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Posts Tagged ‘translational sciecne’

The Relation between Coagulation and Cancer affects Supportive Treatments

Demet Sag, PhD

 

Coagulation and Cancer

There are several supportive therapies for cancer patients. One of the most important one is controlling the blood intake. This is sometimes observe keeping the blood cell count at certain levels, or providing safe blood/blood products to avoid any contaminations or infections,

The relation between cancer and coagulation was known for a long time but it was becoming clear recently.  Having coagulapathies also reduce the survival of patients since they can’t response to given treatments. Thus, it is necessary to give supportive therapies to control the coagulation. Problems in coagulation may develop from inherited (genetics), or acquired due to given therapies that cause varying abnormalities towards bleeding or thrombose at many levels.  The thrombotic events are important since they are the second leading cause of death in cancer patients (after cancer itself).  The presence of these coagulopathies determines the survival rate, length of survival either short-term or long-term, as well as relapses.

Cancer and Coagulation from start to finish:

Thrombotic risk factors in cancer patients

  1. Patient related
  2. Cancer related
  3. Treatment related

.

  1. Patient Related:
  • Older age
  • Bed rest
  • Obesity
  • Previous thrombosis
  • Prothrombotic mutations
  • High leukocyte and platelet counts
  • Comorbidities
  1. Cancer related:

a. Site of cancer:

  • brain,
  • pancreas,
  • kidney,
  • stomach,
  • lung,
  • bladder,
  • gynecologic,
  • hematologic malignancies

b. Stage of cancer:

  • advanced stage and
  • initial period after diagnosis
  1. Treatments:
  • Hospitalization
  • Surgery
  • Chemo- and
  • hormonal therapy
  • Anti-angiogenic therapy
  • Erythropoiesis stimulating agents
  • Blood transfusions
  • CVC, central venous catheters
  • Radiations

Thromboembolic events can be venous or arterial.

Venous events include

  • deep vein thrombosis (DVT),
  • pulmonary embolism (PE)

together categorized as venous thromboembolism (VTE).

Arterial events, include

  • stroke, myocardial infarction and
  • arterial embolism.

increase in the rate of VTEIncrease in the rate of venous thromboembolism (VTE) over time. Results are presented as annual rates of deep venous thrombosis (DVT), pulmonary embolism (PE) without deep venous thrombosis, and both between 1995 and 2003. Significant trends for increasing rates were observed for all 3 diagnoses (P < .0001). The rate of increase was found to be greater in the subgroup of patients who received chemotherapy. Error bars represent 95% confidence intervals.

There is an increase in both venous and arterial eventsrecently with “unacceptably high” event rates documented in the most contemporary studies:

There are significant consequences to the occurrence of thromboembolism in this setting:

  • requirement for long-term anticoagulation,
  • a 12% annual risk of bleeding complications,
  • an up to 21% annual risk of recurrent VTEand
  • potential impact on chemotherapy delivery and patient quality of life.

 

Therapeutic interventions enhance the risk of VTE in cancer.

  • Cancer patients undergoing surgery have a two-fold increased risk of postoperative VTE as compared to non-cancer patients, and this elevation in risk can persist for a period up to 7 weeks
  • Hospitalization also substantially increases the risk of developing VTE in cancer patients (OR 2.34, 95% CI 1.63 – 3.36)
  • The use of systemic chemotherapy is associated with a 2-to 6-fold increased risk of VTE compared to the general population.
  • Anti-angiogenic agents, particularly thalidomide and lenalidomide, have been associated with high rates of VTE when given in combination with dexamethasone or chemotherapy.
  • Bevacizumab-containing regimens have been associated with increased risk for an arterial thromboembolic event (hazard ratio [HR] 2.0, 95% CI 1.05- 3.75) but the data for risk of VTE are conflicting
  • Sunitinib and sorafenib, agents targeting the angiogenesis pathway, have also similarly been associated with elevated risk for arterial (but not venous) events [RR 3.03 (95% CI, 1.25 to 7.37)]

Anticoagulants and Cancer Coagulopathies

There are many studies on coagulation and use of anti-coagulants yet the same patient may also thrombose at any given time so the coagulant therapies should be under close surveillance.  The study (PMID:111278600) by Palereti et all in 2000 to many  compared this issue.

fig1_10.1002_cncr.23062

Palereti et al. showed that:

“The outcome of anticoagulation courses in 95 patients with malignancy with those of 733 patients without malignancy. All patients were participants in a large, nation-wide population study and were prospectively followed from the initiation of their oral anticoagulant therapy.

