scholarly journals Congenital Vitamin K-Dependent Clotting Factors Deficiency Type 1: A Rare Bleeding Disorder

2020 ◽  
Vol 3 (1) ◽  
pp. 8-12
Author(s):  
Sura Ahmed Al-Doory ◽  
Mahmoud Ahmed Radaideh ◽  
Shafeeka Mohamed Saleh ◽  
Mohammed Ali Al Sabbah
Keyword(s):  
Vitamin K ◽  
Protein S ◽  
Clinical Problem ◽  
Homozygous Mutation ◽  
Clotting Factors ◽  
Whole Exome ◽  
History Of ◽  
Factor Assay ◽  
Deficiency Type

Combined deficiency of vitamin K-dependent clotting factors is usually an acquired clinical problem, often resulting from liver disease, malabsorption or warfarin overdose. However, an inherited form of the disease is very rare. Here we report a 4-month-old girl who presented with a 2-week history of multiple bruises and a 1-day history of right thigh swelling after receiving her 4th month vaccine. Laboratory investigations showed anemia (Hb 6.0 g/dL) with extremely prolonged PT and APTT. Factor assay revealed deficiency of vitamin K-dependent clotting factors II, VII, IX, X as well as protein C and protein S. Whole-exome sequencing detected a novel homozygous mutation (c.44-5T>A p.(?)) in the γ-glutamyl carboxylase (GGCX) gene responsible for the autosomal recessive combined vitamin K-dependent clotting factors deficiency type 1.

scholarly journals Vitamin K-dependent protein S is similar to rat androgen-binding protein

1987 ◽  
Vol 243 (1) ◽  
pp. 293-296 ◽  
Author(s):  
M E Baker ◽  
F S French ◽  
D R Joseph
Keyword(s):  
Vitamin K ◽  
Binding Protein ◽  
Protein A ◽  
Serine Proteinase ◽  
Protein S ◽  
Clotting Factors ◽  
The Family ◽  
Androgen Binding Protein ◽  
Dependent Protein ◽  
Androgen Binding

Vitamin K-dependent protein S belongs to the family of clotting factors (e.g. Factors IX and X, and protein C). Unlike the other clotting factors, the C-terminal half (residues 250-634) of protein S is not a serine proteinase. In fact, the function of residues 250-634 of protein S is unknown. By using computer programs designed to detect evolutionary relationships between proteins, we find that this part of protein S is similar to rat androgen-binding protein, a protein produced and secreted by testicular Sertoli cells. The homology between protein S and androgen-binding protein suggests new approaches for elucidating their functions.

scholarly journals Vitamin K-Dependent Coagulation Factors That May be Responsible for Both Bleeding and Thrombosis (FII, FVII, and FIX)

2018 ◽  
Vol 24 (9_suppl) ◽  
pp. 42S-47S ◽  
Author(s):  
Antonio Girolami ◽  
Silvia Ferrari ◽  
Elisabetta Cosi ◽  
Claudia Santarossa ◽  
Maria Luigia Randi
Keyword(s):  
Venous Thrombosis ◽  
Vitamin K ◽  
Protein C ◽  
Protein S ◽  
Coagulation Factors ◽  
Bleeding Tendency ◽  
Clotting Factors ◽  
Protein Z ◽  
Clinical Observations

Vitamin K-dependent clotting factors are commonly divided into prohemorrhagic (FII, FVII, FIX, and FX) and antithrombotic (protein C and protein S). Furthermore, another protein (protein Z) does not seem strictly correlated with blood clotting. As a consequence of this assumption, vitamin K-dependent defects were considered as hemorrhagic or thrombotic disorders. Recent clinical observations, and especially, recent advances in molecular biology investigations, have demonstrated that this was incorrect. In 2009, it was demonstrated that the mutation Arg338Leu in exon 8 of FIX was associated with the appearance of a thrombophilic state and venous thrombosis. The defect was characterized by a 10-fold increased activity in FIX activity, while FIX antigen was only slightly increased (FIX Padua). On the other hand, it was noted on clinical grounds that the thrombosis, mainly venous, was present in about 2% to 3% of patients with FVII deficiency. It was subsequently demonstrated that 2 mutations in FVII, namely, Arg304Gln and Ala294Val, were particularly affected. Both these mutations are type 2 defects, namely, they show low activity but normal or near-normal FVII antigen. More recently, in 2011-2012, it was noted that prothrombin defects due to mutations of Arg596 to Leu, Gln, or Trp in exon 15 cause the appearance of a dysprothrombinemia that shows no bleeding tendency but instead a prothrombotic state with venous thrombosis. On the contrary, no abnormality of protein C or protein S has been shown to be associated with bleeding rather than with thrombosis. These studies have considerably widened the spectrum and significance of blood coagulation studies.

