Exploring why genomic research has succeeded with venous thrombosis but struggles with arterial clots
Imagine you're a detective trying to solve a complex crime, but instead of a single culprit, you're faced with hundreds of minor suspects, each contributing just a small piece to the overall mystery. This is the fundamental challenge facing genomics in the realm of arterial thrombosis—the formation of dangerous blood clots that can trigger heart attacks and strokes. While genetic research has revolutionized our understanding of venous thrombosis (clots in veins), its application to arterial clots has proven far more elusive. This article explores the scientific reasons behind this discrepancy, examining why the "genomic revolution" has largely bypassed arterial thrombosis and what researchers are doing to overcome these hurdles.
Genomics excels at identifying strong, direct genetic effects but struggles with conditions where hundreds or thousands of genes each play a tiny role.
To understand why genomics has struggled with arterial clots, we must first recognize that not all clots are created equal. Venous and arterial thrombosis develop through fundamentally different biological processes, and these differences directly impact how much genetics can explain their formation.
Arterial clots typically form in fast-flowing blood vessels under high pressure. They usually begin when atherosclerotic plaque—a buildup of cholesterol, fat, and other substances—ruptures in the artery wall. The body perceives this rupture as an injury and responds by activating platelets, which clump together to form a clot 1 . This process is primarily mechanical and inflammatory, with genetics playing only an indirect role through factors that influence plaque development, blood pressure, and cholesterol levels.
In contrast, venous clots often form when blood flow slows or stagnates in the low-pressure venous system, typically in the legs. This stagnation activates the body's coagulation system, causing blood to clot through a cascade of chemical reactions involving various clotting factors 1 . Many of these factors have strong genetic determinants, making venous thrombosis more directly influenced by specific genetic variations.
| Characteristic | Arterial Thrombosis | Venous Thrombosis |
|---|---|---|
| Primary Location | Heart, brain (arteries) | Legs, lungs (veins) |
| Blood Flow | Fast-moving, high pressure | Slow-moving, low pressure |
| Key Risk Factors | High blood pressure, high cholesterol, smoking, diabetes | Surgery, immobility, genetic clotting disorders |
| Main Clot Composition | Platelet-rich | Fibrin-rich |
| Strength of Genetic Link | Moderate (indirect) | Strong (direct) |
The powerful genetic component in venous thrombosis is unmistakable. Recent research from Lund University in Sweden has identified three gene variants that, when combined, can increase the risk of venous blood clots by up to 180% 1 . These discoveries build upon the long-established knowledge of Factor V Leiden—a common genetic mutation that significantly elevates clot risk.
"In Sweden, almost half of all cases of venous thrombosis have a genetic explanation" - Professor Bengt Zöller 1
Arterial thrombosis typically occurs as a complication of atherosclerosis (hardening of the arteries)—a condition that develops over decades and involves countless genetic and environmental factors. Unlike venous thrombosis, where single gene mutations can have dramatic effects, arterial disease involves numerous genes, each contributing only slightly to overall risk.
Genomics excels at identifying strong, direct genetic effects but struggles with conditions where hundreds or thousands of genes each play a tiny role. This is precisely the case with arterial thrombosis, where genetic influences are often masked or modified by lifestyle factors such as diet, exercise, and smoking 7 .
Heritability—the proportion of observable differences in a trait between individuals that can be attributed to genetic differences—is significantly lower for arterial thrombotic events compared to venous ones. While approximately 50% of venous thrombosis cases have a clear genetic explanation, the figures for arterial diseases are much more modest 1 .
This doesn't mean genetics is irrelevant to arterial health. Rather, its influence is more subtle and distributed across many biological systems—from how we metabolize fats to how our blood vessels respond to inflammation. This complexity makes it difficult to pinpoint specific "arterial thrombosis genes" with the same precision possible for venous disorders.
To illustrate why genomics has been more successful with venous clots, let's examine the approaches researchers have used to identify key genetic factors.
A 2025 study published in Research and Practice in Thrombosis and Haemostasis demonstrates the powerful genomic approach that has proven so effective for venous thrombosis 1 . The research team:
The researchers identified three specific gene variants—in the ABO, F8, and VWF genes—that significantly increased venous thrombosis risk. Each variant alone raised risk by 10-30%, but their combined effect was dramatic 1 .
| Number of Risk Variants Carried | Increased Risk of Venous Thrombosis |
|---|---|
| 1 variant | 10-30% |
| 3 variants | Approximately 90% |
| 5 variants | 180% |
The critical finding was that multiple variants working together could increase risk nearly as much as the well-known Factor V Leiden mutation. Unlike arterial thrombosis, where genetic effects are diffuse, venous thrombosis presents with these clear, measurable genetic interactions.
This research also highlighted an important distinction: while Factor V Leiden is primarily found in people of European descent, the newly identified variants "are present in between five and fifty per cent of various populations around the globe" 1 , making them relevant across diverse ethnic groups.
Genomic research relies on specialized tools and technologies that enable scientists to read, interpret, and understand our genetic blueprint. Here are some key components of the genomic researcher's toolkit:
| Tool Category | Specific Examples | Function in Research |
|---|---|---|
| Sequencing Technologies | Next-Generation Sequencing (NGS), Whole Genome Sequencing | Determine the precise order of nucleotides in DNA samples |
| Enzymes | DNA polymerases, restriction enzymes, ligases | Amplify, cut, and join DNA molecules for analysis |
| Reagents & Kits | DNA extraction kits, PCR master mixes, purification kits | Isolate, purify, and prepare genetic material for study |
| Analytical Instruments | Mass spectrometers, qPCR machines | Measure and quantify genetic and protein biomarkers |
| Computational Tools | AI algorithms, deep neural networks, bioinformatics software | Analyze massive genomic datasets and identify patterns |
The global market for these tools is expanding rapidly, projected to grow from USD 40 billion in 2024 to USD 128 billion by 2035 8 .
AI-driven models can now process thousands of mass spectrometry spectra in seconds and identify single nucleotide polymorphisms with over 99.5% accuracy 8 .
The statement that "genomics will never be useful in arterial thrombosis" represents an overcorrection to earlier inflated expectations. While it's true that genomics has not revolutionized arterial thrombosis prediction and treatment in the way it has for venous disorders, this doesn't mean it has no role to play.
The future likely lies in integrated approaches that combine genetic information with other types of data.
As one research team noted, "Multi-omics integration is revolutionising the life sciences by providing a thorough, systems-level understanding of biological processes" 8 . This means combining genomic data with information about proteins (proteomics), metabolites (metabolomics), and environmental exposures to build a complete picture of arterial health.
Genomics may never provide the clear, simple answers for arterial thrombosis that it has for venous clots, but it remains a valuable tool in the medical research arsenal. Rather than a revolution, its contribution to understanding arterial disease will likely be incremental—part of a broader puzzle that includes lifestyle, environment, and countless other biological factors. In this more nuanced role, genomics may yet prove useful, just not in the ways we originally imagined.