Inherited Genetic Variation and the Risk of Developing Venous Thrombosis with Thalidomide Treatment in Myeloma Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1624-1624
Author(s):  
David C. Johnson ◽  
Suzanne Grindle ◽  
Faith Davies ◽  
David Gonzalez ◽  
Christine Ramos ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Case Series ◽  
Coagulation System ◽  
Attractive Alternative ◽  
Factor V ◽  
Prothrombotic State ◽  
Clotting Factors ◽  
High Background ◽  
Functional Polymorphisms ◽  
Thalidomide Treatment

Abstract There is a high background risk of venous thrombotic events (VTE) in patients with Multiple Myeloma (MM) and this is significantly increased following treatment with Thalidomide. The risk may be mediated by the production of a prothrombotic state, via an angiopathic mechanism, or alternatively it may arise from the release of prothrombotic factors from dying myeloma cells targeted by the treatment. No unifying evidence of a prothrombotic state has been demonstrated to date and it remains important to understand the mechanism underlying VTEs in order to prevent them effectively. Inherited genetic variants in the form of SNPs can affect the behaviour of clotting factors. These SNPs are functional and well characterised in the coagulation system and we have used them to analyse the mechanism underlying thalidomide induced VTE. As part of the Bank On A Cure TM project we have carried out an analysis of SNPs in 11 genes: GPIIA, ITGA, MTHFR, MTR, PPARG2, TFP1, VCAM, factor V, HABP2, prothrombin and THDB in a case series of 90 patients treated with thalidomide, with and without DVTs. This study showed a significant association with MTHFR and factor V polymorphisms. In order to validate and extend these initial observations we carried out an analysis of a second nested case control study using 131 Myeloma patients from within the MRC Myeloma IX trial, comprising 47 cases with a VTE and 94 age and sex matched controls exposed to the same treatment. We used a SNPlex panel containing 16 functional venous thrombosis associated SNPs, all of these functional polymorphisms have reported mechanisms and biology. We looked at polymorphisms in the genes: fibrinogen A (Ala331Thr), B (-455G>A, Lys478Arg) and G polypeptides (His140Tyr); Coagulation factors V(Arg534Gln), VIII (Glu1260Asp), IX(Ala194Thr), XI (Phe339Cys) and XII(-4G>T); PROCR(Gly219Ser); prothrombin(19911A>G ,20210G>A); MTHFR(Glu429Ala, Ala222Val); Serpine1(-844G>A) and TFPI(Met292Val). We have typed our selected SNPs using the SNPlex™ Genotyping System, which is based on the oligonucleotide ligation/PCR assay with a universal fluorescently labeled ZipChute™ probe detection. The probes are hybridized to complementary ZipCode™ sequences that are part of genotype-specific amplicons. Probes are eluted and detected on a Applied Biosystems 3130x DNA Analyser. This approach is an attractive alternative to existing genotyping methodologies, as it requires only three unlabeled probes per SNP, and consumes very little gDNA. The data analysis on the polymorphisms frequencies is ongoing to examine associations of thalidomide treatment with VTE events and will be presented. These datasets will allow a better definition of the pathogenesis of thalidomide related VTE, so that we can intervene therapeutically in a rational fashion.

scholarly journals Clinical profile of postpartum cerebral venous thrombosis

2017 ◽  
Vol 6 (4) ◽  
pp. 1192
Author(s):  
Umesh G. Rajoor ◽  
Seema B. N.
Keyword(s):  
Venous Thrombosis ◽  
Cerebral Venous Thrombosis ◽  
Clinical Profile ◽  
Coagulation System ◽  
Common Finding ◽  
Prothrombotic State ◽  
Hemorrhagic Infarction ◽  
Economic Class ◽  
Presenting Symptoms ◽  
Laboratory Investigations

Background: Pregnancy and puerperium are most prevalent prothrombotic states leading to cerebral venous thrombosis (CVT). Pregnancy induces several changes in coagulation system, which persists at least during early puerperium, rendering it a prothrombotic state. The objective of the study was to study the clinical profile of postpartum CVT.Methods: A total of 32 consecutive patients admitted in medicine and obstetrics and gynecology ward between April 2012 and March 2015 with radiologically confirmed diagnosis of CVT were included in the study. Detailed history, clinical examination, and laboratory investigations were carried out in all the cases.Results: Out of 32 patients of CVT studied, the age of patients varied from 18 to 40 years. Maximum incidence was seen in 21-30 age group comprising 74% of the cases, with mean age being 25.5 years. Two-third of the patients belongs to the low socio-economic class. The majority of them had subacute presentation with the headache in 93.75%, followed by altered sensorium (90.6%) and convulsions (75%) being the most common presenting symptoms. Radiologically the most common finding noted was hemorrhagic infarction (85.3%), followed by non-hemorrhagic infarction (15.7%).Conclusions: Pregnancy and puerperium are most prevalent prothrombotic states leading to CVT.

