Frequency of protein Z deficiency in patients with ischaemic stroke

Prothrombotic phenotype has been described in protein-Z deficient mice, but the thrombotic risk associated with protein Z deficiency in human beings is unknown. We saw a protein Z plasma concentration deficiency of about 20% in 169 patients, from two hospitals, who had ischaemic stroke, whereas the frequency in 88 controls was about 5%. We saw no increase in the frequency of protein Z deficiency in 56 patients with venous thrombophilia. However, why protein Z deficiency was only observed in arterial thrombosis remains unknown.     

Prothrombotic phenotype of protein Z deficiency

Protein Z (PZ) is a vitamin K-dependent plasma protein whose function has been uncertain. The structure of PZ is very similar to that of the coagulation-related factors VII, IX, and X and PC, but PZ differs from these other proteins in that it is not the zymogen of a serine protease. We have shown recently that PZ forms a calcium ion-dependent complex with activated factor X at phospholipid surfaces and that this interaction leads to the inhibition of activated factor X activity through, in part, the action of a previously unidentified plasma protein named PZ-dependent protease inhibitor. Herein, we report that the presence of PZ dampens the coagulation response in human plasma and that concomitant PZ deficiency dramatically increases the severity of the prothrombotic phenotype of factor V(Leiden) mice. The results indicate that PZ plays a physiologically important role in the regulation of coagulation.     

Prevalence of antiphospholipid antibodies in patients with fetal loss.

The prevalence of antiphospholipid and antinuclear antibodies in 102 patients with at least three unexplained miscarriages before a gestational age of 12 weeks, or at least one intrauterine fetal death after 12 weeks, was investigated and compared with the prevalence in 102 normal pregnant controls. Six patients had a history of thrombosis and six had 'lupus-like' disease. Twenty one patients had anticardiolipin antibodies compared with 10 controls. Serum samples of nine patients and one control contained antinuclear antibodies. The lupus anticoagulant was present in the plasma of five patients with anticardiolipin antibodies. The influence of patient selection on the results was illustrated by the finding that antiphospholipid antibodies and antinuclear antibodies were mainly detected in patients with lupus-like disease or a history of thrombosis. When these patients were excluded there was no significant difference in the prevalence of anticardiolipin and antinuclear antibodies between patients and controls. Therefore, in the absence of lupus-like disease or a history of thrombosis, screening for antiphospholipid antibodies in patients with adverse pregnancy outcomes seems not to be indicated.     

DNACJ12 deficiency in patients with unexplained hyperphenylalaninemia: two new patients and a novel variant

Metabolic Brain Disease - In addition to tetrahydrobiopterin deficiencies and phenylalanine hydroxylase deficiency (phenylketonuria) due to PAH variants, the deficiency of the co-chaperone protein...     

The successful use of protein C concentrate during pregnancy in a patient with type 1 protein C deficiency, previous thrombosis and recurrent fetal loss

The risks of venous thrombosis and fetal loss are increased in patients with protein C deficiency. We describe a patient with a history of thrombosis and recurrent fetal loss who was found to have type 1 protein C deficiency. In view of her history and intolerance of heparin preparations, she was treated with protein C concentrate during the first and third trimesters of her seventh pregnancy. The patient suffered no thromboembolic event during this pregnancy and gave birth to a healthy infant. The implications of the success of this therapeutic strategy are discussed.     

Activated protein C resistance can be associated with recurrent fetal loss

As thrombosis of placental vessels may result in recurrent fetal loss, we analysed 39 consecutive women with recurrent fetal loss of unknown cause for activated protein C resistance. Factor V Leiden (FVL) mutation (19 cases) or APC resistance without FVL (nine cases) were found among these 39 women.   Evaluation of 128 pregnancies in 19 patients with factor V Leiden mutation and 56 gestations in nine women with acquired APC resistance, revealed over 50% first-trimester abortions and 17% late abortions. Intra-uterine fetal death occurred in nine out of 19 FVL patients (47%). Only 34 of 184 gestations (18%) in hereditary or acquired APC-resistance women resulted in a live birth, with 11 of the 34 (32%) being premature deliveries. These data suggest that, in some patients with recurrent fetal loss, hereditary and acquired APC resistance are potential causes of vascular placental insufficiency.     

