scholarly journals Familial Multiple Coagulation Factor Deficiencies (FMCFDs) in a Large Cohort of Patients—A Single-Center Experience in Genetic Diagnosis

2021 ◽  
Vol 10 (2) ◽  
pp. 347
Author(s):  
Barbara Preisler ◽  
Behnaz Pezeshkpoor ◽  
Atanas Banchev ◽  
Ronald Fischer ◽  
Barbara Zieger ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Single Gene ◽  
Genetic Defect ◽  
Genetic Diagnosis ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Molecular Genetic Analysis ◽  
Factor Vii ◽  
Factor Xii ◽  
Activity Levels

Background: Familial multiple coagulation factor deficiencies (FMCFDs) are a group of inherited hemostatic disorders with the simultaneous reduction of plasma activity of at least two coagulation factors. As consequence, the type and severity of symptoms and the management of bleeding/thrombotic episodes vary among patients. The aim of this study was to identify the underlying genetic defect in patients with FMCFDs. Methods: Activity levels were collected from the largest cohort of laboratory-diagnosed FMCFD patients described so far. Genetic analysis was performed using next-generation sequencing. Results: In total, 52 FMCFDs resulted from coincidental co-inheritance of single-factor deficiencies. All coagulation factors (except factor XII (FXII)) were involved in different combinations. Factor VII (FVII) deficiency showed the highest prevalence. The second group summarized 21 patients with FMCFDs due to a single-gene defect resulting in combined FV/FVIII deficiency or vitamin K–dependent coagulation factor deficiency. In the third group, nine patients with a combined deficiency of FVII and FX caused by the partial deletion of chromosome 13 were identified. The majority of patients exhibited bleeding symptoms while thrombotic events were uncommon. Conclusions: FMCFDs are heritable abnormalities of hemostasis with a very low population frequency rendering them orphan diseases. A combination of comprehensive screening of residual activities and molecular genetic analysis could avoid under- and misdiagnosis.

scholarly journals Cold-induced contact surface activation of the prothrombin time in whole blood

Blood ◽  
1982 ◽  
Vol 59 (1) ◽  
pp. 38-42 ◽  
Author(s):  
RN Palmer ◽  
HR Gralnick
Keyword(s):  
Prothrombin Time ◽  
Whole Blood ◽  
Room Temperature ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Factor Xii ◽  
Contact Phase ◽  
Fletcher Factor ◽  
Esterase Inhibitor

Abstract Studies of the prothrombin time (PT) have revealed that contact with borosilicate or commercial siliconized borosilicate markedly shortens the PT. This shortening is related to the activation of the contact phase of blood coagulation. This shortening of the PT occurs in both normal whole blood and plasma when stored in borosilicate or siliconized borosilicate tubes at 4 degree C and to a lesser degree at room temperature. Studies indicated the importance of several coagulation factors in decreasing the PT. The PT did not change in blood deficient in factor XII or in plasma deficient in Fletcher factor or high molecular weight kininogen, while blood deficient in CI esterase inhibitor (CI INH) had the most profound shortening. Shortening of the PT correlated directly with increased levels of factor VII. When purified CI INH was added to normal blood, it markedly reduced the activation of factor VII and the shortening of the PT in a dose-related manner. These studies indicate the pivotal roles of the contact phase of coagulation in initiating activation of the PT and of CI INH in inhibiting the activation of the coagulation factor(s) responsible for the cold-promoted activation of factor VII.

Molecular genetic analysis of Korean patients with coagulation factor XII deficiency

2010 ◽  
Vol 21 (4) ◽  
pp. 308-312 ◽  
Author(s):  
Min-Jung Kwon ◽  
Hee-Jin Kim ◽  
Ki-O Lee ◽  
Chul Won Jung ◽  
Sun-Hee Kim
Keyword(s):  
Genetic Analysis ◽  
Molecular Genetic ◽  
Coagulation Factor ◽  
Molecular Genetic Analysis ◽  
Factor Xii ◽  
Factor Xii Deficiency ◽  
Korean Patients

scholarly journals Cold-induced contact surface activation of the prothrombin time in whole blood

Blood ◽  
1982 ◽  
Vol 59 (1) ◽  
pp. 38-42
Author(s):  
RN Palmer ◽  
HR Gralnick
Keyword(s):  
Prothrombin Time ◽  
Whole Blood ◽  
Room Temperature ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Factor Xii ◽  
Contact Phase ◽  
Fletcher Factor ◽  
Esterase Inhibitor