Based on 744 patient-years of treatment and follow-up, the rates of major (5.4% vs 0.9%), minor (16.2% vs 3.6%) and total (21.6% vs 4.5%) bleeding were statistically significantly higher in cancer patients compared with patients without cancer.

Bleeding was also a more frequent cause of early anticoagulation withdrawal in patients with malignancy (4.2% vs. 0.7%; p <0.01; RR 6.2 (95% CI 1.95-19.4). There was a trend towards a higher rate of thrombotic complications in cancer patients (6.8% vs. 2.5%; p = 0.058; RR 2.5 [CI 0.96-6.5]) but this did not achieve statistical significance”.

They concluded that “patients with malignancy treated with oral anticoagulants have a higher rate of bleeding and possibly an increased risk of recurrent thrombosis compared with patients without malignancy.”

http://www.cancernetwork.com/sites/default/files/figures_diagrams/1502FeinsteinFigure.png

1502FeinsteinFigure

Cancer and Coagulation in more detail at Molecular Level:

Cancer is a complex disease from its initiation to its treatment. In the body the response to drugs generates side effects for being foreign (immune responses and inflammation), toxic, or disturbing the hemostasis of the coagulation system. In addition, activation of oncogenic pathways cab also be activated that may not only effect the development of the cancer but also may induce oncogenes to activate dormant cancer cells. In the coagulation system the balance is important to keep anti-coagulant state, with oversimplification, such as having certain number of tissue factor (TF) that is a receptor determines the anticoagulant state. However, certain pro-oncogenic genes like RAS, EGFR, HER2, MET, SHH and loss of tumor suppressors (PTEN, TP53) change the gene regulation so they alter the expression, activity and vesicular release of coagulation effectors, as exemplified by tissue factor (TF). As a result, there is a bridge between the coagulation-related genes (coagulome) and specific cancer coagulapathies, such as in glioblastoma multiforme (GBM), medulloblastoma (MB), etc. Therefore, these coagulome can be a great target not only to inhibit angiogenesis and tumor growth but also prevent any coagulopathies, use in single genomics/circulating cancer cells as well as grading the level of cancer specifically.

Here in this figures Tumor-hemostatic system interactions http://onlinelibrary.wiley.com/store/10.1111/jth.12075/asset/image_n/jth12075_f1.gif?v=1&t=ifxvwlxk&s=62da078fc1c8d85d58c256e83954181a16f7463b

and Microparticle (MP) production and activities in cancer are well summarized http://onlinelibrary.wiley.com/store/10.1111/jth.12075/asset/image_n/jth12075_f2.gif?v=1&t=ifxvwlzv&s=13f9b775d7417f12e3ae5f879c09ac8825918d61

coagulation and cancer

 

 

http://onlinelibrary.wiley.com/store/10.1111/jth.12075/asset/image_n/jth12075_f1.gif?v=1&t=ifxvwlxk&s=62da078fc1c8d85d58c256e83954181a16f7463b

Tumor-hemostatic system interactions. Tumor cells activate the hemostatic system in multiple ways. Tumor cells may release procoagulant tissue factor, cancer procoagulant and microparticles (MP) that can directly activate the coagulation cascade. Tumor cells may also activate the host’s hemostatic cells (endothelial cells and platelets), by either release of soluble factors or by direct adhesive contact, thus further enhancing clotting activation.

