Fundamentals and Patient Evaluation

2006 ◽  
Author(s):  
Richard C. Becker ◽  
Frederick A. Spencer
Keyword(s):  
General Population ◽  
Venous Thrombosis ◽  
Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Incidence Rates ◽  
Factor V ◽  
Inherited Thrombophilia ◽  
Occult Malignancy ◽  
History Of

Thrombophilia is the term used to describe a tendency toward developing thrombosis. This tendency may be inherited, involving polymorphism in gene coding for platelet or clotting factor proteins, or acquired due to alterations in the constituents of blood and/or blood vessels. An inherited thrombophilia is likely if there is a history of repeated episodes of thrombosis or a family history of thromboembolism. One should also consider an inherited thrombophilia when there are no obvious predisposing factors for thrombosis or when clots occur in a patient under the age of 45. Repeated episodes of thromboembolism occurring in patients over the age of 45 raise suspicion for an occult malignancy. A summary of inherited thrombophilias are summarized in Table 24.1. This list continues to grow, as new genetic polymorphisms and combined mutations are being detected. The prevalence of common thrombophilias is shown in Figure 24.1. Factor V Leiden (FVL) mutation and hyperhomocysteinemia are present in nearly 5% of the general population and are often found in patients with venous thrombosis, while deficiencies of antithrombin (AT), protein C, and protein S are relatively uncommon. Elevated levels of factor VIII (FVIII) are uncovered frequently in the general population and in patients with thrombosis. This is not surprising as FVIII is an acute-phase reactant that increases rapidly after surgery or trauma; however, prospective studies have shown that FVIII elevation in some patients cannot be attributed to a stress reaction and probably represents mutations in the genes regulating FVIII synthesis or release (Kyrle et al., 2000). The same may be true for factors IX and XI. The relative risks for thrombosis among patients with inherited thrombophilias have been determined. While AT mutations are the least common, they are associated with a substantial risk of venous thrombosis; similar risk is seen with protein C and S deficiency. In contrast, the lifetime risk of having a thromboembolic event in an individual heterozygous for FVL is comparatively low (Martinelli et al., 1998). Incidence rates markedly increase with age, and are highest among those with AT deficiency, followed by protein C and protein S, and least with FVL.

Prothrombin Fragment F1+2 Is not Predictive for Recurrent Venous Thromboembolism

1997 ◽  
Vol 77 (05) ◽  
pp. 0829-0833 ◽  
Author(s):  
P A Kyrle ◽  
S Eichinger ◽  
I Pabinger ◽  
A Stümpflen ◽  
M Hirschl ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Venous Thrombosis ◽  
Protein C ◽  
Oral Anticoagulants ◽  
Factor V Leiden ◽  
Factor V ◽  
Recurrent Thrombosis ◽  
Prothrombin Fragment ◽  
Recurrent Venous Thromboembolism ◽  
History Of

SummaryIt would be important to estimate in advance the risk of recurrent thrombosis. Deficiencies of antithrombin, protein C or protein S, or resistance to activated protein C are associated with a biochemically detectable prethrombotic state. It is thus far unknown whether in patients with a history of thromboembolism but without a defined clotting abnormality a heightened coagulation activation is detectable.We investigated the value of prothrombin fragment Fl+2 (FI+2) as a predictor of recurrent venous thromboembolism. Furthermore, we compared the Fl+2 levels of thrombosis patients without a defined clotting defect to those of Factor V Leiden patients with a history of venous thrombosis and to those of healthy controls. 180 patients without a defined clotting abnormality and 73 patients with Factor V Leiden were prospectively followed after discontinuation of oral anticoagulants for venous thrombosis and Fl+2 was measured at regular intervals.Recurrent venous thromboembolism occurred in 23 (9%) of the 253 patients. Before or at several time points after oral anticoagulants, no significant difference in Fl+2 levels was found in patients with and without recurrent thrombosis. Fl+2 levels at 3 weeks and prior to recurrence were not significantly different in both patient groups. Over a one-year observation period, Fl+2 levels of both patients with and without Factor V Leiden were higher than those of the controls. No difference in Fl+2 was seen between patients with and without Factor V Leiden.We conclude that monitoring of Fl+2 is not suitable for identification of individuals at risk of recurrent venous thrombosis. Permanent hemostatic system activation is detectable both in patients with a defined abnormality of the clotting system and in patients in whom a particular defect has not (yet) been identified.

