The Influence of Hypothyroid Metabolic Status on Blood Coagulation and the Acquired von Willebrand Syndrome.

The intent of this prospective study aimed to identify the influence of hypothyroid metabolic status on the coagulation and fibrinolytic system and association with the acquired von Willebrand syndrome (VWS-ac). We compared 54 patients without substitution therapy after radical thyroidectomy with 58 control subjects without pathological thyroid-stimulating-hormone (TSH)-values. Patients with TSH > 17.5 mU/L over a period of >4 weeks were included. The control-collective was selected based on age and sex to match the patient-collective. The data were collected using laboratory coagulation tests and patient questionnaires; a bleeding score was determined. There were significant differences in the measurement of activated-partial-thromboplastin-time (aPTT/p = 0.009), coagulation-factor VIII (p < 0.001) and von-Willebrand-activity (VWF-ac/p = 0.004) between the patient and control groups. The patient cohort showed an increased aPTT and decreased factor VIII and VWF-ac. 29.7% of the patient-collective compared to 17.2% of the control subjects met the definition of VWS-Ac (p = 0.12). The bleeding score showed significantly more bleeding symptoms in patients with a laboratory constellation of VWS-ac (no family history; p = 0.04). Our results suggest hypocoagulability in hypothyroid patients. Hypothyroidism appears to have a higher incidence of VWS-ac. The increased risk of bleeding complications in hypothyroid patients may be of relevant importance for the outcome, especially in the context of invasive interventions.

No Evidence for Classic Thrombotic Microangiopathy in COVID-19.

BACKGROUND: Coronavirus disease-2019 (COVID-19) triggers systemic infection with involvement of the respiratory tract. There are some patients developing haemostatic abnormalities during their infection with a considerably increased risk of death. MATERIALS AND METHODS: Patients (n = 85) with SARS-CoV-2 infection attending the University Medical Center, Mainz, from 3 March to 15 May 2020 were retrospectively included in this study. Data regarding demography, clinical features, treatment and laboratory parameters were analyzed. Twenty patients were excluded for assessment of disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) due to lack of laboratory data. RESULTS: COVID-19 patients (n = 65) were investigated, 19 with uncomplicated, 29 with complicated, and 17 with critical course; nine (13.8%) died. Seven patients showed overt DIC according to the ISTH criteria. The fibrinogen levels dropped significantly in these patients, although not below 100 mg/dl. Hallmarks of TMA, such as thrombocytopenia and microangiopathic haemolytic anaemia, were not detected in any of our COVID-19 patients. ADAMTS13 activity was mildly to moderately reduced in 4/22 patients, all having strongly elevated procalcitonin levels. CONCLUSION: DIC occurred in 7/65 COVID-19 patients but fibrinogen and platelet consumption were compensated in almost all. ADAMTS13 assays excluded TTP and hallmarks of classic TMA were absent in all investigated patients. We hypothesize that the lacking erythrocyte fragmentation and only mild platelet consumption in severe COVID-19 are due to a microangiopathy predominantly localized to the alveolar microcirculation with a low blood pressure gradient.

Influence of Personality, Resilience and Life Conditions on Depression and Anxiety in 104 Patients Having Survived Acute Autoimmune Thrombotic Thrombocytopenic Purpura.

Autoimmune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening, relapsing disease in which an acquired deficiency of the enzyme ADAMTS13 leads to generalised microvascular thrombosis. Survivors have a high prevalence of depression and impaired cognitive function. The aim of this study was to determine whether life circumstances and personality have an influence on the development and severity of depression and anxiety in iTTP patients and how they impact the quality of life. With validated questionnaires, we examined the prevalence of depression and anxiety symptoms in 104 iTTP patients, as well as parameters of subjective cognitive deficits, quality of life, attitude to life and resilience. iTTP patients had significantly more depressive symptoms (p < 0.001), a tendency to have anxiety disorders (p = 0.035) and a significantly worse cognitive performance (p = 0.008) compared to the controls. Sex, age, physical activity and partnership status had no significant influence on depression, whereas the number of comorbidities did. Lower scores of resilience, attitude to life and quality of life were reported by patients compared to controls. iTTP patients had a high prevalence of depression and anxiety, as well as a more negative attitude to life and low resilience. Resilience correlated negatively with the severity of the depression. Furthermore, quality of life and cognitive performance were significantly reduced.