 

 tumor and coagulation cascade

 

http://onlinelibrary.wiley.com/store/10.1111/jth.12075/asset/image_n/jth12075_f2.gif?v=1&t=ifxvwlzv&s=13f9b775d7417f12e3ae5f879c09ac8825918d61

Microparticle (MP) production and activities in cancer. Tumor cells actively release MP but also promote MP formation by platelets. Tissue factor (TF) and phosphatidylserine (PS) expression on the surfaces of both platelet- and tumor-derived MP are involved in blood clotting activation and thrombus formation. On the other hand, the elevated content of proangiogenic factors in platelet-derived MP (VEGF, vascular endothelial growth factor, FGF, fibroblast growth factor, PDGF, platelet-derived growth factor), render these elements also important mediators of the neangiogenesis process. Finally, intracellular transfer of MP may occur between cancer cells, leading to a horizontal propagation of oncogenes and amplification of their angiogenic phenotype.

 

Immune Response and Cancer with Coagulopathies:

  1. I. Goufman et al also suggested that plasma level of IgG autoantibodies to plasminogen changes during cancer coagulopathies.

Their data based on ELISA measurements of their patients:

  • with benign prostatic hyperplasia (n=25),
  • prostatic cancer (n=17),
  • lung cancer (n=15), and
  • healthy volunteers (n=44).

High levels of IgG to plasminogen were found

  • in 2 (12%) of 17 healthy women, in 1 (3.6%) of 27 specimens in a healthy man,
  • in 17 (68%) of 25 specimens in prostatic cancer,
  • in 10 (59%) of 17 specimens in lung cancer,
  • in 5 (30%) of 15 specimens in benign prostatic hyperplasia.

Comparison of plasma levels of anti-plasminogen IgG by affinity chromatography showed 3-fold higher levels in patients with prostatic cancer vs. healthy men.

Structure and function of platelet receptors initiating blood clotting.

There is a missed or overlooked concept about coagulation and cancer. In their article they mainly focused on the structure and function of key platelet receptors taking role in the thorombus formation and coagulation.

At the clinical level, recent studies reveal the link between coagulation and other pathophysiological processes, including platelet activation, inflammation, cancer, the immune response, and/or infectious diseases. These links are likely to underpin the coagulopathy associated with risk factors for venous thromboembolic (VTE) and deep vein thrombosis (DVT). At the molecular level, the interactions between platelet-specific receptors and coagulation factors could help explain coagulopathy associated with aberrant platelet function, as well as revealing new approaches targeting platelet receptors in diagnosis or treatment of VTE or DVT. Glycoprotein (GP)Ibα, the major ligand-binding subunit of the platelet GPIb-IX-V complex, that binds the adhesive ligand, von Willebrand factor (VWF), is co-associated with the platelet-specific collagen receptor, GPVI. The GPIb-IX-V/GPVI adheso-signaling complex not only initiates platelet activation and aggregation (thrombus formation) in response to vascular injury or disease but GPIbα also regulates coagulation through a specific interaction with thrombin and other coagulation factors.

Clinical Data and Some Samples of Biomarkers:

Development of biomarkers and management of cancer coagulapathies are underway since there are times this coagulapathies may be as deadly as the cancer itself.

The sample study and data from Reference: Alok A. Khorana, M.D. Cancer and Coagulation. Am J Hematol. 2012 May; 87(Suppl 1): S82–S87. Published online 2012 Mar 3. doi:  10.1002/ajh.23143 PMCID: PMC3495606. NIHMSID: NIHMS386379

Resource: PMC full text: Am J Hematol. Author manuscript; available in PMC 2013 May 1.

Published in final edited form as:

Am J Hematol. 2012 May; 87(Suppl 1): S82–S87.

Published online 2012 Mar 3. doi:  10.1002/ajh.23143

Copyright/License ►Request permission to reuse

Table 1

Selected Clinical Risk Factors and Biomarkers for Cancer-associated Thrombosis

Patient-associated risk factors
 Older age
 Race
 Gender
 Medical comorbidities
 Obesity
 Prior history of thrombosis
Cancer-associated risk factors
 Primary site
 Stage
 Cancer histology (higher for adenocarcinoma than squamous cell)
 Time after initial diagnosis (highest in first 3-6 months)
Treatment-associated risk factors
 Chemotherapy
 Anti-angiogenic agents
 Hormonal therapy
 Erythropoiesis-stimulating agents
 Transfusions
 Indwelling venous access devices
 Radiation
 Surgery
Biomarkers
Currently widely available
 Platelet count (≥350,000/mm3)23
 Leukocyte count (> 11,000/mm3)23
 Hemoglobin (< 10 g/dL)23
 D-dimer25,26
Investigational and/or not widely available
 Tissue factor (antigen expression, circulating microparticles, antigen or activity)3133