4g/5g Prevalence in 223 Patients with Thrombosis and in 162 Healthy Controls, from the Centre Region of Portugal.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4057-4057
Author(s):  
Rosa Maia ◽  
Emilia Cortesao ◽  
Catarina Geraldes ◽  
Luis Simoes ◽  
Carla Simoes ◽  
...  
Keyword(s):  
Protein C ◽  
Antithrombin Iii ◽  
Factor V Leiden ◽  
Protein S ◽  
Mthfr C677t ◽  
Insertion Polymorphism ◽  
Factor V ◽  
Centre Region ◽  
History Of ◽  
Pai 1

Abstract A deletion/insertion polymorphism (4G or 5G) in the promoter of the PAI-1 gene has been suggested to be involved in regulation of the synthesis of the inhibitor, the 4G allele being associated with enhanced gene expression, and therefore related with thrombosis. In the present work we studied the prevalence of 4G/5G polymorphism in 223 unrelated patients with history of objectively confirmed thromboembolism, and in 162 healthy unrelated controls, both groups natural from all centre regions of Portugal. In this normal cohort, the prevalence of 4G/4G is 23%, 4G/5G is 38% and 5G/5G is 39%; in the affected population is, respectively, 47%, 21.5% and 30%, which means that 4G/4G is twice more frequent in the patients with thrombosis. When we relate the age of the first thrombosis episodes in the three groups, we find no significative difference, as the respective media is 36.8; 38.6 and 35.5 years in the 4G/4G, 4G/5G and 5G/5G group, respectively. This data suggest that this polymorphism by itself, even in homozygosity, is not associated with earlier thrombosis. In our patients, we studied the presence of Lupus Anticoagulant, Factor V Leiden, Factor IIG20210A, MTHFR C677T, and also Antithrombin III, Protein S and Protein C levels. We analyse the prevalence of the three mutations in patients with DVP, PTE, ischemic and venous CVA and we only find a significative difference in the 4G/4G group: 46.2% patients with DVP and 48.2% patients with PTE (23% in normal cohort). In conclusion, in the centre region of Portugal, the prevalence of 4G/4G is 23%, 4G/5G is 38% and 5G/5G is 39%; in our cohort of unrelated patients the only significative difference is in the 4G/4G group (47%); this variation maintain in the DVP and PTE group. We did not find difference at the age of the first thrombotic episode, in the three groups.

Retrospective Review of Hypercoagulability in Minority Populations at an Inner City Hospital’s General Hematology Clinic.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3973-3973
Author(s):  
Pritesh R. Patel ◽  
Manila Gaddh ◽  
Sunita Nathan ◽  
Griza Decebal ◽  
Rosalind Catchatourian ◽  
...  
Keyword(s):  
African American ◽  
Inner City ◽  
Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Minority Populations ◽  
Factor V ◽  
History Of ◽  
Prothrombin Gene Mutation ◽  
Prothrombin Gene