[Asymmetric dimethylarginine (ADMA) in retinal vein occlusion-Results from the Gutenberg RVO study]. / Asymmetrisches Dimethylarginin (ADMA) bei retinalen Venenverschlüssen ­ Ergebnisse aus der Gutenberg-RVO-Studie.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is considered an independent cardiovascular risk factor (cvRF) and thus represents a potential new biomarker for retinal vein occlusion (RVO). METHODS: Overall, 92 patients with RVO and the same number of matched controls were included in the Gutenberg RVO study. All patients underwent a standardized examination for cvRF at the study center of the population-based Gutenberg health study (GHS) as well as ophthalmological examinations and intensive laboratory tests. This article presents a substudy of patients (≤65 years old) and the controls in whom ADMA was additionally determined by high performance liquid chromatography (HPLC) at baseline and 4-6 weeks later. RESULTS: Out of 44 patients with RVO 22 had central retinal vein occlusion (CRVO), 15 had branch retinal vein occlusion (BRVO) and 7 had hemiretinal vein occlusion (hemi-RVO). The ADMA levels were 0.383 ± 0.094 µM (mean ± standard deviation) in RVO patients at baseline and 0.380 ± 0.093 µM (p = 0.514, initial vs. follow-up) after the follow-up period versus 0.360 ± 0.077 µM (p = 0.175, controls vs. RVO) in controls (n = 44). Arterial hypertension was the most prevalent risk factor in 22 (50%) of the patients and in 11 (25%) of the controls (odds ratio, OR 2.77, 95% confidence interval, CI 0.97-7.95; p = 0.058). The ADMA values above the 95th percentile (>0.530 µM) were detected in 4 patients with RVO (9.1%) but not in any of the controls (p = 0.041, RVO vs. controls). CONCLUSION: Hypertension is the most important risk factor for RVO. Due to the high number of hypertensive patients in the cohort, the relevance of ADMA as an independent risk factor could neither be confirmed nor disproved.

Hypertension and multiple cardiovascular risk factors increase the risk for retinal vein occlusions: results from the Gutenberg Retinal Vein Occlusion Study.

OBJECTIVE: Although several risk factors for retinal vein occlusion (RVO) are known, what triggers RVO is unclear in many cases. We aimed to evaluate the relevance of multiple risk factors in patients with RVO. METHODS: The Gutenberg RVO Study is an observational case-control study that assessed thrombophilic, cardiovascular, ophthalmic, and drug-related risk factors in participants with RVO and the same number of matched controls. Conditional logistic regression analysis was chosen to estimate the risk of RVO due to several risk factors. RESULTS: Of 92 patients with RVO, 46 (50%) had central RVO, 31 (33.7%) had branch RVO, and 15 (16.3) had hemi-RVO. Systemic hypertension was associated with RVO [any RVO: odds ratio (OR): 1.81; 95% confidence interval (CI): 1.14-2.88; branch RVO: OR: 2.56; 95% CI: 1.08-6.10]. The most frequent combinations of risk factors were hypertension with dyslipidemia (33 of 92, 35.9%) and hyperhomocysteinemia and high levels of factor VIII (10 of 92, 10.9%). An increase in the risk sum score by one additional risk factor corresponded to ORs of 1.74 (95% CI: 1.31-2.32) for cardiovascular risk factors, 1.38 (95% CI: 1.04-1.82) for thrombophilic risk factors, and 1.43 (95% CI: 1.20-1.70) for the total number of risk factors for RVO. CONCLUSION: Cardiovascular risk factors are more important than other risk factors for the presence of RVO. The risk of RVO increased by approximately 40% with any additional risk factor and by 70% with any additional cardiovascular risk factor.