Clinical Problem Solving: Decreased Level of Consciousness and Unexplained Hydrocephalus

2022 ◽  
pp. 194187442110567
Author(s):  
Naomi Niznick ◽  
Ronda Lun ◽  
Daniel A. Lelli ◽  
Tadeu A. Fantaneanu
Keyword(s):  
Decision Making ◽  
Differential Diagnosis ◽  
Clinical Decision Making ◽  
Clinical Problem ◽  
Clinical Decision ◽  
Decision Making Process ◽  
Clinical Problem Solving ◽  
Level Of Consciousness ◽  
History Of

We present a clinical reasoning case of 42-year-old male with a history of type 1 diabetes who presented to hospital with decreased level of consciousness. We review the approach to coma including initial approach to differential diagnosis and investigations. After refining the diagnostic options based on initial investigations, we review the clinical decision-making process with a focus on narrowing the differential diagnosis, further investigations, and treatment.

scholarly journals Effective Hemostasis During Minor Surgery in a Case of Hereditary Combined Deficiency of Vitamin K-dependent Clotting Factors

2009 ◽  
Vol 16 (2) ◽  
pp. 221-223 ◽  
Author(s):  
Mario Lapecorella ◽  
Mariasanta Napolitano ◽  
Francesco Bernardi ◽  
Mirko Pinotti ◽  
Piero Sandro Sbrighi ◽  
...  
Keyword(s):  
Vitamin K ◽  
Protein S ◽  
Coagulation Factors ◽  
Treatment Modalities ◽  
Clotting Factors ◽  
Minor Surgery ◽  
Life Threatening ◽  
Warfarin Reversal ◽  
Surgical Setting ◽  
Combined Deficiency

Combined deficiency of the vitamin K-dependent clotting factors (VKCFD) is a rare bleeding disorder involving defective gamma-carboxylation of coagulation factors II , VII, IX and X as well as natural anticoagulants protein C and protein S. The disease is characterized by a cluster of different, often life threatening, bleeding symptoms occurring both spontaneously and in a surgical setting. In the present paper we describe two different treatment modalities to be used both in a programmed surgical procedure and in an emergency scenario. As this disease is a natural model that resembles oral anticoagulation, our experience discloses a possible rationale in the use of recombinant activated FVII for warfarin reversal.

Pyruvate carboxylase deficiency type C as a differential diagnosis of diabetic ketoacidosis

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Neslihan Doğulu ◽  
Ümmühan Öncül ◽  
Engin Köse ◽  
Zehra Aycan ◽  
Fatma Tuba Eminoğlu
Keyword(s):  
Diabetic Ketoacidosis ◽  
Pyruvate Carboxylase ◽  
Laboratory Findings ◽  
Case Presentation ◽  
First Case ◽  
Whole Exome ◽  
History Of ◽  
Type C ◽  
Deficiency Type ◽  
Level Analysis

Abstract Objectives Type C pyruvate carboxylase (PC) deficiency is extremely rare, and has been described in only a few patients in literature to date. Herein, we present the case of a four-year-old patient admitted with diabetic ketoacidosis and diagnosed with type C PC deficiency based on clinical and biochemical findings. Case presentation A Turkish girl was referred to the intensive care unit at the age of three-years with a three-day history of vomiting and abdominal pain. Upon physical examination, the patient was found to be experiencing lethargy, dehydration, and Kussmaul breathing. Hyperglycemia, metabolic acidosis, and ketonemia were detected. Clinical and laboratory findings pointed to a prediagnosis of diabetic ketoacidosis. Intravenous fluid, bicarbonate, and insulin treatments were initiated. Elevated alanine and proline levels were recorded in plasma amino acid analysis, while urinary organic acid level analysis revealed increased lactate, pyruvate, 3-OH-butyrate, and acetoacetate levels. Whole exome sequencing revealed homozygous c.584C>T (p.Ala195Val) mutation in the PC gene. Conclusions To date, there have been no reports in literature of type C phenotype patients manifesting with DKA. Our case is the first case with the type C phenotype to be admitted with clinical and laboratory findings of DKA.

scholarly journals Successful Pregnancy Outcome in a Patient with Protein S Deficiency: A Case Report