Abstract Background: Although much is known about the incidence of hypercoagulable disorders in the Caucasian population, data is lacking in many other racial groups. We therefore retrospectively analyzed charts of all patients referred to our inner city hospital’s general hematology clinic from January 2003 to December 2006 for evaluation of possible hypercoagulable state. Methods: We reviewed charts for all patients referred for investigation of thrombophilia or hypercoagulable state seen in our clinic. Data regarding history of thrombosis was recorded. In the case of venous thromboembolic disease possible precipitants were noted. Demographic data and family history were noted. A clinical diagnosis of hypercoagulability was made based on whether the patient had any of the following: age <40; strong family history of thrombosis; unusual location of thrombosis; 2 or more thrombotic events; lack of precipitant to thrombotic episode. Laboratory data was gathered on the following: factor V leiden mutation; prothrombin gene mutation; MTHFR mutation; antithrombin III levels; protein C and protein S function; antiphospholipid antibodies. Results: 59 patients were referred. Of these 12 patients were excluded from further analysis as the reason for referral was investigation of ischemic stroke or myocardial infarction. Using the above clinical criteria 33 patients were identified as having hypercoagulability. Diagnoses and demographics are noted in tables 1 and 2. Conclusions: Our study illustrates several important practical points about the investigation of hypercoagulable patients. A larger number of protein C or S deficiencies would likely have been diagnosed had these studies been performed prior to starting anticoagulation. Similarly it is likely that the proportion of patients diagnosed with antiphospholipid antibody syndrome is high as it is possible to test for this condition whilst patients are anticoagulated. It is therefore appropriate that the best time for testing be disseminated more widely to general internal medicine providers. Importantly it appears that certain diagnostic tests would have a much higher yield in minority populations. It is likely that resources would be better allocated if African American patients in particular were tested initially for the antiphospholipid antibodies and activated protein C resistance rather than prothrombin gene mutations or factor V Leiden. Further prospective studies are planned to confirm these findings. Baseline demographics Race Gender Age Male Female <40 years >40 years All patients 12 21 22 11 African American 6 12 11 7 White 3 5 5 3 Hispanic 1 3 4 0 Asian 2 1 2 1 Diagnosis by ethnic group Race Diagnosis Antiphospholipid Protein S def. ATIII def. V Leiden MTHFR Multiple Disorders Unknown No cases of Protein C deficiency or Prothrombin Gene Mutation identified All patients 12 3 3 1 (heterozygous) 1 2 15 African American 5 2 2 0 1 1 9 White 3 0 0 1 (heterozygous) 0 0 4 Hispanic 2 1 1 0 0 1 1 Asian 2 0 0 0 0 0 1

scholarly journals Inherited Hypercoagulable States

1997 ◽  
Vol 2 (4) ◽  
pp. 313-320 ◽  
Author(s):  
A Koneti Rao ◽  
Sunita Sheth ◽  
Robert Kaplan
Keyword(s):  
Arterial Thrombosis ◽  
Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Thromboembolic Events ◽  
Heparin Cofactor Ii ◽  
Predisposing Factor ◽  
Inherited Thrombophilia ◽  
Prothrombin Gene

Hypercoagulable states are a group of conditions associated with increased predisposition to thromboembolic events. Most of the inherited abnormalities recognized to date are associated with venous thromboembolism (VTE) rather than arterial thrombosis. The well-recognized inherited hypercoagulable states are the deficiencies of antithrombin, protein C and protein S, and the resistance to APC (factor V Leiden). These entities represent aberrations in the natural anticoagulant systems that exist in plasma. Other causes of inherited thrombophilia include abnormalities in the proteins of the fibrinolytic system, dysfibrinogenemias, deficiency of heparin cofactor II, abnormal thrombomodulin, elevated levels of histidine-rich glycoprotein, and the recently described variation in the prothrombin gene. One entity that has become firmly established as a predisposing factor for recurrent VTE is hyperhomocysteinemia. About half of VTE episodes in patients with inherited thrombophilias occur in relation to events that are generally recognized as predisposing states, such as surgery, pregnancy (particularly puerperium) and immobilization. In this review, the risks of VTE associated with inherited risk factors are discussed, and guidelines for the diagnosis and management are presented.

scholarly journals Compound Homozygous Factor V Leiden and Heterozygous Prothrombin Gene Mutation: The First Report in a Pregnant African with Extensive Thrombosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5056-5056
Author(s):  
Livingstone Gayus Dogara ◽  
Joseph Ogirima Ovosi ◽  
Caleb Mohammed ◽  
Bilkisu Farouk ◽  
Ziphozonke Mafika ◽  
...  
Keyword(s):  
Blood Cells ◽  
Research Funding ◽  
Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
African Countries ◽  
C Protein ◽  
History Of ◽  
In Pregnancy