Relapse Rate in Survivors of Acute Autoimmune Thrombotic Thrombocytopenic Purpura Treated with or without Rituximab.

BACKGROUND: Autoimmune thrombotic thrombocytopenic purpura (iTTP) is caused by autoantibody-mediated severe a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) deficiency leading to micro-angiopathic haemolytic anaemia (MAHA) and thrombocytopenia with organ damage. Patients survive with plasma exchange (PEX), fresh frozen plasma replacement and corticosteroid treatment. Anti-CD20 monoclonal antibody rituximab is increasingly used in patients resistant to conventional PEX or relapsing after an acute bout. OBJECTIVE: This retrospective observational study focused on the relapse rate and possible influencing factors including treatment with rituximab first introduced in 2003. PATIENTS AND METHODS: Seventy patients treated between January 2003 and November 2014 were evaluated. Number, duration, clinical manifestations, laboratory data and treatment of acute episodes were documented. Diagnostic criteria of acute iTTP were thrombocytopenia, MAHA, increased lactate dehydrogenase and severe ADAMTS13 deficiency. RESULTS: Fifty-four female and 16 male patients had a total of 224 acute episodes over a median observation period of 8.3 years. The relapse rate was 2.6% per month, for women 2.4% and for men 3.5% per month. Since 2003, 17 patients with a first iTTP episode were treated with rituximab, whereas 28 were not. There was a trend towards lower relapse rates after rituximab treatment over the ensuing years. However, this was statistically not significant. CONCLUSION: This analysis does not show a significant reduction of acute iTTP relapses by rituximab given during an acute bout. Initial episodes are characterized by more severe clinical signs compared with the less severe relapses. Furthermore, men suffer significantly more frequent and considerably more serious acute relapses.

Author Correction: ADAMTS-13 regulates neutrophil recruitment in a mouse model of invasive pulmonary aspergillosis.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Procoagulant activity during viral infections.

The abundance of evidence suggest that inflammation of immune and non-immune cells may lead to an imbalance of the pro- and anti-coagulant state during viral infections. During systemic infections, the endothelium plays a critical role in regulating hemostasis, and severe imbalances of endothelial function and activation can contribute to organ failure. Viral infections may elevate plasma levels of procoagulant markers such as TAT and D-dimer TF-positive MPs as well as von Willebrand factor (vWF). Although multiple clinical studies are showing the association of viral infection and increased prothrombotic risk, the pathological mechanisms have not been fully identified for most viral infections. Viral infection mediated TLRs activation is both cell type- and species-specific and explains the difficulties in correlating murine model data with the human data. In this review, we briefly discuss the TF-dependent coagulation activation, Toll-like receptors (TLRs) signaling during viral infections, and their contributions to the procoagulant response.

ADAMTS-13 regulates neutrophil recruitment in a mouse model of invasive pulmonary aspergillosis.

Von Willebrand factor (VWF) is secreted as an acute phase protein during inflammation. ADAMTS-13 regulates the size and prothrombotic activity of VWF by it's specific proteolytic activity. To determine the relevance of this regulatory pathway for the innate inflammatory response by polymorphonuclear neutrophils (PMN), we employed a mouse model of invasive pulmonary aspergillosis (IPA) where PMN functionality is crucial for fungal clearance and survival. IPA was induced by intratracheal application of Aspergillus fumigatus (A. fumigatus) conidia in wildtype (129/Sv/Pas) or ADAMTS-13 deficient (Adamts13 -/-) mice. While neutropenic mice developed lethal IPA, all wildtype mice survived the infection. In contrast to wildtype or VWF deficient mice, Adamts13 -/- mice displayed more severe signs of disease with a lethal course in 24% with an increased fungal burden and signs of acute lung injury. Histology sections demonstrated a more pronounced perivascular leukocyte infiltration in support of a dysregulated inflammatory response in Adamts13 -/- mice. Importantly, we observed no general defect in the activation of neutrophil functions in response to conidia or hyphae in vitro. Therefore, we conclude that the proteolytic regulation of VWF by ADAMTS-13 or ADAMTS-13 by itself is an important mechanism to control PMN recruitment in acute inflammatory processes, such as fungal pneumonias.

