בדיקה גנטית לסיכון לקרישי דם: מתי היא באמת מועילה?

קפיצה לפרק

• הסבר על מוטציות תרומבופיליה שכיחות
• המלצות ונחיות לסקירה
• תועלת קלינית של תוצאות הבדיקה
• סיכונים של בדיקה גנטית באנשים ללא תסמינים
• ייעוץ מעשי למצבים בסיכון גבוה
• תמלול מלא

הסבר על מוטציות תרומבופיליה שכיחות

ד"ר פייר מנוצ'י, MD, מתאר את המוטציות הגנטיות השכיחות ביותר המקושרות לסיכון מוגבר לתרומבוזיס ורידי. אלו מוטציות gain-of-function בגורמי קרישה. מוטציית פקטור V ליידן גורמת לפקטור VIII פעיל יתר על המידה, המוביל להיווצרות יתר של קרישים. מוטציה בגן פרותרומבין גורמת לייצור יתר של תרומבין, האנזים הסופי במפל הקרישה.

ד"ר מנוצ'י, MD, מדגיש הבחנה קריטית. מוטציות אלו הן גורמי סיכון, לא ערובה למחלה. הן מגבירות סיכון יחסי, אך הסיכון המוחלט לאירוע תרומבוטי נותר נמוך עבור רוב הנשאים. הוא מציין שמוטציות אלו שכיחות remarkably, קיימות בכ-6% מהאוכלוסייה הכללית במדינות מערביות.

המלצות ונחיות לסקירה

ד"ר פייר מנוצ'י, MD, מתאר תרחישים ברורים בהם לא מומלצת בדיקה גנטית. אין צורך בסקירה אוכלוסייתית של אנשים בריאים. בדיקה גם לא מומלצת עבור אנשים העומדים בפני מצבי סיכון גבוה חולפים, כמו ניתוח גדול כגון החלפת מפרק ירך.

הוא מתייחס specifically להפניה שכיחה. גינקולוגים לפעמים מבקשים בדיקה עבור נשים צעירות לפני מרשם גלולות משולבות אסטרוגן-פרוגסטרון. ד"ר מנוצ'י, MD, קובע שהנחיות אינן תומכות בפרקטיקה זו. סיכון המוטציה נדיר מדי כדי להצדיק סקירה אוניברסלית. סיכון התרומבוזis מהריון עצמו דומה לסיכון מגלולות עבור נשאי מוטציה.

תועלת קלינית של תוצאות הבדיקה

סיבה ראשית against בדיקה שגרתית היא חוסר ההשפעה שלה על הטיפול בחולה. ד"ר מנוצ'י, MD, מסביר שגילוי מוטציית תרומבופיליה לאחר קריש אינו משנה את הטיפול. משך הטיפול בנוגדי קרישה נשאר זהה ללא קשר למעמד הגנטי של החולה.

הערך העיקרי של הבדיקה הוא often פסיכולוגי, מענה על "הלמה" behind אירוע תרומבוטי, especially בחולים צעירים. עם זאת, ד"ר מנוצ'י, MD, מזהיר שבדיקה שלילית אינה שוללת סיבות אחרות. Often, no single cause is found. He concludes that these tests are "quite useless" for guiding therapy or predicting future risk.

סיכונים של בדיקה גנטית באנשים ללא תסמינים

ד"ר פייר מנוצ'י, MD, מדגיש חסרונות משמעותיים לבדיקת individuals ללא תסמינים. תוצאה positive יכולה ליצור "תג של תכונה גנטית," causing unnecessary anxiety and fear. This is particularly concerning for children, as testing labels them with a condition that is not a disease.

He shares compelling data from a study of centenarians. The prevalence of these mutations was 6%, identical to the general population. This proves carriers can live extremely long, healthy lives. The mutations may have even offered a historical survival advantage by reducing fatal bleeding during childbirth or injury.

Dr. Mannucci, MD, also warns of unexpected familial discoveries. If a patient's parents test negative for a mutation the patient has, it can raise difficult questions about paternity. This illustrates the unintended consequences of pursuing genetic information without a strong medical indication.

ייעוץ מעשי למצבים בסיכון גבוה

ד"ר פייר מנוצ'י, MD, provides practical guidance for managing thrombosis risk. He uses the example of a long-haul flight traveler with multiple risk factors. His recommendation is firmly against prophylactic medication like low molecular weight heparin or aspirin.

Instead, Dr. Mannucci, MD, advocates for non-pharmacological measures. These include maintaining hydration with water, avoiding alcohol and sugary drinks, and preventing immobility by walking in the cabin regularly. He stresses that a healthy lifestyle and awareness are the best defenses, not preemptive drug therapy. This approach is consistent with international literature and expert consensus, as noted by Dr. Anton Titov, MD, during the discussion.