Abstract Background: Factor V Leiden (FVL) mutation and Protein gene G20210A mutation (PGM) are the most common inherited thrombophilias in the world. (Limdi NA et.al, Blood Cells Mol Dis. 2006 Sep-Oct;37(2):100-6) Both are inherited in an autosomal recessive fashion with individuals who are homozygous having higher risk of thrombosis compared to those who are heterozygous.(Rodger MA et.al, PLoS Med. 2010 Jun 15;7(6):e1000292.) The global prevalence of FVL and PGM is variable with Caucasians carrying the highest prevalence and Africans living in Africa, Asians and Native Americans having the lowest rate of these mutations; it is zero in West and Southern African countries, 2.4%-3.9% in North African countries including Morocco, Tunisia, and Algeria. (Limdi NA et.al, Blood Cells Mol Dis. 2006 Sep-Oct;37(2):100-6, Dziadosz M et. al, Blood Coagul Fibrinolysis. 2016 Jul;27(5):481-9) Pregnancy increases the risk of developing venous thromboembolism (VTE) by 0.05-1.8 %, (Eldor A, Thromb Haemost. 2001 12.12.2017;86(07):104-11) which is 4 to 5 fold greater than in non-pregnant female.(Croles FN et.al, BMJ. 2017;359, Greer IA, N Engl J Med. 2015 Aug 6;373(6):540-7) Inheritance of FVL and PGM increases the risk for development of VTE in pregnancy, the risk is higher with homozygous than heterozygous mutations.(Rodger MA et.al, PLoS Med. 2010 Jun 15;7(6):e1000292.) Concurrent presentation of FVL and PGM in pregnancy presenting as thrombosis is not common. Aim: The aim of this case report is to present a patient of African descent with concurrent FVL and PGM mutation who had thrombosis during pregnancy. The Case: A 32-year-old Nigerian female who was 28 weeks pregnant presented to the gynecologist with a swollen left leg. Physical examination and the Wells score were very suggestive of a deep vein thrombosis (DVT). The Duplex Doppler performed confirmed a diagnosis of bilateral lower limb DVT. The patient was referred to a physician, who together with the haematologist performed a thrombophilia screen including FVL, PGM, Protein C, Protein S and Anticardiolipin antibody tests. The D-DIMERS were raised and the viral markers including HIV, HBV, and HCV were negative. The PT, APTT and full blood counts were normal. The thrombophilia tests revealed that the patient was homozygous for FVL and also heterozygous for the PGM mutations. The rest of the thrombophilia screen including Protein C, Protein S and Antithrombin tests were all negative. She has no family history of thrombosis; no past history of hormone based contraceptives. She was counselled on the need for using anticoagulation, low molecular weight heparin (LMWH) during the rest of her pregnancy period, and therapeutic anticoagulation with a LMWH at a dose of 1mg/kg twice a day until onset of labour was started. During labour LMWH was discontinued, delivery was per vaginal and was uncomplicated. Postpartum LMWH was continued at therapeutic doses for six weeks with no bleeding or thrombotic events. After six weeks, the patient was started on lifelong warfarin. Results (See Table) Discussion: To our knowledge this is a first case of a patient born and living in Africa presenting with thrombosis and found to have homozygous FVL and heterozygous PGM during pregnancy, the one report that is similar was in a second generation South African woman of German, Dutch and French ancestry. (Wilson J et. al, Medical Technology SA. [Case Report]. December 2011;25(2):4) Most reports have shown ethnic and regional affectation. (Limdi NA et.al, Blood Cells Mol Dis. 2006 Sep-Oct;37(2):100-6, Bavikatty NR, et.al, Am J Clin Pathol. 2000 Aug;114(2):272-5) There is no single agreed reason as to why the mutation is rare in Africa though founder effect is being studied to define how the mutation came about, it could have taken place before divergence of race. (Jadaon MM. [Thrombosis, Familiar Thrombophilia]. 2011 2011-11-28;3(1) We could not do family studies to help define the origin of this mutation whether it is denovo for Nigeria; this has to do with sentiments about genetic inheritance in Africa. Conclusion: Concurrent inheritance of both FVL and PGM is possible in Africa. This rare case has open opportunities to revisit the prevalence of thrombophilia in Nigeria and other African countries. Disclosures Mahlangu: Alnylam: Consultancy, Research Funding, Speakers Bureau; Biomarin: Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Research Funding; Chugai: Consultancy; Amgen: Consultancy; Bayer: Research Funding; Biogen: Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding.

Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5314-5322 ◽  
Author(s):  
Willem M. Lijfering ◽  
Jan-Leendert P. Brouwer ◽  
Nic J. G. M. Veeger ◽  
Ivan Bank ◽  
Michiel Coppens ◽  
...  
Keyword(s):  
Family History ◽  
Venous Thrombosis ◽  
Protein C ◽  
Positive Family History ◽  
Protein S ◽  
Factor V ◽  
Recurrence Rates ◽  
Thrombotic Risk ◽  
History Of ◽  
Fv Leiden

Abstract Thrombophilia screening is controversial. In a retrospective family cohort, where probands had thrombosis and a thrombophilic defect, 2479 relatives were tested for thrombophilia. In antithrombin-, protein C–, and protein S–deficient relatives, annual incidences of venous thrombosis were 1.77% (95% CI, 1.14-2.60), 1.52% (95% CI, 1.06-2.11), and 1.90% (95% CI, 1.32-2.64), respectively, at a median age of 29 years and a positive family history of more than 20% symptomatic relatives. In relatives with factor V (FV) Leiden, prothrombin 20210G>A, or high FVIII levels, these were 0.49% (95% CI, 0.39-0.60), 0.34% (95% CI, 0.22-0.49), and 0.49% (95% CI, 0.41-0.51), respectively. High FIX, FXI, and TAFI, and hyperhomocysteinemia were not independent risk factors. Annual incidence of major bleeding in antithrombin-, protein C–, or protein S–deficient relatives on anticoagulants was 0.29% (95% CI, 0.03-1.04). Cumulative recurrence rates in relatives with antithrombin, protein C, or protein S deficiency were 19% at 2 years, 40% at 5 years, and 55% at 10 years. In relatives with FV Leiden, prothrombin 20210G>A, or high levels FVIII, these were 7%, 11%, and 25%, respectively. Considering its clinical implications, thrombophilia testing should address hereditary deficiencies of antithrombin, protein C, and protein S in patients with first venous thrombosis at young age and/or a strong family history of venous thrombosis.

scholarly journals Primary Thrombophilia in Mexico: A Single Tertiary Referral Hospital Experience

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4717-4717
Author(s):  
Dennis Lacayo-Leñero ◽  
Angel Gabriel Vargas-Ruiz ◽  
Olga Barrales-Benítez ◽  
Darinel Hernández-Hernández ◽  
Andrés Valencia-Martínez
Keyword(s):  
Protein C ◽  
Age At Onset ◽  
Factor V Leiden ◽  
Protein S ◽  
Mthfr C677t ◽  
Factor V ◽  
Tertiary Referral Hospital ◽  
Unusual Site ◽  
Mthfr C677t Polymorphism ◽  
History Of