Mice deficient in the anti-haemophilic coagulation factor VIII show increased von Willebrand factor plasma levels.

Von Willebrand factor (VWF) is the carrier protein of the anti-haemophilic Factor VIII (FVIII) in plasma. It has been reported that the infusion of FVIII concentrate in haemophilia A patients results in lowered VWF plasma levels. However, the impact of F8-deficiency on VWF plasma levels in F8-/y mice is unresolved. In order to avoid confounding variables, we back-crossed F8-deficient mice onto a pure C57BL/6J background and analysed VWF plasma concentrations relative to C57BL/6J WT (F8+/y) littermate controls. F8-/y mice showed strongly elevated VWF plasma concentrations and signs of hepatic inflammation, as indicated by increased TNF-α, CD45, and TLR4 transcripts and by elevated macrophage counts in the liver. Furthermore, immunohistochemistry showed that expression of VWF antigen was significantly enhanced in the hepatic endothelium of F8-/y mice, most likely resulting from increased macrophage recruitment. There were no signs of liver damage, as judged by glutamate-pyruvate-transaminase (GPT) and glutamate-oxalacetate-transaminase (GOT) in the plasma and no signs of systemic inflammation, as white blood cell subsets were unchanged. As expected, impaired haemostasis was reflected by joint bleeding, prolonged in vitro clotting time and decreased platelet-dependent thrombin generation. Our results point towards a novel role of FVIII, synthesized by the liver endothelium, in the control of hepatic low-grade inflammation and VWF plasma levels.

Depression and cognitive deficits as long-term consequences of thrombotic thrombocytopenic purpura.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is an acute life-threatening microangiopathy with a tendency of relapse characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, and spontaneous von Willebrand factor-induced platelet clumping leading to microthrombi. The brain is frequently affected by microthrombi leading to neurologic abnormalities of varying severity. STUDY DESIGN AND METHODS: The aim of this observational cohort study was to investigate the prevalence of depression and cognitive deficits in 104 patients having survived acute TTP. TTP survivors were repeatedly assessed by means of different standardized questionnaires to evaluate depression (IDS-SR) and mental performance (FLei). We received answers of 104 individual TTP patients and 55 of them participated in both surveys. RESULTS: Seventy-one of the 104 responding TTP patients (68%) suffered from depression and the severity of depression was similar in both surveys performed 1 year apart. Furthermore, TTP patients had considerably lower cognitive performance than controls. There was no correlation between prevalence of depression and cognitive deficits and the number and the severity of acute episodes. Impairment of mental performance correlated with the severity of depression (rs  = 0.779). CONCLUSION: The prevalence of depression and cognitive deficits was significantly higher in TTP patients. Cognitive impairment seemed to be a consequence of depression, almost independently of number and severity of TTP episodes.

Idiopathic thrombotic thrombocytopenic purpura: strongest risk factor for relapse from remission is having had a relapse.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare, episodic clinical syndrome involving the production of thrombi in the microvasculature accompanied by thrombocytopenia and symptoms of organ ischemia. Idiopathic TTP develops when a patient produces antibodies that react with the protease ADAMTS13. The course after an episode is unpredictable; patients may relapse frequently or never. There is no laboratory value that can reliably predict potential relapse. STUDY DESIGN AND METHODS: To assess diagnostic and predictive values for risk of relapse, plasma samples from 27 patients with idiopathic TTP in remission were analyzed for anti-ADAMTS13 immunoglobulin (Ig)G, ADAMTS13 activity, and ADAMTS13 inhibitor titer. Patients were recruited at the Department of Hematology at the University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany. RESULTS: Anti-ADAMTS13 IgG was detected in 12 patients (44%); their median level of ADAMTS13 activity was nondetectable. Patients with anti-ADAMTS13 IgG had a median number of three previous relapses, whereas the 15 patients without presence of IgG (56%) had a median number of one previous relapse (p < 0.001; Mann-Whitney U test). The concentration of free anti-ADAMTS13 IgG and the levels measuring inhibitory activity (Bethesda unit) were positively correlated. CONCLUSION: A subgroup of TTP patients in remission with anti-ADAMTS13 IgG and nondetectable ADAMTS13 activity showed an increased risk for relapsing disease as demonstrated by their number of past relapses. The positive correlation we observed between anti-ADAMTS13 IgG and inhibitor levels supports the theory of ADAMTS13 inhibition as the crucial mechanism causing severe deficiency in ADAMTS13 activity in TTP.