Thrombophilic dimension of recurrent fetal loss in Indian patients

We studied the prevalence of acquired and genetic thrombophilia in 198 women with recurrent fetal loss who were having three or more than three abortions. Seventy-nine women had only early pregnancy losses, that is, first trimester abortions, 30 women had only late pregnancy losses, that is, second and third trimester abortions whereas 89 had both early and late pregnancy losses. The control group included 100 age-matched fertile parous women who did not have any obstetric complications and had at least one normal healthy child. Several genetic and acquired thrombophilia markers were studied. The strongest association was observed with anticardiolipin (odds ratio 22.6, confidence interval 5.7-89, P = 0) followed by lupus anticoagulant, anti-beta2 glycoprotein-1, antiannexin. Association of antiphospholipid antibody syndromes was detected with the time of pregnancy loss in anticardiolipin, lupus anticoagulants, which was significantly associated with early pregnancy loss as compared with second and third trimester loss. In case of beta2 glycoprotein-1, antiannexin it was less significantly associated with early pregnancy loss as compared with second and third trimester loss. The risk of fetal loss with protein S deficiency was the highest risk observed for any heritable thrombophilia, followed by protein C, factor V Leiden, endothelial protein C receptor, antithrombin III deficiency and beta448 fibrinogen polymorphism. Modest risks were also observed with 5,10-methylenetetrahydrofolate reductase, plasminogen activator inhibitor 4G/4G polymorphisms and beta448 fibrinogen polymorphism. A combination of two or more than two genetic risk factors were observed in 55 (27.7%), whereas the genetic and acquired risk factors were observed in 107 (54%) of the cases. Thrombophilia is an important contributing factor for both early and late pregnancy losses; approximately two-thirds of our cases of unexplained fetal losses could be explained by acquired or heritable thrombophilia or both, which is in line with other western studies.     

Correction to: DNAJC12 deficiency in patients with unexplained hyperphenylalaninemia: two new patients and a novel variant

Metabolic Brain Disease - A Correction to this paper has been published: https://doi.org/10.1007/s11011-021-00759-8     

High incidence of tachyarrhythmias detected by an implantable loop recorder in patients with unexplained syncope

BACKGROUND: Syncope is a complex clinical syndrome that may be challenging with respect to a definite diagnosis. The implantable loop recorder (ILR) is a useful tool to define but also to exclude an arrhythmic aetiology. AIM: To investigate the causes of recurrent syncope or near-syncope with respect to underlying arrhythmias in non-selected consecutive patients monitored with an ILR. METHODS: A retrospective study was conducted including 55 patients (34 men, 21 women; age 60+/-19 years) with unexplained syncope who received an ILR for prolonged monitoring at our institution between April 1998 and October 2006. RESULTS: Forty (73%) patients had a recurrence of syncope or near-syncope. Structural heart disease was present in 18 (33%) patients, 4 of them having an ejection fraction <35%. An arrhythmia was detected as the cause of syncope in 25 (46%) patients. The ILR was successful in establishing a symptom-rhythm correlation in 63%. The mean follow-up period from implantation to occurrence of the detected arrhythmias was 9+/-8 months. Bradyarrhythmias were recorded in 12 (22%) patients, whereas tachyarrhythmias were found in 13 (24%) patients. Narrow QRS tachycardia was the underlying arrhythmia in 6 patients and wide QRS tachycardia in 7 patients. A pacemaker was implanted in all 12 patients with bradyarrhythmias. Implantable cardioverter defibrillator (ICD) therapy was indicated in 6 patients with adjunctive catheter ablation in 3 of them. Four patients presenting with paroxysmal supraventricular tachycardia were treated with radiofrequency catheter ablation. CONCLUSION: The ILR helped efficaciously to determine the correct diagnosis and appropriate treatment of recurrent syncope. A considerably high proportion of tachyarrhythmias was detected in this non-selected consecutive population. The majority of patients with tachyarrhythmic syncope required defibrillator implantation and/or radiofrequency ablation.     

Protein Z-dependent protease inhibitor deficiency produces a more severe murine phenotype than protein Z deficiency

Protein Z (PZ) is a plasma vitamin K–dependent protein that functions as a cofactor to dramatically enhance the inhibition of coagulation factor Xa by the serpin, protein Z–dependent protease inhibitor (ZPI). In vitro, ZPI not only inhibits factor Xa in a calcium ion–, phospholipid-, and PZ-dependent fashion, but also directly inhibits coagulation factor XIa. In murine gene-deletion models, PZ and ZPI deficiency enhances thrombosis following arterial injury and increases mortality from pulmonary thromboembolism following collagen/epinephrine infusion. On a factor V_Leiden genetic background, ZPI deficiency produces a significantly more severe phenotype than PZ deficiency, implying that factor XIa inhibition by ZPI is physiologically relevant. The studies in mice suggest that human PZ and ZPI deficiency would be associated with a modest thrombotic risk with ZPI deficiency producing a more severe phenotype.      