Abstract Background: Thrombophilia is a complex hypercoagulable state that predisposes to thrombosis. Several thrombophilia reports have been conducted in Mexicans with lack of statistical significance. The objective of this study was to describe the prevalence of primary thrombophilia in a tertiary referral hospital in Mexico. Material and methods: Retrospective study of patients referred for primary thrombophilia between January 2011 and May 2015.. Thrombophilia study included: MTHFR C677T, anti-phopholipid antibodies, protein C, protein S, antithrombin, factor VIII, factor V Leiden, prothrombin mutation G20210A, APCR, JAK2 V617F, homocysteine. We used descriptive statistics according to the distribution of the variables. We used measures of central tendency and dispersion: average, median. All analyses were performed using the SPSS for Windows 20.0® Results: We identified 224 patients referred for thrombophilia testing in a 4 year period. At the time of statistical analysis 129 patients were excluded for lacking data.Ninety five patients were included.Median age at onset was 36 years. (Table 1) Nine of 60 (15%) female patients reported previous use of contraceptives and 13/60 (21.6%) reported previous obstetric morbidity. (Table 2). We identified at least one anomaly related with thrombophilia in 90/95 patients (94.7%). Eighty patients (84.1%) presented the MTHFR C677T polymorphism; heterozygous 51/95 (53.6%) presenting with hyperhomocysteinemia 18/51 (35.2%) and homozygous 29/95 (30.5%) presenting with hyperhomocysteinemia 10/29 (34.4%).Factor V Leiden was found in 5/95 (5.2%) heterozygous. It co-occurred with APCR in 3/5 cases (60%).In 44 patients we found an isolated anomaly associated with thrombophilia (46.3%). In 51/95 (53.6%) we identified co-occurring anomalies associated with thrombophilia. (Table 3). The median of co-occurring anomalies was 2 (2-4). Conclusions: The MTHFR C677T polymorphism has a very high prevalence in Mexicans compared to the low prevalence of anticoagulant protein deficiency and factor V Leiden mutation. Table 1. Demographic characteristics. Demographic characteristics No. Patients (%) -Gender Male Female Total 35 (36.8) 60 (63.1) 95 (100) -Age Median years (range) 36 (17-75) -Family history of thrombosis -Cardiovascular risk factors Arterial Hypertension Diabetes mellitus Dyslipidemia Smoking 15 (15.7) 13 (13.6) 11 (11.5) 13 (13.6) 15 (15.7) -Surgery related thrombosis 3 (3.1) -Cancer related thrombosis 3 (3.1) -Autoimmune disease SLE Other autoimmune disease 11 (11.5) 3 (3.1) 8 (8.4) SLE: Systemic Lupus Erythematosus. Table 2. Thrombosis characteristics. Thrombosis characteristics No. Patients (%) -Thrombotic events Median (range) 1 (1-4) -Affected territory Venous Arterial Mixed 80 (84.2) 14 (14.7) 1 (1) -Thrombophilia testing indication Age at onset <45 years. Family history of thrombosis Unusual site thrombosis Intra abdominal thrombosis Cerebral vein thrombosis Other unusual site thrombosis Recurrent thrombosis Obstetric morbidity More than one indication for testing 91 (95.7) 77 (81) 15 (15.7) 48 (50.5) 25/48 (52) 11/48 (22.9) 12/48 (25) 26 (27.3) 13/60 (21.6) 62 (65.2) -Treatment VKA LMWH Clopidogrel NOAC's ASA None ND 44 (46.3) 3 (3.1) 1 (1) 8 (8.4) 14 (14.7) 6 (6.3) 19 (20) VKA: Vitamin K Antagonist LMWH: Low Molecular Weight Heparin; NOAC's: New oral anticoagulants; ASA: acetylsalicylic acid. ND: Not described. Table 3. Results of thrombophilia anomalies. TROMBOPHILIA TOTAL FREQUENCY ISOLATED FREQUENCY CO-OCCURRING WITH ANOTHER THROMBOPHILIA ANOMALY. -MTHFR C677T heterozygous 51/95 (53.6%). 22/51 (43.1%) 29/51 (56.8%) -Hyperhomocysteinemia 36/95 (37.8%). 6/36 (16.6%) 30/36 (83.3%) -MTHFR C677T homoczygous 29/95 (30.5%). 14/29 (48.2%) 15/29 (51.7%) -APCR 13/95 (13.6%). 0 13/13 (100%) -F V Leiden G1691A 5/95 (5.2%) 0 5/5 (100%) -Protein C deficiency 5/95 (5.2%) 0 5/5 (100%) -Elevated FVIII levels (>150%) 4/95 (4.2%) 0 4/4 (100%) -Protein S deficiency 3/95 (3.1%) 1/3 (33.3%) 2/3 (66.6%) -APS 3/95 (3.1%) 0 3/3 (100%) -Prothrombin G20210A 2/95 (2.1%). 0 2/2 (100%) -JAK2V617F 1/95 (1.0%) 1/1 (100%) 0 -Antithrombin deficiency 0 0 0 MTHFR: methylentetrahidrofolate reductase; APCR: Activated protein C resistance; APS: Antiphospholipid syndrome. Disclosures No relevant conflicts of interest to declare.