Identification of platelet function defects by multi-parameter assessment of thrombus formation.

Assays measuring platelet aggregation (thrombus formation) at arterial shear rate mostly use collagen as only platelet-adhesive surface. Here we report a multi-surface and multi-parameter flow assay to characterize thrombus formation in whole blood from healthy subjects and patients with platelet function deficiencies. A systematic comparison is made of 52 adhesive surfaces with components activating the main platelet-adhesive receptors, and of eight output parameters reflecting distinct stages of thrombus formation. Three types of thrombus formation can be identified with a predicted hierarchy of the following receptors: glycoprotein (GP)VI, C-type lectin-like receptor-2 (CLEC-2)>GPIb>α6ß1, αIIbß3>α2ß1>CD36, α5ß1, αvß3. Application with patient blood reveals distinct abnormalities in thrombus formation in patients with severe combined immune deficiency, Glanzmann's thrombasthenia, Hermansky-Pudlak syndrome, May-Hegglin anomaly or grey platelet syndrome. We suggest this test may be useful for the diagnosis of patients with suspected bleeding disorders or a pro-thrombotic tendency.

Thromboelastographic phenotypes of fibrinogen and its variants: clinical and non-clinical implications.

INTRODUCTION: Thromboelastography (TEG), a widely used clinical point of care coagulation test, is poorly understood. To investigate its fibrin determinants we used normal and variant fibrinogen isolates. MATERIALS AND METHODS: We focused mainly on the TEG maximum signal amplitude (MA), a shear modulus and clot stiffness indicator. Isolates included normal des-αC, cord, and abnormal congenital variants with amino acid substitutions or deletions that impaired fibrin polymerization. Heterophenotypic congenital isolates were from cryoprecipitate-depleted plasma owing to their more diminished clot MA than their cryoprecipitate counterparts. By colorimetric assay, the amount of fibrinogen adsorbed by untreated TEG cups was 83.5±12.4 pM/cm(2), n=18. Thrombin-induced clots were obtained at pH6.4 or 7.4, the latter containing 8mM CaCl2, and 14% afibrinogenemic plasma with and without gel-sieved platelets. RESULTS AND CONCLUSIONS: Measured by the water droplet contact angle, >90% reduction of surface hydrophobicity by exposure of TEG cup and pin to ozone plasma decreased MA by 74%. Increasing normal fibrinogen or thrombin concentrations progressively increased MA. Platelets increased MA further ~2 fold, except for ≥10 fold for des-αC clots. Examined in the absence of platelets, MA of heterophenotypic fibrin variants averaged 21%, n=15. The results imply that essential MA determinants include hydrophobic fibrinogen/fibrin adsorption and each polymerization contact site, with substantial enhancement by platelets. Also, cryoprecipitate-harvested soluble fibrinogen/fibrin complexes contained mostly normal molecules, while cryoprecipitate-depleted plasma contained mostly variant molecules. Moreover, significantly decreased MA by fibrinogen anomalies and/or low level thrombin generation can potentially impact clinical interpretation of MA.

A role for Toll-like receptor mediated signals in neutrophils in the pathogenesis of the anti-phospholipid syndrome.