Resistance to Activated Protein C and Factor V Leiden as Risk Factors for Venous Thrombosis

1995 ◽  
Vol 74 (01) ◽  
pp. 449-453 ◽  
Author(s):  
Rogier M Bertina ◽  
Pieter H Reitsma ◽  
Frits R Rosendaal ◽  
Jan P Vandenbroucke
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V

Phospholipid-Protein Interactions in the Formation of Prothrombin Activator

1965 ◽  
Vol 14 (03/04) ◽  
pp. 431-444 ◽  
Author(s):  
E. R Cole ◽  
J. L Koppel ◽  
J. H Olwin
Keyword(s):  
Complex Formation ◽  
Protein Interactions ◽  
Calcium Ions ◽  
Fixed Number ◽  
Factor V ◽  
Clotting Factors ◽  
Number Of Binding Sites ◽  
C Complex ◽  
Autoprothrombin C

SummarySince Ac-globulin (factor V) is involved in the formation of prothrombin activator, its ability to complex with phospholipids was studied. Purified bovine Ac-globulin was complexed to asolectin, there being presumably a fixed number of binding sites on the phospholipid micelle for Ac-globulin. In contrast to the requirement for calcium ions in the formation of complexes between asolectin and autoprothrombin C, calcium ions were not required for complex formation between asolectin and Ac-globulin to occur ; in fact, the presence of calcium prevented complex formation occurring, the degree of inhibition being dependent on the calcium concentration. By treating isolated, pre-formed aso- lectin-Ac-globulin complexes with calcium chloride solutions, Ac-globulin could be recovered in a much higher state of purity and essentially free of asolectin.Complete activators were formed by first preparing the asolectin-calcium- autoprothrombin C complex and then reacting the complex with Ac-globulin. A small amount of this product was very effective as an activator of purified prothrombin without further addition of calcium or any other cofactor. If the autoprothrombin C preparation used to prepare the complex was free of traces of prothrombin, the complete activator was stable for several hours at room temperature. Stable preparations of the complete activator were centrifuged, resulting in the sedimentation of most of the activity. Experimental evidence also indicated that activator activity was highest when autoprothrombin C and Ac-globulin were complexed to the same phospholipid micelle, rather than when the two clotting factors were complexed to separate micelles. These data suggested that the in vivo prothrombin activator may be a sedimentable complex composed of a thromboplastic enzyme, calcium, Ac-globulin and phospholipid.

Inhibition of Fibrinolytic Activity In-Vivo by Dexamethasone Is Counterbalanced by an Inhibition of Platelet Aggregation

1992 ◽  
Vol 68 (01) ◽  
pp. 069-073 ◽  
Author(s):  
J J J van Giezen ◽  
J W C M Jansen
Keyword(s):  
Platelet Aggregation ◽  
Fibrinolytic Activity ◽  
Ex Vivo ◽  
Dose Range ◽  
Coagulation System ◽  
Loop Model ◽  
Prothrombotic State ◽  
Inhibition Of Platelet Aggregation ◽  
Pai 1

SummaryDexamethasone decreases the fibrinolytic activity in cultured medium of several cell types by an induction of PAI-1 synthesis. As a result of this enhanced PAI-1 synthesis a prothrombotic state is expected in patients treated with dexamethasone. However, such a prothrombotic state is not reported as a major adverse effect. We have studied the effects of dexamethasone (dose range: 0.1–3.0 mg/kg) on the fibrinolytic system of rats after a 5 day pretreatment period. It appeared that dexamethasone dose dependently decreased the fibrinolytic activity (a dose of 1 mg/kg showed a reduction of about 40%). This reduced fibrinolytic activity could be functionally translated into an increased thrombus size as measured with a venous thrombosis model: thrombus size was increased by 50% with 1 mg/kg dexamethasone. No effects could be measured on the coagulation system, but it appeared that ex-vivo measured platelet aggregation was dose dependently inhibited by dexamethasone treatment. This effect resulted in-vivo in prolonged obstruction times as measured with a modified aorta-loop model. These results indicate that the expected prothrombotic state due to a diminished fibrinolytic activity caused by dexamethasone is counterbalanced by an inhibition of platelet aggregation.