2017 ◽  
Vol 6 (2) ◽  
pp. 134-135
Author(s):  
Khaleda Khanam ◽  
Rehnuma Karim ◽  
Shakila Khanum
Keyword(s):  
Case Report ◽  
Pregnant Woman ◽  
Vitamin K ◽  
Fetal Loss ◽  
Protein S ◽  
Protein S Deficiency ◽  
Successful Pregnancy ◽  
S Deficiency ◽  
Coagulation Proteins ◽  
History Of

Protein S is a vitamin K-dependent anticoagulant and has a central role in the regulation of coagulation. The mechanism of action of protein S has been one of the least understood amongst the vitamin K-dependent coagulation proteins. A deficiency of protein S predisposes to recurrent thromboembolism and fetal loss. Here we report a case of protein S deficiency in a 28- year-old pregnant woman, who had a history of complete abortion at 22 of weeks of gestation and her 2nd pregnancy was managed properly with a successful fetal outcome.Birdem Med J 2016; 6(2): 134-135

Familial Thrombophilia: A Review Analysis

1996 ◽  
Vol 2 (4) ◽  
pp. 227-236 ◽  
Author(s):  
Angelique G. M. van den Belt ◽  
Martin H. Prins ◽  
Menno V. Huisman ◽  
Jack Hirsh
Keyword(s):  
Risk Factor ◽  
Odds Ratio ◽  
Protein C ◽  
Antithrombin Iii ◽  
Family Members ◽  
Protein S ◽  
Biochemical Abnormality ◽  
Thrombotic Disease ◽  
History Of ◽  
Deficiency Type

The correct approach to the management of the asymptomatic carrier with a recognized inherited thrombophilic disorder is uncertain because reliable in formation of the risk of spontaneous (unprovoked) throm bosis in these disorders is not available. To determine the best available estimate of the annual incidence of spon taneous thrombosis in asymptomatic carriers of disorders that have been linked to familial thrombophilia, we per formed a literature review. Using Medline search from 1965 to 1992, supplemented by manual searches, we re trieved all articles that presented data on antithrombin III, protein C, protein S, dysfibrinogenemia, plasmino gen, histidine-rich glycoprotein, heparin cofactor II, and fibrinolysis in relation to thrombosis. Publications were included in the analysis if they (1) reported one or more probands with thrombotic disease and a heterozygous biochemical abnormality of the hemostatic system, (2) assessed the presence of this abnormality in family mem bers independent of the presence or absence of a history of thrombotic disease, and (3) assessed the presence of a history of thrombotic disease in all available family mem bers. The biochemical status and clinical details of all family members reported were extracted from each eligi ble article. For each abnormality the odds ratio for throm bosis was compared in family members with and without the biochemical abnormality. If applicable, thrombosis- free survival and age-specific incidences of thrombosis were calculated. The thrombotic episodes were classified as spontaneous or secondary to a recognized risk factor, and the proportion of spontaneous episodes was calcu lated. The influence of diagnostic suspicion bias in symp tomatic patients with a family history of thrombosis was reduced by recalculating the absolute incidence of throm bosis from the odds ratio after adjusting the incidence of venous thrombosis in nonaffected family members to that observed in the general population. Statistically signifi cant associations between the presence of a biochemical abnormality and a history of venous thrombosis were found for antithrombin III deficiency types 1 and 2a and 2b, protein C deficiency type 1, and protein S deficiency type I. Dysfibronogenemia was statistically significantly associated with venous as well as arterial thrombosis. Thirty-five to 67% of the events were classified as being provoked, as they occurred following exposure to a rec ognized risk factor for thrombosis. The recalculated an nual incidence of spontaneous thrombosis was 0.6 to 1.6%/year. It is concluded that this relatively low inci dence does not warrant life-long continuous use of anti coagulant prophylaxis since the reported risk of major and fatal bleeding associated with the use of oral antico agulants is 2-3 and 0.4%/year, respectively.

VKCFD2 – from clinical phenotype to molecular mechanism

2016 ◽  
Vol 36 (S 02) ◽  
pp. S13-S20 ◽  
Author(s):  
K. J. Czogalla ◽  
M. Watzka ◽  
J. Oldenburg
Keyword(s):  
Vitamin K ◽  
Physiological Activity ◽  
Coagulation Factors ◽  
Clotting Factor ◽  
Clotting Factors ◽  
Vitamin K Cycle ◽  
Factor Deficiency ◽  
Er Retention ◽  
Deficiency Type ◽  
Diagnosis Therapy