scholarly journals Circulating Activated Protein C in Thrombophilia Carriers

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4948-4948
Author(s):  
Thijs E van Mens ◽  
Joost C.M. Meijers ◽  
Saskia Middeldorp
Keyword(s):  
Venous Thrombosis ◽  
Lower Limit ◽  
Protein C ◽  
Thrombin Generation ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Prothrombin G20210a ◽  
Factor V ◽  
Limit Of Quantification ◽  
Inherited Thrombophilia

Abstract Background: Inherited thrombophilias are genetic disorders in which mutation carriers have an elevated risk of venous thromboembolism through abnormalities in the coagulation cascade. These abnormalities all lead to increased thrombin generation. The mutations, of which factor V Leiden and prothrombin G20210A are the most common, therefore likely increase thrombin mediated protein C activation in plasma. Previous findings have however been inconsistent. Increased activation of protein C in inherited thrombophilia would be interesting in light of various unexplained phenotypes described in thrombophilia carriers. Examples of such phenotypes include improved fertility, increased risk of miscarriage, protection from diabetic nephropathy, decreased susceptibility to and mortality from sepsis and decreased mortality in acute respiratory distress syndrome. These do not appear directly related to increased coagulation in carriers. Activated protein C (APC) possesses a wide range of signaling functions and interactions with multiple pathways. These result in anti-apoptotic, anti-inflammatory, gene-expression, regenerative and endothelial stabilizing effects. Such properties can easily be thought to play a role in the above described phenotypes. APC has indeed been shown to possess beneficial properties in numerous animal injury models. Due to its pleiotropic nature, APC might be a promising candidate for further research into the unexplained phenotypes observed in inherited thrombophilia. Aim: To investigate if plasma APC concentrations are higher in thrombophilia carriers as compared to non-carriers. Methods: We performed a cross-sectional observational study comparing the APC plasma levels of factor V Leiden and prothrombin G20210A mutation hetero- and homozygotes with non-carriers. Exclusion criteria comprised use of anticoagulant medication and recent venous thrombosis or risk factors for venous thrombosis. We measured APC using a recently developed highly sensitive oligonucleotide-based capture assay, with a limit of detection of 0.022 ng/ml and the ability to quantify APC upward of 0.116 ng/ml (lower limit of quantification) (Müller et al., 2012). In addition we determined APC-protein C inhibitor complex (APC-PCI) as a secondary measure of protein C activation, and prothrombin fragment 1+2 (F1+2) concentration as a measure of thrombin generation using immunoassays. Parametric and non-parametric descriptive and inferential statistics were applied as appropriate. Results: We included 19 thrombophilia carriers and 18 non-carriers (Table 1). APC was detectable in 47% of carriers and in 39% of non-carriers (p = 0.74). APC was above the lower limit of quantification in only 19% of all subjects, with no difference between the groups (Figure 1). The median APC-PCI concentration in carriers and non-carriers were 5 AU (IQR 3.5-10.5) vs. 5 AU (IQR 3.0-8.0) (p = 0.338); and mean F1+2 concentrations were 266 pmol/L and 194 pmol/L in carriers and non-carriers respectively (p = 0.075). Discussion: We did not find increased circulating APC concentrations in thrombophilia carriers. Given the low number of subjects with quantifiable APC in the study, elevated APC levels in carriers versus non-carriers cannot be fully excluded. Local elevation at the site of thrombin formation still seems plausible, and our data do show a trend towards increased thrombin generation in thrombophilia carriers. However, we also show that systemic concentrations are generally below 0.116 ng/ml, which is an order of magnitude lower than concentrations previously reported as physiological levels. A prominent role for APC in non-coagulation related thrombophilia phenotypes might therefore be questioned. References Müller, J. et al. (2012). Journal of Thrombosis and Haemostasis : JTH, 10(3), 390-8. Measured APC concentrations above the limit of quantification, according to thrombophilia carriership status. Measured APC concentrations above the limit of quantification, according to thrombophilia carriership status. Figure 1 Figure 1. Disclosures Middeldorp: Boehringer Ingelheim: Consultancy; GSK: Consultancy, Honoraria; Aspen: Consultancy, Honoraria; BMS/Pfizer: Consultancy, Honoraria; Bayer: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Sanquin: Consultancy.