Coagulation Disorders in Thrombocythaemia, a Study of Seven Cases

1962 ◽  
Vol 07 (01) ◽  
pp. 114-128 ◽  
Author(s):  
Stefan Niewiarowski ◽  
Halina Zywicka ◽  
Zbigniew Latałło
Keyword(s):  
Liver Parenchyma ◽  
Platelet Factor 4 ◽  
Coagulation System ◽  
Severe Bleeding ◽  
Clotting Factors ◽  
Platelet Factor ◽  
Antiheparin Activity ◽  
Thromboplastic Activity ◽  
Bleeding Episodes ◽  
Routine Coagulation

SummaryThe blood coagulation system has been studied in 7 patients with thrombocythaemia. 4 of these patients had thrombocythaemia after splenectomy, 2 of them had thrombocythaemia associated with myeloid leukemia, and 1 thrombocythaemia associated with polycythaemia. Severe bleeding episodes were noted in 5 cases, 2 patients had only mild bleeding symptoms.Each patient was examined several times. The period of observations varied from 2 months to 3 years. Platelet count varied from 350 000 to 3 800 000 per mm3.Bleeding time and tourniquet test were normal in all cases. Routine coagulation and fibrinolysis studies did not reveale characteristic abnormalities in plasma clotting factors. A decrease of prothrombin complex components was observed in 4 cases. This disturbance was due to the coexisting injury of liver parenchyma or myeloid changes but not to an increase of platelets or to the abnormalities in the platelet system.An increase of antiheparin activity was found in the plasma of 4 patients. This activity is probably due to the escape of platelet factor 4 from destroyed or qualitatively changed platelets into plasma.Platelet clotting factors were investigated in isolated platelet suspensions, A significant decrease of platelet factor 1 was observed in all patients and a decrease of platelet factor 4 in 5 patients. In 2 cases platelet factor 4 increased. Platelet thromboplastic activity showed a great variety of disturbances in conformity with other workers observations.Recent views on the pathogenesis of bleedings in thrombocythaemia are discussed. On the basis of their own investigations the authors suggest that the significant disturbances of platelet function may contribute to the development of bleeding, and that the increase of antiheparin activity in plasma may produce hypercoagulability and favorize the formation of thrombi.

Screening for the FV: Q506 Mutation – Evaluation of Thirteen Plasma-based Methods for their Diagnostic Efficacy in Comparison with DNA Analysis

1997 ◽  
Vol 77 (03) ◽  
pp. 436-439 ◽  
Author(s):  
Armando Tripodi ◽  
Barbara Negri ◽  
Rogier M Bertina ◽  
Pier Mannuccio Mannucci
Keyword(s):  
Venous Thrombosis ◽  
Large Scale ◽  
Dna Analysis ◽  
Genetic Defect ◽  
Laboratory Diagnosis ◽  
Economic Benefits ◽  
Factor V ◽  
Factor X ◽  
Diagnostic Efficacy ◽  
Dna Test

SummaryThe factor V (FV) mutation Q506 that causes resistance to activated protein C (APC) is the genetic defect associated most frequently with venous thrombosis. The laboratory diagnosis can be made by DNA analysis or by clotting tests that measure the degree of prolongation of plasma clotting time upon addition of APC. Home-made and commercial methods are available but no comparative evaluation of their diagnostic efficacy has so far been reported. Eighty frozen coded plasma samples from carriers and non-carriers of the FV: Q506 mutation, diagnosed by DNA analysis, were sent to 8 experienced laboratories that were asked to analyze these samples in blind with their own APC resistance tests. The APTT methods were highly variable in their capacity to discriminate between carriers and non-carriers but this capacity increased dramatically when samples were diluted with FV-deficient plasma before analysis, bringing the sensitivity and specificity of these tests to 100%. The best discrimination was obtained with methods in which fibrin formation is triggered by the addition of activated factor X or Russell viper venom. In conclusion, this study provides evidence that some coagulation tests are able to distinguish carriers of the FV: Q506 mutation from non-carriers as well as the DNA test. They are inexpensive and easy to perform. Their use in large-scale clinical trials should be of help to determine the medical and economic benefits of screening healthy individuals for the mutation before they are exposed to such risk factors for venous thrombosis as surgery, pregnancy and oral contraceptives.