Studies of the prothrombin time (PT) have revealed that contact with borosilicate or commercial siliconized borosilicate markedly shortens the PT. This shortening is related to the activation of the contact phase of blood coagulation. This shortening of the PT occurs in both normal whole blood and plasma when stored in borosilicate or siliconized borosilicate tubes at 4 degree C and to a lesser degree at room temperature. Studies indicated the importance of several coagulation factors in decreasing the PT. The PT did not change in blood deficient in factor XII or in plasma deficient in Fletcher factor or high molecular weight kininogen, while blood deficient in CI esterase inhibitor (CI INH) had the most profound shortening. Shortening of the PT correlated directly with increased levels of factor VII. When purified CI INH was added to normal blood, it markedly reduced the activation of factor VII and the shortening of the PT in a dose-related manner. These studies indicate the pivotal roles of the contact phase of coagulation in initiating activation of the PT and of CI INH in inhibiting the activation of the coagulation factor(s) responsible for the cold-promoted activation of factor VII.

Analysis of Children with Coagulation Test Abnormality in Pre-Surgical Evaluation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4080-4080
Author(s):  
Seung Yeon Kwon ◽  
Jung Woo Han ◽  
Sung Chul Won ◽  
Jaewoo Song ◽  
Chuhl Joo Lyu
Keyword(s):  
Surgical Procedures ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Factor Xii ◽  
Surgical Evaluation ◽  
Bleeding History ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Prothrombine time (PT) and activated prothrombine time (aPTT) are common tests used for screening of coagulation function before surgical procedures. We analyzed underlying causes of abnormal coagulation test results which were incidentally found during pre-surgical evaluation in healthy patients without definite bleeding history. Total 58 children referred to pediatric hematoloy service for abnormal PT and aPTT results in pre-surgical evaluation between June 2006 and May 2008 were analyzed retrospectively by review of medical records. 50 patients showed aPTT prolongation, 5 patients PT prolongation, 2 patients PT and aPTT prolongation and another three patients showed normal PT and aPTT. Among 55 patients with abnormal results, 25 patients (43%) were recovered spontaneously during their follow up tests, 17 patients (29%) showed lower level of certain coagulation factor than reference range and the other 13 patients were lost during follow up despite of recommendation for further evaluation. Mean value of international normalized ratio (INR) for PT and aPTT of the patients recovered spontaneously were 1.05±0.11, 44.53±5.01seconds(s), and 1.12±0.11, 47.0±5.36s in patients with lower level of coagulation factor, showing significant increase of PTT in patients with lower factor levels (p<0.05). Median time required for spontaneous recovery was four weeks and 18 patients (72%) were recovered within this time. Among 17 patients with lower level of certain coagulation factor then reference level, there were 11 patients with low factor XII level, three patients with low factor VIII level, three patients with low von Willebrand factor, two patients each for low factor VII and factor XI and one patient with low factor V level. Among them three patients with low level in von Willebrand factor, one patient with low factor VII and two patients with low factor XI showed deficient level of coagulation factors requiring factor replacement for the surgical procedures. From this analysis of patients with incidentally found PT or aPTT prolongation, 43% of patients were spontaneously recovered during follow up period within 4 weeks in median. However, we also found that 29% of patients had relatively lower level of coagulation factor than reference range. Even though most of them were factor XII decrease which is not closely related with bleeding tendency, six patients had significant deficiencies of coagulation factors requiring factor replacement during surgical procedures. These results suggest that we should keep following up and undergo adequate evaluation for underlying coagulation factor deficiencies in patients who have sustaining PT and aPTT prolongation abnormalities despite of absence of any bleeding history.

Targeted deletion of murine coagulation factor XII gene-a model for contact phase activation in vivo

2004 ◽  
Vol 92 (09) ◽  
pp. 503-508 ◽  
Author(s):  
Hans-Ulrich Pauer ◽  
Thomas Renné ◽  
Bernhard Hemmerlein ◽  
Tobias Legler ◽  
Saskia Fritzlar ◽  
...  
Keyword(s):  
Fetal Loss ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Mendelian Inheritance ◽  
Biological Role ◽  
Factor Xii ◽  
Wild Type ◽  
Contact Phase ◽  
Health And Disease