 

 

Table 2

Predictive Model for chemotherapy-associated VTE23

Patient Characteristics Risk Score
Site of cancer
 Very high risk (stomach, pancreas) 2
 High risk (lung, lymphoma, gynecologic, bladder, testicular) 1
Prechemotherapy platelet count 350000/mm3 or more 1
Hemoglobin level less than 10g/dl or use of red cell growth factors 1
Prechemotherapy leukocyte count more than 11000/mm3 1
Body mass index 35kg/m2 or more 1

High-risk score ≥ 3

Intermediate risk score =1-2

Low-risk score =0

 

 

Rates of VTE According to Risk Score

Study Type, f/u N Low-risk (score=0) Intermediate–risk (score =1-2) High-risk (score≥3)
Khorana et al23, 2008 Development cohort, 2.5 mos 2701 0.8% 1.8% 7.1%
Khorana et al23, 2008 Validation cohort, 2.5 mos 1365 0.3% 2% 6.7%
Kearney et al67, 2009 Retrospective, 2 yrs 112 5% 15.9% 41.4%
Price et al68, 2010 Retrospective, pancreatic, NA 108 – * 14% 27%
Ay et al36, 2010 Prospective, 643 days 819 1.5% 9.6% (score= 2) 17.7%
3.8% (score=1)
Khorana et al69, 2010 Prospective**, 3 mos 30 – *** 27%
Moore et al2, 2011 Retrospective, cisplatin-based chemotherapy only 932 13% 17.1% 28.2%
Mandala et al37, 2011 Retrospective, phase I patients only, 2 months 1,415 1.5% 4.8% 12.9%

NA=not available

*Pancreatic cancer patients are assigned a score of 2 based on site of cancer and therefore there were no patients in the low-risk category

**included 4-weekly screening ultrasonography

***enrolled only high-risk patients

Table 4

ASCO and NCCN Recommendations for Treatment of VTE in Cancer

ASCO NCCN
Initial treatment
LMWH is the preferred approach for the initial 5-10 days LMWH, UFH or factor Xa antagonists according to patient’s characteristics and clinical situation
Long term treatment
LMWH for at least 6 months is preferred. LMWH is preferred
VKA are acceptable when LMWH is not available. Indefinite anticoagulation in patients with active cancer or persistent risk factors
Indefinite anticoagulation in patients with active cancer.
Thrombolytic therapy in initial treatment
Restricted to patients with life- or limb-threatening thrombotic events Restricted to massive or submassive PE with moderate or severe right ventricular enlargement or dysfunction
Inferior vena cava filters
Restricted to patients with contraindications to anticoagulation or recurrent VTE despite adequate long-term LMWH Restricted to patients with contraindications to or failure of anticoagulation, cardiac or pulmonary dysfunction severe enough to make any new PE life-threatening or multiple PE with chronic pulmonary hypertension
Treatment of catheter-related thrombosis
NA LMWH or VKA for as long as catheter is in place or for 1 to 3 months after catheter removal
 Soluble P-selectin (> 53.1 ng/mL)65
 Factor VIII66
 Prothrombin fragment F 1+2 (>358 pmol/L) 26

 

 

 

Genome Analysis at the crossroads of Coagulation and Cancer

, Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disordersGenome Medicine, 2015, 7,1

Phenotype similarity clustering of cases according to HPO terms. Heat map showing pairwise phenotypic similarity among affected members of pedigrees, cases with classical syndromes and cases with variants in ACTN1. The groups are ordered through complete-linkage hierarchical clustering within each class and P values of phenotypic similarity are shown in a scatterplot superimposed over a histogram showing the distribution of P values.

