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
- Patient related
- Cancer related
- Treatment related
.
- Patient Related:
- Older age
- Bed rest
- Obesity
- Previous thrombosis
- Prothrombotic mutations
- High leukocyte and platelet counts
- Comorbidities
- 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
- 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 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
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
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.
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:
- 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 |
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)31–33
Table 2 Predictive Model for chemotherapy-associated VTE23
High-risk score ≥ 3 Intermediate risk score =1-2 Low-risk score =0
|
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Rates of VTE According to Risk Score
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
|
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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 disorders, Genome 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
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.
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Further Reading:
Mari Tinholt, Hans Kristian Moen Vollan, Kristine Kleivi Sahlberg, Sandra Jernström, Fatemeh Kaveh, Ole Christian Lingjærde,Rolf Kåresen, Torill Sauer, Vessela Kristensen, Anne-Lise Børresen-Dale, Per Morten Sandset, Nina Iversen, Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF, Breast Cancer Research, 2015, 17, 1
Chaabane, L. Tei, L. Miragoli, L. Lattuada, M. von Wronski, F. Uggeri, V. Lorusso, S. Aime, In Vivo MR Imaging of Fibrin in a Neuroblastoma Tumor Model by Means of a Targeting Gd-Containing Peptide, Molecular Imaging and Biology, 2015,
Daniela Bianconi, Alexandra Schuler, Clemens Pausz, Angelika Geroldinger, Alexandra Kaider, Heinz-Josef Lenz, Gabriela Kornek, Werner Scheithauer, Christoph C. Zielinski, Ingrid Pabinger, Cihan Ay, Gerald W. Prager, Integrin beta-3 genetic variants and risk of venous thromboembolism in colorectal cancer patients, Thrombosis Research, 2015,
Olumide B Gbolahan, Trista J Stankowski-Drengler, Abiola Ibraheem, Jessica M Engel, Adedayo A Onitilo, Management of chemotherapy-induced thromboembolism in breast cancer, Breast Cancer Management, 2015, 4, 4, 187
Ami Schattner, Meital Adi, Mobile menace- floating aortic arch thrombus, The American Journal of Medicine, 2015,
Chuang-Chi Liaw, Hung Chang, Tsai-Sheng Yang, Ming-Sheng Wen, Pulmonary Venous Obstruction in Cancer Patients,Journal of Oncology, 2015, 2015, 1
Esther Rabizadeh, Izhack Cherny, Doron Lederfein, Shany Sherman, Natalia Binkovsky, Yevgenia Rosenblat, Aida Inbal, The cell-membrane prothrombinase, fibrinogen-like protein 2, promotes angiogenesis and tumor development, Thrombosis Research, 2015, 136, 1, 118
Anna Falanga, Marina Marchetti, Laura Russo, The mechanisms of cancer-associated thrombosis, Thrombosis Research,2015, 135, S8
I. Goufman, V. N. Yakovlev, N. B. Tikhonova, R. B. Aisina, K. N. Yarygin, L. I. Mukhametova, K. B. Gershkovich, D. A. Gulin,Autoantibodies to Plasminogen and Their Role in Tumor Diseases, Bulletin of Experimental Biology and Medicine, 2015, 158,4, 493
Trisha A. Rettig, Julie N. Harbin, Adelaide Harrington, Leonie Dohmen, Sherry D. Fleming, Evasion and interactions of the humoral innate immune response in pathogen invasion, autoimmune disease, and cancer, Clinical Immunology, 2015, 160, 2,244
Sarah K Westbury, Ernest Turro, Daniel Greene, Claire Lentaigne, Anne M Kelly, Tadbir K Bariana, Ilenia Simeoni, Xavier Pillois, Antony Attwood, Steve Austin, Sjoert BG Jansen, Tamam Bakchoul, Abi Crisp-Hihn, Wendy N Erber, Rémi Favier,Nicola Foad, Michael Gattens, Jennifer D Jolley, Ri Liesner, Stuart Meacham, Carolyn M Millar, Alan T Nurden, Kathelijne Peerlinck, David J Perry, Pawan Poudel, Sol Schulman, Harald Schulze, Jonathan C Stephens, Bruce Furie, Peter N Robinson, Chris van Geet, Augusto Rendon, Keith Gomez, Michael A Laffan, Michele P Lambert, Paquita Nurden, Willem H Ouwehand, Sylvia Richardson, Andrew D Mumford, Kathleen Freson, Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders, Genome Medicine, 2015, 7,1
Ades, S. Kumar, M. Alam, A. Goodwin, D. Weckstein, M. Dugan, T. Ashikaga, M. Evans, C. Verschraegen, C. E. Holmes,Tumor oncogene (KRAS) status and risk of venous thrombosis in patients with metastatic colorectal cancer,Journal of Thrombosis and Haemostasis, 2015, 13, 6
Marcel Levi, Cancer-related coagulopathies, Thrombosis Research, 2014, 133, S70
Axel C. Matzdorff, David Green, Management of venous thromboembolism in cancer patients, Reviews in Vascular Medicine,2014, 2, 1, 24
Claude Bachmeyer, Milène Buffo, Bérénice Soyez, No Evidence Not to Prescribe Thromboprophylaxis in Hospitalized Medical Patients with Cancer, The American Journal of Medicine, 2014, 127, 7, e33
Nathalie Magnus, Esterina D’Asti, Brian Meehan, Delphine Garnier, Janusz Rak, Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer, Thrombosis Research, 2014, 133, S1
Maria Sofra, Anna Antenucci, Michele Gallucci, Chiara Mandoj, Rocco Papalia, Claudia Claroni, Ilaria Monteferrante, Giulia Torregiani, Valeria Gianaroli, Isabella Sperduti, Luigi Tomao, Ester Forastiere, Perioperative changes in pro and anticoagulant factors in prostate cancer patients undergoing laparoscopic and robotic radical prostatectomy with different anaesthetic techniques, Journal of Experimental & Clinical Cancer Research, 2014, 33, 1, 63
Taslim A. Al-Hilal, Farzana Alam, Jin Woo Park, Kwangmeyung Kim, Ick Chan Kwon, Gyu Ha Ryu, Youngro Byun, Prevention effect of orally active heparin conjugate on cancer-associated thrombosis, Journal of Controlled Release, 2014, 195, 155
Samridhi Sharma, Sandipan Ray, Aliasgar Moiyadi, Epari Sridhar, Sanjeeva Srivastava, Quantitative Proteomic Analysis of Meningiomas for the Identification of Surrogate Protein Markers, Scientific Reports, 2014, 4, 7140
W. Yau, P. Liao, J. C. Fredenburgh, A. R. Stafford, A. S. Revenko, B. P. Monia, J. I. Weitz, Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits,Blood, 2014, 123, 13, 2102
Anna Falanga, Laura Russo, Viola Milesi, The coagulopathy of cancer, Current Opinion in Hematology, 2014, 21, 5, 423
Sarah J. Barsam, Raj Patel, Roopen Arya, Anticoagulation for prevention and treatment of cancer-related venous thromboembolism, British Journal of Haematology, 2013, 161, 6
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