SummaryTo analyze the biological role of factor XII (FXII, Hageman Factor) in vivo, we generated mice deficient for FXII using a gene targeting approach on two distinct genetic backgrounds, i.e. mixed C57Bl/6J X 129X1/SvJ and inbred 129X1/SvJ. Homozygous FXII knockout (FXII-/-) mice showed no FXII plasma activity and had a markedly prolonged activated partial thromboplastin time (aPTT). In contrast, coagulation factors XI, VIII, IX, X,VII,V, II and fibrinogen did not differ between FXII-/- mice and their wild-type littermates. Heterozygous matings segregated according to the Mendelian inheritance indicating that FXII deficiency does not increase fetal loss. Furthermore, matings of FXII-/- males and FXII-/females resulted in normal litter sizes demonstrating that total FXII deficiency in FXII-/females does not affect pregnancy outcome. Also, gross and histological anatomy of FXII-/mice was indistinguishable from that of their wild-type littermates on both genetic backgrounds. Thus it appears that deficiency of murine FXII does not cause thrombophilia or impaired fibrinolysis in vivo. These results indicate that FXII deficiency does not affect hemostasis in vivo and we anticipate that the FXII-/mice will be helpful to elucidate the biological role(s) of FXII in health and disease.

scholarly journals Postprandial coagulation factor VII activity: the effect of monounsaturated fatty acids

1997 ◽  
Vol 77 (4) ◽  
pp. 537-549 ◽  
Author(s):  
Helen M. Roche ◽  
Michael J. Gibney
Keyword(s):  
Fatty Acids ◽  
Regression Analysis ◽  
Plasma Lipid ◽  
Area Under The Curve ◽  
Coagulation Factor ◽  
Random Order ◽  
Monounsaturated Fatty Acids ◽  
Factor Vii ◽  
Activity Levels ◽  
Coagulation Factor Vii

The present study investigated the effect of monounsaturated fatty acids (MUFA) on postprandial coagulation factor VII activity. Fifteen healthy male volunteers consumed three meals containing equal amounts (40g) of fat, but providing different proportions of MUFA (12,17 and 24% energy)in random order. Fasting and postprandial blood samples were drawn every hour for 9 h. The magnitude of the postprandial triacylglycerolaemic response and the postprandial plasma nonesterifled fatty acid (NEFA) concentrations were not significantly different following the three meals. Coagulation factor VII was activated during postprandial triacylglycerolaemia but the area under the curve of postprandial coagulation factor VII activity was not significantly different following the three meals. Regression analysis showed that fasting factor VII activity was the single mast important factor affecting postprandial factor VII activity, irrespective of plasma lipid concentrations and meal fat composition. Peak postprandial factor VII activity was attained significantly earlier following the high-MUFA meal compared with the low-MUFA meal (6·33 (SD 2·16) h, 3·60 (SD 1·81)h respectively; P = 0·016). Regression analysis showed that meal MUFA content was the primary determinant of time to peak postprandial factor VII activity. Although the magnitude of postprandial coagulation factor VII activity was not affected by meal MUFA content, peak postprandial factor VII activity occurred earlier and fasting activity levels were quickly restored following the high-MUFA meal. A short-lived increase in factor VII activity may be more beneficial than a prolonged thrombotic response.

Coagulation factor levels in neurosurgical patients with mild prolongation of prothrombin time: effect on plasma transfusion therapy

2011 ◽  
Vol 114 (1) ◽  
pp. 3-7 ◽  
Author(s):  
Karén Matevosyan ◽  
Christopher Madden ◽  
Samuel L. Barnett ◽  
Joseph E. Beshay ◽  
Cynthia Rutherford ◽  
...  
Keyword(s):  
Prothrombin Time ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Scientific Data ◽  
Factor Vii ◽  
Plasma Transfusion ◽  
Transfusion Therapy ◽  
Study Results ◽  
Neurosurgical Patients ◽  
Transfusion Guidelines

Object Neurosurgical patients often have mildly prolonged prothrombin time (PT) or international normalized ratio (INR). In the absence of liver disease this mild prolongation appears to be due to the use of very sensitive PT reagents. Therefore, the authors performed relevant coagulation factor assays to assess coagulopathy in such patients. They also compared plasma transfusion practices in their hospital before and after the study. Methods The authors tested 30 plasma specimens from 25 patients with an INR of 1.3–1.7 for coagulation factors II, VII, and VIII. They also evaluated plasma orders during the 5-month study period and compared them with similar poststudy periods following changes in plasma transfusion guidelines based on the study results. Results At the time of plasma orders the median INR was 1.35 (range 1.3–1.7, normal reference range 0.9–1.2) with a corresponding median PT of 13.6 seconds (range 12.8–17.6 seconds). All partial thromboplastin times were normal (median 29.0 seconds, range 19.3–33.7 seconds). The median factor VII level was 57% (range 25%–124%), whereas the hemostatic levels recommended for major surgery are 15%–25%. Factors II and VIII levels were also within the hemostatic range (median 72% and 118%, respectively). Based on these scientific data, plasma transfusion guidelines were modified and resulted in a 75%–85% reduction in plasma orders for mildly prolonged INR over the next 2 years. Conclusions Neurosurgical patients with a mild prolongation of INR (up to 1.7) have hemostatically normal levels of important coagulation factors, and the authors recommend that plasma not be transfused to simply correct this abnormal laboratory value.