Westbury et al. Genome Medicine 2015 7:36   doi:10.1186/s13073-015-0151-5
Download authors’ original image

Phenotype clusters 18 and 29. Illustrative subgraphs of the HPO showing terms for the phenotype clusters 18 (15 cases) and 29 (16 cases). Arrows indicate direct (solid) or indirect (dashed) is a relations between terms in the ontology. DMPV: decreased mean platelet volume; PA: phenotypic abnormality; Plt-agg: platelet aggregation abnormality.

Westbury et al. Genome Medicine 2015 7:36   doi:10.1186/s13073-015-0151-5
Download authors’ original image

s13073-015-0151-5-5 s13073-015-0151-5-6

Rare variants identified inACTN1
Case Transcript variant ENST00000394419 Protein variant ENSP00000377941.4 HGMD variant Classification PLT, ×109/L MPV, fL, and/or presence of macrothrombocytes Bleeding phenotype
B200726 14:69392385 A/C F37C No LPV 57 18.1, macrothrombocytes None
B200207 14:69392358 C/T R46Q Yes PV 53 >13, macrothrombocytes None
B200209 PV 76 >13, macrothrombocytes Mild
B200212 PV 98 >13, macrothrombocytes None
B200254 PV 34 >13, macrothrombocytes None
B200735 PV 52 12.0, macrothrombocytes None
B200746 14:69392359 G/A R46W No LPV 96 15.2, macrothrombocytes None
B200197 14:69392344 G/C Q51E No LPV 113 >13, macrothrombocytes Mild
B200836 14:69387750 C/T V105I Yes PV 53 NA, macrothrombocytes None
B200837a PV 75 NA, macrothrombocytes None
B200671 14:69371375 C/T E225K Yes PV 97 13.7, macrothrombocytes Mild
B200716 PV 82 15.0, macrothrombocytes None
B200398 14:69369274 C/T V228I No LPV 31 15.4, macrothrombocytes Mild
B200280 14:69358897 C/T R320Q No LPV 108 15.1, macrothrombocytes Mild
B200281a LPV 111 13.9, macrothrombocytes None
B200835 14:69352254 C/T A425T No VUS 50 10.0, no macrothrombocytes Mild
B200283 14:69349768 A/G L547P No LPV 91 13.3, macrothrombocytes Mild
B200048 14:69349648 G/A A587V No VUS 390 NA, no macrothrombocytes Mild
B200284 14:69346749 G/T T737N No LPV 60 16.1, macrothrombocytes Mild
B200285a LPV 48 16.8, macrothrombocytes Mild
B200741 14:69346747 G/A R738W Yes PV 94 12.9, macrothrombocytes None
B200745 PV 70 14.5, macrothrombocytes None
B200750 14:69346746 C/T R738Q No LPV 106 14.0, macrothrombocytes None
B200414 14:69346704 C/G R752P No LPV 121 11.4, macrothrombocytes Mild

aAffected family member.

Westbury et al.

Westbury et al. Genome Medicine 2015 7:36   doi:10.1186/s13073-015-0151-5

Rare variants identified inMYH9and validated by Sanger sequencing
Case Transcript variant ENST00000216181 Protein variant ENSP00000216181 HGMD variant Classification PLT, ×109/L MPV, fL and/or presence of macrothrombocytes OtherMYH9-RD characteristics
B200760 22:36744995 G/A S96L Yes PV 180 Macrothrombocytes None
B200771 22:36705438 C/A D578Y No VUS 184 10.1 None
B200423 22:36696237 G/A A971V No VUS 262 10.2 None
B200024 22:36691696 A/G S1114P Yes VUS 164 NA None
B200245 VUS 53 11.1, Macrothrombocytes None
B200243 22:36691115 G/A R1165C Yes PV 22 Macrothrombocytes None
B200594 PV 46 Macrothrombocytes None
B200595a PV 61 Macrothrombocytes None
B200614 22:36688151 C/T D1409N No VUS 319 9.8 None
B200752 VUS 149 10.1, Macrothrombocytes None
B200855 VUS 95 16.8, Macrothrombocytes None
B200208 22:36688106 C/T D1424N Yes PV 99 13.6 None
B200010 22:36685249 G/C S1480W No VUS 244 NA None
B200244 22:36678800 G/A R1933X Yes PV 26 Macrothrombocytes Döhle inclusions

Other MYH9-RD characteristics sought were the presence of Döhle inclusions, cataract, deafness or renal pathology.

aFather of B200594.