Evaluating diagnostic strategy of older patients with unexplained unintentional body weight loss: a hospital-based study

Unexplained unintentional weight loss (UUWL) is a common health problem in older adults, and raises significant diagnostic challenges. Currently, there is no consensus or guideline to help physicians approach these patients. The main purpose of this study is to evaluate physicians’ behaviors in evaluating elderly patients with UUWL and to compare the diagnostic strategy of internists and geriatricians. From January of 2008 to December of 2009, medical records of all elderly patients admitted to Taipei Veterans General Hospital with UUWL were obtained for study. All diagnostic procedures used during admissions were evaluated and the final diagnosis for each patient was obtained. Overall, data of 136 patients (mean age: 79.8 ± 6.3 years, 80.9% males) were obtained for study with their mean weight loss of 8.6 ± 6.4 kg. Among them, 79 (58.1%) patients were admitted to the geriatric evaluation and management unit (GEMU) and 57 (41.9%) patients were admitted to the general medical wards. There were no statistically significant differences in terms of age, sex, mean age and average weight loss between these two groups. After extensive diagnostic effort, the most common diagnostic entity was benign organic disease (33.8%), followed by unknown (25.7%), neuropsychiatric disorder (23.5%), and malignancy (16.9%). Tumor markers are commonly used, including carcinoembryonic antigen (CEA) (80.9%), prostate specific antigen (PSA) (81.8%), and carbohydrate 19-9 (CA 19-9) (65.4%). Imaging studies were also commonly used diagnostic tools, including gastrointestinal endoscopy (70.6%), colonoscopy (42.6%) and computerized tomography (44.1%). Compared with internists, geriatricians were more likely to order PSA testing (70.5% vs. 89.4%, p = 0.021). In contrast, internists were more likely to order CA-199 (75.4%% vs. 58.2%, p = 0.045), and to arrange gastrointestinal endoscopy than geriatricians (82.4% vs. 62.0%%, p = 0.013). In conclusion, cancer accounts for only 16.9% of all elderly patients with UUWL in this study, tumor markers are very commonly used for screening of occult cancer. Compared with internists, geriatricians are more likely to order PSA and to establish neuropsychiatric diagnosis, and internists are more prone to order carbohydrate (CA 19-9) and gastrointestinal endoscopy.     

High frequency of antithrombin 3 and protein C deficiency following autologous bone marrow transplantation for lymphoma.

To investigate the possibility that a hypercoagulable state develops during autologous bone marrow transplantation (BMT), we measured levels of circulating natural anticoagulants and fibrinolytic proteins before and weekly during the hospital course of 18 patients undergoing autologous BMT for Hodgkin's and non-Hodgkin's lymphoma. Patients received either weekly (standard dose group) or daily (high dose group) vitamin K supplements with their total parenteral nutrition. By day 14 there had been a significant drop in protein C activity (mean of 95% of normal to 52%), protein C antigen (mean of 105% of normal to 70%), and antithrombin 3 activity (111% of normal to 83%), and an increase in fibrinogen (471-621 mg/dl) and tissue plasminogen activator (6.9-13.8 ng/ml). No changes were seen in free or total protein S, plasminogen activator inhibitor, prothrombin time or partial thromboplastin time. The decreases in protein C and antithrombin 3 persisted through day 28 after transplantation. The drop in protein C correlated strongly with decrease in serum albumin, suggesting impaired synthesis of these proteins by the liver. No differences were seen in any of these parameters between the standard and high dose groups. Deficiencies in anticoagulant proteins antithrombin 3 and protein C and a rise in fibrinogen without a concomitant improvement in fibrinolytic variables create a potentially hypercoagulable state which may contribute to the thrombotic complications of autologous BMT.     

Hereditary protein C deficiency in Indian patients with venous thrombosis

Approximately, 4-11 % of the patients with idiopathic venous thrombosis (VT) show protein C (PC) deficiency. The molecular pathology of PC deficiency was analyzed in 102 patients; 98 healthy controls were also studied to assess the association of various polymorphisms with reduced PC levels. PROC gene mutations were detected only in 8 (7.8 %) patients with reduced PC levels. PROC promoter region CG polymorphisms showed statistically significant association with reduced PC levels (p < 0.001). PC deficiency in Indian VT patients can, thus, largely be explained by PROC gene promoter CG polymorphisms; only a small fraction of the patients show specific mutations in PROC gene.