International Normalized Ratio Versus Plasma Levels of Coagulation Factors in Patients on Vitamin K Antagonist Therapy

2011 ◽  
Vol 135 (4) ◽  
pp. 490-494 ◽  
Author(s):  
Gene Gulati ◽  
Megan Hevelow ◽  
Melissa George ◽  
Eric Behling ◽  
Jamie Siegel
Keyword(s):  
Vitamin K ◽  
Warfarin Therapy ◽  
Clinical Laboratory ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
International Normalized Ratio ◽  
Activity Levels ◽  
Factor X ◽  
Life Threatening ◽  
Average Factor

Abstract Context.—The key question when managing patients on warfarin therapy who present with life-threatening bleeding is how to use the international normalized ratio (INR) to best direct corrective therapy. The corollary question for the clinical laboratory is at what level will the INR reflect a critical value that requires notifying the clinician. Objective.—To determine the levels of vitamin K–dependent factors over a range of INR values. Design.—Evaluation of the vitamin K–dependent coagulation factor levels on plasma remnants from patients in whom a prothrombin time and INR was ordered to monitor warfarin therapy. There were a total of 83 specimens evaluated with an INR range from 1.0 to 8.26. Results.—The mean activity levels of all 4 factors remained near or above 50% when the INR was less than 1.5. The average factor X level was 23% when the INR range was 1.6 to 2.5, but levels of factors II, VII, and IX did not drop below the hemostatic range until the INR was greater than 2.5. At an INR of 3.6 or more, the activity levels of all 4 factors were less than 30% in more than 90% of the specimens. Conclusion.—Levels of factors II, VII, IX, and X declined with increasing INR but not at the same rate and not to the same level at a given INR. However, most of the values were below the hemostatic value once the INR was 3.6 or more, the level that was also considered critical for physician notification.

The molecular basis of low activity levels of coagulation factor VII: a Brazilian cohort

Haemophilia ◽  
2015 ◽  
Vol 21 (5) ◽  
pp. 670-680 ◽  
Author(s):  
F.Y. Rabelo ◽  
L. L. Jardim ◽  
M. B. Landau ◽  
T. Gadelha ◽  
M. F. B. Corrêa ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Activity Levels ◽  
Coagulation Factor Vii ◽  
Low Activity ◽  
Brazilian Cohort

Coagulation Factors Are Activators Of Human Plasma “Prorenin”

1981 ◽  
Author(s):  
D H Osmond ◽  
S R Tatemichi ◽  
E A Wilczynski ◽  
A D Purdon
Keyword(s):  
Human Plasma ◽  
Coagulation Factor ◽  
Plasma Renin ◽  
Coagulation Factors ◽  
Coagulation System ◽  
Activation Process ◽  
Special Importance ◽  
Factor Xii ◽  
Renin Content

We have demonstrated that human plasma “prorenin”, an inactive precursor of the blood pressure regulating enzyme renin, can be activated by cold, e.g. -4 to +4°C for 1-30 days (Can. J. Physiol. Pharmacol. 51:705, 1973). Several workers have reported cold activation of the coagulation system. Suspecting a link between these two cold- activated enzyme systems, we established that in factor XII deficient plasma, the rate of cold activation of prorenin is halved (Lancet i, 1313, 1978). Trypsinization of plasma can mimic within 1 minute the effect of prolonged cold (Circ. Res. Suppl . 1, 41:171, 1977), and can overcome specific coagulation factor deficiencies in varying degrees. FXII, VII, V, and especially FX deficient plasmas, all have subnormal basal active renin levels, implying an impaired state of prorenin conversion in vivo. FXII deficientplasma activates least by cold, suggesting special importance of FXII for operation of cold activation. All the plasmas activate better with 0.5 mg trypsin/ml plasma than with cold, except FX, suggesting that it especially mediates tryptic activation. Increasing the trypsin concentration corrects for factor deficiencies in varying degrees, implying some non-specificity and interchangeability of factor requirements for prorenin activation. Our data point to a hierarchy of factor importance, and to a “cascade7#x201D; of prorenin activation, by which plasma renin content can be rapidly increased. Thus, plasma renin activity is a function of renal release of renin, plus renin formation from renal (and possibly extrarenal) prorenin by an activation process involving the coagulation system.

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