Westbury et al.

Westbury et al. Genome Medicine 2015 7:36   doi:10.1186/s13073-015-0151-5

Pathogenic and likely pathogenic variants identified in genes associated with autosomal recessive and X-linked recessive bleeding and platelet disorders
Case Position Gene Ref Alt Genotype HGMD Effecta Haematological HPO terms Other HPO terms Classification:
Variant Phenotype
B200286 3:148881737 HPS3 G C C|C Yes Abnormal splicing Bleeding with minor or no trauma, subcutaneous haemorrhage, menorrhagia, postpartum haemorrhage, impaired ADP-induced platelet aggregation, impaired epinephrine-induced platelet aggregation, epistaxis, prolonged bleeding after surgery, prolonged bleeding after dental extraction, increased mean platelet volume. Hypothyroidism, visual impairment, nystagmus, albinism. PV Explained
B200412 3:148858819 HPS3 T TA T|TA No Frameshift Impaired epinephrine-induced platelet aggregation, bleeding with minor or no trauma, subcutaneous haemorrhage, epistaxis, menorrhagia, prolonged bleeding after surgery, abnormal dense granules. Ocular albinism. LPV Possibly explained
3:148876539 HPS3 G A G|A No W593a LPV
B200068 10:103827041 HPS6 C G C|G No L604V Increased mean platelet volume. Congenital cataract, strabismus, maternal diabetes. LPV Possibly explained
10:103827554 HPS6 C G C|G No L775V LPV
B200196 X:48542673 WAS C T T Yes T45M Thrombocytopenia, abnormal bleeding, decreased mean platelet volume, abnormal platelet shape. Recurrent infections. PV Explained
B200725 X:48544145 WAS T C C Yes F128S Monocytosis, neutrophilia, thrombocytopenia, leukocytosis, subcutaneous haemorrhage, gastrointestinal haemorrhage. PV Explained
B200443 X:138633272 F9 G A A Yes R191H Reduced factor IX activity, impaired ADP-induced platelet aggregation, bleeding with minor or no trauma, spontaneous haematomas, abnormal number of dense granules. PV Partially explained
B200452 X:154124407 F8 C G G Yes S2125T Reduced factor VIII activity, persistent bleeding after trauma, prolonged bleeding after surgery, prolonged bleeding after dental extraction, bleeding requiring red cell transfusion, impaired collagen-induced platelet aggregation, bleeding with minor or no trauma, joint haemorrhage, abnormal platelet shape, abnormal number of dense granules. PV Partially explained
B200772 X:154176011 F8 A G G No F692S Reduced factor VIII activity, bruising susceptibility, impaired ADP-induced platelet aggregation, impaired collagen-induced platelet aggregation, impaired thromboxane A2 agonist-induced platelet aggregation, impaired ristocetin-induced platelet aggregation, impaired arachidonic acid-induced platelet aggregation, impaired thrombin-induced platelet aggregation, abnormal platelet granules, bleeding with minor or no trauma. LPV Possibly partially explained

Alt: alternative; Ref: reference.

aEffect considered relative to the Consensus Coding Sequence (CCDS) for each gene.

Westbury et al.

Westbury et al. Genome Medicine 2015 7:36   doi:10.1186/s13073-015-0151-5

Table 2

TFPI and TF tumor mRNA expression across clinicopathological breast cancer subtypes