Reversal of DIRECT-ACTING Oral Anticoagulants in Urgent Surgery of the Proximal Aorta: case Series and Review of the literature

2019 ◽  
Vol 24 (38) ◽  
pp. 4534-4539 ◽  
Author(s):  
Eric Zimmermann ◽  
Fawzi Ameer ◽  
Berhane Worku ◽  
Dimitrios Avgerinos
Keyword(s):  
Oral Anticoagulants ◽  
Aortic Surgery ◽  
Management Strategies ◽  
Case Series ◽  
Published Data ◽  
Review Of Literature ◽  
Clotting Factors ◽  
Urgent Surgery ◽  
Direct Acting ◽  
Direct Acting Oral Anticoagulants

Introduction: Proximal aorta interventions impose significant bleeding risk. Patients on concomitant anticoagulation regimens compound the risk of bleeding in any surgery, but especially cardiothoracic interventions. The employment of direct-acting oral anticoagulants (DOAC), namely those that target clotting factors II or X, has expanded at a precipitous rate over the last decade. The emergence of their reversal agents has followed slowly, leaving clinicians with management dilemmas in urgent surgery. We discuss current reversal strategies based on the available published data and our experience with proximal aortic surgery in patients taking DOACs. Literature Search: We performed a review of literature and present three cases from our experience to offer insight into management strategies that have been historically successful. A review of literature was conducted via PubMed with the following search string: (NOAC or DOAC or TSOAC) and (aorta or aortic or (Stanford and type and a)). Case Presentation: We present three case presentations that illustrate the importance of DOAC identification and offer management strategies in mitigating associated bleeding risks in urgent or emergent surgeries. Conclusion: Treatment teams should be aware of the technical limitations of identifying and reversing DOACs. In view of the tendency toward publishing positive outcomes, more scientific rigor is required in the area of emergency DOAC reversal strategies.

Concurrent Factor V Leiden and Protein C Deficiency Presenting as Mesenteric Venous Thrombosis

2016 ◽  
Vol 82 (4) ◽  
pp. 96-98 ◽  
Author(s):  
Lev N. Korovin ◽  
Mustafa Raoof ◽  
John B. Kettelle ◽  
James H. McClenathan ◽  
Jitesh A. Patel
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Mesenteric Venous Thrombosis ◽  
Protein C Deficiency

Should the factor V Leiden mutation be screened among ethnic Malays with venous thrombosis?

2010 ◽  
Vol 125 (5) ◽  
pp. 471-472 ◽  
Author(s):  
H.J. Ng ◽  
E.S. Koay ◽  
A. Abdul Ghafar ◽  
L.C. Lim ◽  
L.H. Lee
Keyword(s):  
Venous Thrombosis ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation

Cerebral Venous Thrombosis After Epidural Blood Patch: Coincidence or Causal Relation? A Case Report and Review of the Literature

Cephalalgia ◽  
2008 ◽  
Vol 28 (7) ◽  
pp. 769-773 ◽  
Author(s):  
M Kueper ◽  
SL Goericke ◽  
O Kastrup
Keyword(s):  
Venous Thrombosis ◽  
Cerebral Venous Thrombosis ◽  
Epidural Blood Patch ◽  
Causal Relation ◽  
Common Symptom ◽  
Factor V ◽  
Review Of The Literature ◽  
Post Dural Puncture Headache ◽  
Blood Patch ◽  
The Right

We report on a female patient who developed post-dural puncture headache (PDPH) after epidural analgesia for delivery. Treatment with epidural blood patch led to complete headache remission and the patient was discharged. Two days later the patient was readmitted with hemihypaesthesia and mild hemiparesis of the right side. Magnetic resonance imaging showed a small left parietal cortical haemorrhage probably following cerebral venous thrombosis (CVT). Coagulation screening detected heterozygous Factor V mutation. Headache is a common symptom of PDPH and CVT. Review of the literature revealed five patients in puerperal state, who developed CVT in close temporal relationship after blood patch treatment for PDPH. Change of headache character with loss of postural influence was reported frequently before diagnosis of CVT was confirmed. These findings may indicate a causal relationship.

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