The anti-phospholipid syndrome (APS) is characterized by recurrent thrombosis and occurrence of anti-phospholipid antibodies (aPL). aPL are necessary, but not sufficient for the clinical manifestations of APS. Growing evidence suggests a role of innate immune cells, in particular polymorphonuclear neutrophils (PMN) and Toll-like receptors (TLR) to be additionally involved. aPL activate endothelial cells and monocytes through a TLR4-dependent signalling pathway. Whether this is also relevant for PMN in a similar way is currently not known. To address this issue, we used purified PMN from healthy donors and stimulated them in the presence or absence of human monoclonal aPL and the TLR4 agonist LPS monitoring neutrophil effector functions, namely the oxidative burst, phagocytosis, L-Selectin shedding and IL-8 production. aPL alone were only able to induce minor activation of PMN effector functions at high concentrations. However, in the additional presence of LPS the activation threshold was markedly lower indicating a synergistic activation pathway of aPL and TLR in PMN. In summary, our results indicate that PMN effector functions are directly activated by aPL and boosted by the additional presence of microbial products. This highlights a role for PMN as important innate immune effector cells that contribute to the pathophysiology of APS.

The role of human leukocyte antigens as predisposing and/or protective factors in patients with idiopathic thrombotic thrombocytopenic purpura.

Fifty-four adult German patients suffering from idiopathic thrombotic thrombocytopenic purpura (TTP) have been examined for HLA class II. All patients presented autoantibodies against ADAMTS13 and ADAMTS13 activity levels <5%. Blood samples have been analyzed for HLA-DRB1 and DQB1 alleles using sequence-specific primer PCR and sequence-specific oligonucleotide PCR. Reference data of German bone marrow and blood donors were obtained from www.allelefrequencies.net. The results were evaluated employing two-sided binomial tests, and p values were corrected using the Benjamini-Hochberg procedure. A significant accumulation for DQB1*02:02 (p < 0.001) and DRB1*11 (p = 0.003) was found within the patient group. Twenty percent (DQB1*02:02) or 48.1% (DRB1*11) of TTP patients were tested positive for the particular HLA antigen compared to 1.2% (DQB1*02:02) or 23.5% (DRB1*11) in the control group. A tendency for a reduced occurrence of HLA-DRB1*04 was revealed (7.4% in patients compared to 24.6% in controls). An association between the HLA antigens DQB1*02:02 and DRB1*11 and disease susceptibility for idiopathic TTP has been found. A higher risk for disease outbreak within persons carrying the mentioned alleles can be assumed. The reduced occurrence of HLA-DRB1*04 in TTP patients indicates a possible protective effect of this HLA allele in disease development.

Acquired haemophilia caused by non-haemophilic factor VIII gene variants.

The aetiology of anti-factor VIII (FVIII) autoantibody formation in acquired haemophilia remains unknown. We hypothesised that encounter of antigenically different, allogeneic FVIII may challenge inhibitor formation after presentation on MHC class II. Eighteen consecutive cases with acquired haemophilia were enrolled (nine females, nine males). A control group comprised 50 male and 50 female healthy blood donors. The coding region of the FVIII gene and the HLA-DRB1 genotype were studied. The presentation of foreign FVIII variants on the patient's MHC class II alleles was predicted using SYFPEITHI algorithm. A rare FVIII variant (E2004K) was found in one patient with acquired haemophilia after massive transfusion; the 2004 K allele was predicted to be presented on the patient's HLA-DRB1*0101. Moreover, distribution of a polymorphism (D1241E) was significantly skewed comparing patients and controls. Three of three patients with transfusion-associated disease carried 1241D in homozygous or hemizygous form and were predicted to present 1241E (foreign), but not 1241D (self), on their HLA-DRB1*0301. Therefore, encounter of 1241E may result in the presentation of a new T cell epitope in these patients. The same conditions were not found in any patient with acquired haemophilia of other causes. The expected frequency in the general Caucasoid population undergoing transfusion is 3% to 4%. In conclusion, encounter of variant allogeneic FVIII presented on a suitable MHC background could be a risk factor for inhibitor formation.