  mRNA expression (tumor) Protein levels (plasma)
Characteristic Groups Total TFPI (α + β) P TFPIα P TFPIβ P TF P Total TFPI P Free TFPI P TF P
T-status T1 −0.146 0.054 −0.135 0.257 −0.084 0.201 −0.023 0.652 72.01 0.013 10.82 0.997 4.14 0.125
T2-T3 0.085 0.018 0.060 0.054 65.02 10.82 4.66
Grade G1-G2 −0.022 0.850 −0.005 0.424 −0.033 0.743 0.271 0.003 71.04 0.082 10.66 0.682 4.63 0.557
G3 −0.045 −0.113 0.004 −0.229 66.12 10.97 4.14
N-status Negative −0.109 0.091 −0.136 0.127 −0.082 0.104 0.005 0.881 69.93 0.183 10.77 0.869 4.95 0.282
Positive 0.104 0.078 0.110 0.032 66.00 10.90 4.14
ER status Positive −0.067 0.317 −0.082 0.557 −0.056 0.183 0.001 0.784 69.42 0.240 10.91 0.671 4.42 0.409
PR status Negative 0.076 0.011 0.123 0.057 65.44 10.52 5.28
Positive −0.131 0.021 −0.145 0.075 −0.112 0.014 0.085 0.244 69.81 0.195 11.19 0.175 4.32 0.246
HER2-status Negative 0.161 0.108 0.182 −0.127 65.92 10.08 5.04
Negative −0.072 0.054 −0.101 0.073 −0.041 0.154 0.004 0.731 68.45 0.893 10.68 0.287 4.47 0.428
Positive 0.313 0.301 0.228 0.103 69.09 12.05 4.78
HR status Yes 0.076 0.326 0.007 0.587 0.114 0.221 0.016 0.991 64.78 0.161 10.41 0.568 5.26 0.470
No −0.066 −0.080 −0.052 0.014 69.57 10.94 4.47
Triple-negative status Yes −0.051 0.886 −0.110 0.718 0.041 0.635 −0.158 0.326 63.21 0.072 10.06 0.345 5.23 0.969
No −0.029 −0.048 −0.027 0.055 69.73 10.99 4.57

Median values for TFPI and TF mRNA expression in tumors and protein levels in plasma according to clinically defined groups. Corresponding P-values (unadjusted) are shown. Significant P-values in bold. TFPI, tissue factor pathway inhibitor; TF, tissue factor; HER2, human epidermal growth factor receptor 2.Abbreviations: T, tumor; G, grade; N, node; ER, estrogen receptor; PR, progesterone receptor; HR, hormone receptor.

Table 3

Significant association between TFPI single nucleotide polymorphisms (SNPs) and clinicopathological characteristics and molecular subtypes

Characteristic SNP Risk allele Odds ratio 95% CI P False discovery rate
T status
T1 Reference Reference Reference Reference
T2 to T3 rs10153820 A 3.14 1.44, 6.86 0.004 0.056
TN status (ER-/PR-/HER2-negative)
No Reference Reference Reference Reference
Yes rs8176541a G 2.62 1.11, 5.35 0.026 0.092
rs3213739a G 2.58 1.34, 4.99 0.005 0.033
rs8176479a C 3.10 1.24, 7.72 0.015 0.071
rs2192824a T 2.44 1.39, 4.93 0.002 0.033
N status
Positive Reference Reference Reference Reference
Negative rs10179730 G 3.34 1.42, 7.89 0.006 0.083
Basal tumor subtype
Non-basal Reference Reference Reference Reference
Basal rs3213739a G 2.23 1.15, 4.34 0.018 0.107
rs8176479a C 2.79 1.12, 6.96 0.028 0.107
rs2192824a T 2.41 1.24, 4.65 0.009 0.107
rs10187622a C 5.20 1.17, 23.20 0.031 0.107
Luminal B tumor subtype
Non-luminal B Reference Reference Reference Reference
Luminal B rs16829086a T 2.09 1.03, 4.25 0.041 0.191
rs10179730a G 3.53 1.47, 8.46 0.005 0.066
rs10187622a T 2.73 1.24, 6.03 0.013 0.091
Normal-like tumor subtype
Non-normal-like Reference Reference Reference Reference
Normal-like rs5940 T 22.17 4.43, 110.8 0.0002 0.003

aSNPs representing a haplotype effect. SNPs are listed by ascending chromosome positions. TFPI, tissue factor pathway inhibitor; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor 2.