Inpatient Thrombophilia Workup in Patients with Acute Venous Thromboembolism

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4720-4720
Author(s):  
Vivek Rashmikant Mehta ◽  
Uzma Khan ◽  
Aparna Basu ◽  
Asif Jan ◽  
Bolanie Gbadamosi ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Family History ◽  
Gene Mutation ◽  
Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Test Results ◽  
History Of ◽  
Acute Venous Thromboembolism

Abstract Background Any inherited or acquired condition that increases the risk of developing deep venous thrombosis or pulmonary embolism is considered a thrombophilic disorder. Some examples of inherited causes of thromboembolic disorders are Factor V Leiden mutation (FVL), Prothrombin gene mutation, Protein C deficiency (low or dysfunctional), Protein S deficiency (low or dysfunctional), Anti-thrombin (AT) deficiency (low or dysfunctional). Use of these studies in clinical practice has been questioned. We attempted to identify if there are populations of patients that undergo more inpatient screening for inherited causes of venous thromboembolism (VTE). Methods Retrospective chart review of patients admitted with PE or DVT in a community teaching hospital between May 2012 and December 2014. Only patients who had DVT confirmed with ultrasound or PE confirmed with CT angiogram or had high probability of PE on V/Q scan were included in the study. Individual charts were reviewed to see if thrombophilia workup was ordered. Results A total of 704 patients with acute venous thromboembolism were identified who met our inclusion criteria for the study. Of this 111 patients (15.76%) had one or more thrombophilia screening studies ordered. Risk factors related to venous thromboembolism were evaluated for all of the 704 patients. In our patient population, patients who were smokers (31% vs 20%), had history of sleep apnea (9% vs 3%), a past medical history (PMH) of VTE (37% vs 25%) or who had a family history (FH) of VTE (11% vs 4%) were more likely to have a thrombophilia workup ordered. Table 2 shows the frequency of individual thrombophilia studies ordered among the 111 patients who had testing performed and table 3 shows distribution of positive results. Table. Test Result Abnormal Test Results ANA 1 Decreased AT III 10 Decreased Protein C 10 Decreased Protein S 7 Increased Homocysteine 6 Factor V Leiden 4 PT Gene Mutation 1 APLA 1 Conclusion The largest numbers of positive test results were noted for Protein C, Protein S and Antithrombin III and these are known to be affected by acute thrombosis and therefore could be false positives. Our study shows that those patients with PMH or FH of VTE were more likely to have thrombophilia studies. There is no consensus opinion as to whether to perform thrombophilia screenings in acute care settings. Given this and the fact that personal or family history of VTE do not usually modify future treatment decisions and that there may be significant number of false positives we do not recommend routine screening in these patient populations. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

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
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