Changes of coagulation parameters during high altitude expedition.

PRINCIPLES: Data on changes of haemostatic parameters at altitudes above 5000 m are very limited. So far it is unknown, whether altered coagulation could contribute to the development of acute mountain sickness. METHODS: Thirty four healthy mountaineers were randomised to two acclimatisation protocols and undertook an expedition on Muztagh Ata (7549 m) in China. Tests were performed at five altitudes up to 6865 m. Haemostatic parameters, such as PT, aPTT, D-Dimer, APC-Resistance (APCR), von Willebrand Factor activity (RCo), ADAMTS-13 & C-Natriuretic Peptide (CNP) were assessed together with Lake Louise AMS score. RESULTS: D-Dimer significantly increased with increasing altitude (median 0.62 to 0.81 mcg/L, p <0.0001). During ascent, PT increased (83% to >100%) and APCR decreased significantly from 0.95 to 0.8 (p <0.01). Furthermore, a significant increase of aPTT (38 to 43 sec) was paralleled by significant changes of RCo (102% to 62%) (both p <0.001). There were no significant changes in ADAMTS-13 and CNP. No significant relationship between investigated parameters and AMS scores could be detected. When comparing the participants of the two acclimatisation protocols, there was an overall higher RCo in patients with a faster ascent protocol (p = 0.04). This was accompanied by lower ADAMTS-13 of the coagulation system in these patients (p = 0.04). CONCLUSIONS: Coagulation parameters change significantly during hypobaric hypoxia. Whereas we could detect no association between AMS scores and coagulation parameters, our results do show some parameters to be associated with an acclimatisation protocol and a successful ascent to the summit.

Inherited dysfibrinogenemia: clinical phenotypes associated with five different fibrinogen structure defects.

Hereditary dysfibrinogenemia is a rare clotting disorder, which results from mutations in at least one of the three fibrinogen genes. We examined the frequency of hemostatic clinical and laboratory anomalies at presentation of 37 probands from 12 unrelated families with five different defects (Aalpha R16C, gamma A357T, gamma318-319 del, gamma M310T, and Aalpha R16S), among. The median age was 51 years (11-86 years). Among 62% who were women three (13%) had experienced one or more spontaneous abortion. More than half of the probands had experienced one or more undue bleeding episode, easy bruising being by far the most common. In 19% of probands (9/37, all above age of 50 years), had experienced at least one episode of arterial or venous thrombosis. Among these, were two (7%) with deep venous thrombosis, seven with arterial thrombosis, and five (14%) had experienced both. We propose that the higher frequency of prolonged PT than aPTT, in ours and in other reported studies, reflects the polymerization delay, which in aPTT is attenuated owing to contact activation prior to calcium addition.

Evolution of recombinant factor VIII safety: KOGENATE and Kogenate FS/Bayer.

The use of factor VIII (FVIII) concentrates in the treatment of hemophilia A has raised important safety issues, historically of pathogen transmission and increasingly of inhibitor development to FVIII treatment. While manufacturing processes of current recombinant FVIII products have been shaped entirely around preventing pathogen transmission, the same modifications that afford a greater margin of safety could affect immunogenicity of the product, consequences of which could only be seen through long-term clinical experience. This review summarizes pathogen safety and inhibitor reports from clinical trials, post-marketing surveillance studies, and study reports on KOGENATE and its successor, Kogenate FS/Bayer. Although KOGENATE and Kogenate FS/Bayer are nearly identical products, subtle manufacturing improvements to address the need for greater margins of safety from a pathogen transmission perspective have also led to a potentially improved immunogenicity profile (15% in previously untreated/minimally treated patients with severe hemophilia A for Kogenate FS/Bayer). Notably, there has been no occurrence of pathogen contamination, and minimal de novo inhibitor formation in previously treated patients throughout the use of both products. Overall, KOGENATE and Kogenate FS/Bayer have a long history of safety in a variety of clinical settings, including treatment of bleeding, surgical management, and prophylaxis therapy.