Table 4

Significant correlations between TFPI single nucleotide polymorphisms (SNPs) and TFPI mRNA expression in breast tumors

Probe SNP Region Alleles a Minor allele frequency Beta r P False discovery rate
TFPIα rs2192824b Intronic C:T 0.490 −0.209 −0.180 0.029 0.200
TFPIα rs7594359b Intronic C:T 0.483 −0.219 −0.184 0.025 0.200
TFPIβ rs3213739b Intronic G:T 0.417 0.187 0.213 0.010 0.032
TFPIβ rs8176479b Intronic C:A 0.238 0.184 0.192 0.021 0.049
TFPIβ rs2192824b Intronic C:T 0.490 −0.267 −0.273 0.001 0.011
TFPIβ rs12613071b Intronic T:C 0.158 0.284 0.208 0.011 0.032
TFPIβ rs2192825b Intronic T:C 0.466 −0.251 −0.249 0.002 0.012
TFPIβ rs7594359b Intronic C:T 0.483 −0.248 −0.247 0.002 0.012
TFPIα + β rs2192824b Intronic C:T 0.490 −0.168 −0.161 0.050 0.187
TFPIα + β rs12613071b Intronic T:C 0.158 0.238 0.164 0.048 0.187
TFPIα + β rs7594359b Intronic C:T 0.483 −0.190 −0.178 0.030 0.187

aMajor:minor. bSNPs representing a haplotype effect. mRNA expression was assayed by the Agilent Human V2 Gene Expression 8x60k array, and probes for tissue factor pathway inhibitor (TFPI)α, TFPIβ and total TFPI (TFPIα + β) mRNA were analyzed. Alleles for the positive DNA strand (UCSC annotated) are shown, and SNPs are listed by ascending chromosome positions.

“Eight TFPI SNPs were found to be correlated to total TFPI protein levels in patient plasma (Table 5). The A-T-A-C-T-A-C-G haplotype composed of these eight SNPs (rs8176541-rs3213739-rs8176479-rs2192824-rs2192825-rs16829088-rs7594359-rs10153820) represented a common haplotype (frequency 0.19) with quite strong correlation to total TFPI protein; r = 0.481 (B = 14.62, P = 6.35 × 10−10). No correlation between TFPI SNPs and free TFPI protein, or between TF SNPs and TF protein in plasma was observed (P >0.05, data not shown). Adjusting for age had no effect on the correlation (data not shown).”

Table 5

Significant correlations between TFPI single nucleotide polymorphisms (SNPs) and total TFPI protein levels in plasma

Protein SNP Region Alleles a Minor allele frequency Beta r P False discovery rate
Total TFPI rs8176541b Intronic G:A 0.283 15.64 0.571 7.69 × 10−14 1.08 × 10−12
Total TFPI rs3213739b Intronic G:T 0.417 11.35 0.488 5.38 × 10−10 3.77 × 10−9
Total TFPI rs8176479b Intronic C:A 0.238 12.22 0.480 1.20 × 10−9 5.62 × 10−9
Total TFPI rs2192824b Intronic C:T 0.490 −9.88 −0.404 3.81 × 10−7 1.07 × 106
Total TFPI rs2192825b Intronic T:C 0.466 −7.55 −0.301 2.40 × 10−4 5.30 × 10−4
Total TFPI rs16829088b Intronic G:A 0.250 11.23 0.424 1.00 × 10−7 3.51 × 10−7
Total TFPI rs7594359b Intronic C:T 0.483 −6.90 −0.275 6.90 × 10−4 0.001
Total TFPI rs10153820b Near 5UTR G:A 0.125 −7.79 −0.215 0.009 0.016

aMajor:minor. bSNPs representing a haplotype effect for total tissue factor pathway inhibitor (TFPI). Alleles for the positive DNA strand (UCSC annotated) are shown.

In sum, combination of molecular physiology and genomics will improve the conditions of the patients not only to diagnose early or to monitor the disease but also to streamline the current drugs to be more efficient and therapeutic.

References:

·         PMID: 25480646, Gardiner EE1, Andrews RK. Structure and function of platelet receptors initiating blood clotting. Adv Exp Med Biol. 2014;844:263-75. doi: 10.1007/978-1-4939-2095-2_13.

 

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