. Proposed mechanisms include reduced renal elimination of homocysteine and impaired nonrenal disposal, possibly because of inhibition of crucial enzymes in the methionine-homocysteine metabolism by the uremic milieu. Absolute or relative deficiencies of folate, vitamin B6, or vitamin B12 may also play a role. Several case-control and prospective studies have now indicated that hyperhomocystenemia is an independent risk factor for atherothrombotic disease in patients with predialysis and end-stage renal disease. In renal patients, plasma homocysteine concentration can be reduced by administration of folic acid in doses ranging from 1 to 15 mg per day. In more than 50% of the cases, however, the homocysteine concentration remains above 15 micromol/L. The effects of vitamin B12 or vitamin B6 are unclear. Large intervention trials are now needed to establish whether homocysteine-lowering therapy will reduce atherothrombotic events in patients with renal failure. These studies are now planned or are ongoing.

[Fever of unknown origin caused by the adult form of Still's disease]. / Febris e causa ignota verklaard door de volwassen vorm van de ziekte van Still.

In three patients, two women aged 70 and 19 years and a man aged 33 years with long-lasting fever no diagnosis was made after extensive diagnostic work-up. After exclusion of infectious, malignant and rheumatic diseases, adult-onset Still's disease was diagnosed in all three patients on the basis of clinical and laboratory criteria. Adult-onset Still's disease is an important but less well known cause of fever. Clinically, adult-onset Still's disease is characterized by the triad of fever, skin rash and arthritis/arthralgia. A greatly elevated serum ferritin level proved to be an additional valuable diagnostic clue. Treatment consists of non-steroidal anti-inflammatory drugs, corticosteroids or immunosuppressive agents. The long-term prognosis is usually good, but severe joint destruction may occur. All three patients recovered.

Carotid artery stiffness in patients with end-stage renal disease: no effect of long-term homocysteine-lowering therapy.

BACKGROUND: The excess of cardiovascular disease in end-stage renal disease (ESRD) patients is unexplained, but could relate to altered intrinsic vascular wall properties, such as increased arterial stiffness, which could be mediated by hyperhomocysteinemia. We investigated potential determinants of carotid artery stiffness in ESRD patients and the effect of long-term homocysteine-lowering treatment. PATIENTS AND METHODS: Fifty-four patients on maintenance dialysis treatment were studied at baseline. Fourty-one patients completed the treatment protocol, which consisted of a 12-week treatment with folic acid 5 mg daily with or without betaine 4 g per day, and of 1 or 5 mg of folic acid thereafter for 40 weeks. Both phases were randomized. Compliance and distensibility coefficients (CC and DC) and the stiffness index (beta) of the common carotid artery were determined at baseline and after 52 weeks of treatment using a non-invasive vessel wall movement detector system. RESULTS: At baseline, plasma total homocysteine was elevated (44.1+/-33.7 micromol/l), but showed no relationship with CC, DC or beta. Age and mean arterial pressure (MAP) were the only independent determinants of CC and DC, whereas beta was associated with age only. Plasma homocysteine showed a sustained decrease after therapy (20.7+/-9.0 micromol/l at week 52). No significant changes occurred in CC (from 0.59+/-0.21 to 0.60+/-0.22 mm2/kPa; p = 0.47), in DC (from 14.9+/-6.1 to 15.3+/-6.2 10(-3)/kPa; p = 0.55), or in beta (from 10.9+/-4.7 to 11.2+/-4.4; p = 0.64). No independent determinants were detected for the change in CC, whereas the change in DC was inversely related to the change in MAP (stand. r = -0.58; p<0.0002). The decrease in MAP after therapy was significant (p = 0.003) and was related to the dialysis mode (p = 0.003) and smoking status (p = 0.02). CONCLUSION: Folic acid treatment of hyperhomocysteinemia has no major effect on carotid artery stiffness in chronic dialysis patients. The results do, however, emphasize the importance of tight blood pressure control in these patients.