SummaryVitamin K 2,3-epoxide reductase complex, subunit 1 (VKORC1) is an enzyme essential for the vitamin K cycle. VKORC1 catalyses the reduction of vitamin K 2,3-epoxide to the quinone form of vitamin K and further to vitamin K hydroquinone. The generated vitamin K hydroquinone serves as substrate for the enzyme γ-glutamyl-carboxylase which modifies all vitamin K-dependent proteins, allowing them to bind calcium ions necessary for physiological activity. Vitamin K-dependent proteins include the coagulation factors FII, FVII, FIX, FX, and proteins C, S und Z. Insufficient VKORC1 enzyme activity results in deficiency of the vitamin K-dependent clotting factors leading to haemorrhagic disorders. This phenotype is known as vitamin K clotting factor deficiency type 2 (VKCFD2). Worldwide, only four families of independent origin have been reported with this rare bleeding disorder. Affected family members carry the mutation VKORC1:p.Arg98Trp in homozygous form, the only mutation found so far to be associated with VKCFD2. Now, ten years after the identification of the VKORC1 gene, the molecular pathomechanism of VKCFD2 has been clarified. The Arg98Trp mutation disrupts an ER retention motif of VKORC1 leading to mislocalisation of the protein to outside the endoplasmatic reticulum. In this review, we summarize the clinical data, diagnosis, therapy and molecular patho -mechanism of VKCFD2.

scholarly journals Novel mutation in the RAB3GAP1 gene, the first diagnosed Warburg Micro syndrome case in Syria

2020 ◽  
Vol 2020 (4-5) ◽  
Author(s):  
Soubhi Tenawi ◽  
Rawan Al Khudari ◽  
Diana Alasmar
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Recessive Disease ◽  
Novel Mutation ◽  
Homozygous Mutation ◽  
Muscular Hypotonia ◽  
Congenital Cataracts ◽  
Whole Exome ◽  
Warburg Micro Syndrome ◽  
Rare Autosomal Recessive Disease

Abstract Warburg Micro syndrome is a rare autosomal recessive disease due to mutation in the RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20 genes. It is commonly seen in consanguineous marriages, characterized by optic (microcornea, microphthalmia, congenital cataracts), neurologic )microcephaly, corpus callosum hypoplasia, severe mental retardation( and hypogonadism; some non-typical findings could be present (cardiomyopathy, peripheral neuropathy). We report a novel homozygous mutation in the RAB3GAP1 gene in a 7-month-old boy from healthy nonconsanguineous parents from the same village in Syria, with bilateral congenital cataracts, hypogonadism, muscular hypotonia and severe developmental delay. Whole exome sequencing (WES) showed a homozygous mutation in the c.2195del p.(Pro732Glnfs*6) in exon 19 of the RAB3GAP1 gene, which is likely pathogenic and correlates with Warburg Micro syndrome type 1.

GENE STRUCTURE OF VITAMIN K-DEPENDENT PROTEIN S; A REGION HOMOLOGOUS TO SEX HORMONE BINDING GLOBULIN (SHBG) REPLACES THE SERINE PROTEASE REGION OF FACTORS IX, X AND PROTEIN C

1987 ◽  
Author(s):  
C-M Edenbrandt ◽  
S Gershagen ◽  
P Femlund ◽  
R Wydro ◽  
J Stenflo ◽  
...  
Keyword(s):  
Amino Acids ◽  
Vitamin K ◽  
Protein C ◽  
Protein S ◽  
Sex Hormone ◽  
Human Protein ◽  
Sex Hormone Binding Globulin ◽  
Hormone Binding ◽  
Clotting Factors ◽  
S Gene

It has recently been shown that the similarity between coagulation factors IX, X and protein C in the protein sequence is also evident in the organization of their genes. To further elucidate the relation of protein S to the other vitamin K-dependent clotting factors, we are now characterizing the human protein S gene. The size of the gene was estimated to be more than 45 kb, by hybridization of a cDNA for human protein S with chromosomal DNA in a Southern blot.We have isolated three overlapping clones from a human genomic DNA library in bacteriophage λ Charon 4A, which cover approximately 40 kb of the gene. The clones have been mapped by single- and double restriction enzyme digestion. Genomic subclones in pUC 18 which hybridize with cDNA probes for protein S have been isolated and sequenced to establish the intron/exon structure of the gene. The 5’- part of the human protein S gene closely resembles the corresponding part of the genes for factors IX, X and protein C. However, the thrombin sensitive region (amino acids 46-75), which is unique for protein S among the vitamin K-dependent clotting factors, is coded for by a separate exon. The 3'- end of the protein S gene, coding for amino acids 247-635, is not homologous to the catalytic region of the vitamin K-dependent serine proteases but shows a significant homology to human sex hormone binding globulin (SHBG).

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