תמלול מלא

ד"ר אנטון טיטוב, MD: קרישי דם בוורידי הרגליים ותרומבוזיס בוורידי האגן יכולים להוביל לתסחיף ריאתי. קרישי דם often happen in people with a genetic mutation in several genes, such as protein C, protein S, or antithrombin. Blood group type can also affect predisposition to forming blood clots. How do people usually find out that they have a genetic mutation predisposing them to blood clot formation or thrombosis?

ד"ר פייר מנוצ'י, MD: It is a long story with which I was involved because I was a member of the WHO panel many years ago. The scale of functionally important mutations of coagulation factors gave us the state of hypercoagulability. We explained them to some extent. Some, albeit not all, causes of venous thrombosis—but not arterial thrombosis—were discovered.

Now we know that mutations happen with high frequency, so it's relevant in the general population. We mainly deal with gain-of-function mutations. One blood clotting risk mutation is called Factor Five Leiden. As I mentioned, Factor Five Leiden mutation gives a very active Factor V, which, of course, leads to an excess formation of coagulation. It leads to higher coagulability and is a risk factor for thrombosis.

I want to emphasize that the Factor Five Leiden mutation risk factor doesn't mean you will inevitably get the disease thrombosis. It means that you are at more risk than a person without a mutation to develop thrombosis. But we must distinguish the relative risk from the absolute risk, which is still very low, even in these patients.

Then the other established gain-of-function mutation can exist in another coagulation factor, prothrombin. And of course, even there, you have an excess formation of thrombin, the final enzyme in blood coagulation. This has been just as important a discovery. It didn't get the Nobel Prize, but certainly, in our field, prothrombin mutation has been a fundamental discovery.

The problem is what to do with these mutations. Because if you take together these two mutations, they are very frequent in the general population. In the general population of Western countries, together, Factor Five Leiden and prothrombin mutations reach 6%. So the probability of being positive for Factor 5 Leiden or prothrombin mutation is potentially relatively high. But again, you must consider that these are risk factors for thrombosis. It is not a certain indication that they will get thrombosis.

ד"ר אנטון טיטוב, MD: What are the current recommendations about Factor 5 Leiden and prothrombin mutations? When should patients be tested for these mutations?

ד"ר פייר מנוצ'י, MD: Certainly, there is no need to test in a generally healthy population. No need for testing even in persons who are undergoing procedures with an additional risk of thrombosis, such as surgery, particularly hip replacement surgery, or women who take oral contraceptives. Because even though, of course, the two risk factors tend to be additive, if not multiplicative, it is still too rare. It is too rare a mutation to justify performing this screening.

For example, which is the most frequent of our referrals, sometimes the gynecologist asks to do these mutation analyses in young women who take combined estrogen-progesterone contraceptives. Usually, we don't recommend testing for thrombosis-related mutations. This is in the guidelines for the reasons I mentioned. So they are of very little use because there are many women who are taking contraceptive pills but who do not develop thrombosis.

And you have to consider that if they don't take the contraceptive pill, they may get pregnant, or they will get pregnant. And pregnancy, of course, carries a risk of thrombosis that is equal to that of these contraceptive medications and thrombosis-predisposing mutations. So that's why, in general, there is no recommended screening for Factor Five Leiden, Protein C, and Protein S mutations, not even in the general population. Not even in situations like the intake of oral contraceptives or before surgery accompanied by a higher risk of thrombosis. So screenings are not recommended.

They are usually done, as I said, with very little evidence, to understand why a person developed thrombosis. Screening for thrombosis-predisposing mutations happens, particularly in young people. Because when a person develops thrombosis, as you know, venous thrombosis and arterial thrombosis are conditions associated with age.

Just to give you an idea, a woman in the reproductive age has 1 in 10,000 odds of developing venous thromboembolism during the time of her reproductive age, let us say till the age of 40 or 45. The situation changes when women get older because, for instance, in menopause, the risk is 1 in 1,000. And it gets much higher when they are over 60 or 70 years of age because the thrombosis risk is 1 in 100.

The calculation is that it is not worthy of a general screening for thrombosis-predisposing mutations in the general population. But you will ask why. It is because it has been shown. For example, I have developed thrombosis. I want to know why I developed thrombosis. So besides all the other risk factors, I do a test for Factor Five Leiden, Protein C, or Protein S mutations.

But what do I do with that information? I learn one of the possible risk factors for my thrombosis. But does it affect my future treatment or my future behavior? And the answer is no because the therapy does not change in the sense that you will not change the treatment of the patient who developed thrombosis. Patients will be treated for the same period, depending on other conditions, as if they had not their thrombosis-predisposing mutations.

Information about thrombosis-predisposing mutations also does not impinge upon the duration of the anticoagulant therapy. In other words, you don't treat them for longer if they have this mutation that increases thrombosis risk. So altogether, you see, there is a general recommendation not to carry out these studies because they don't help prevent thrombosis. They cannot help to tailor the treatment of those who develop thrombosis.

And so, they are only helpful to help understand why patients develop thrombosis. But usually, mutations are considered one of the several risk factors for thrombosis. Sometimes you don't find a cause of thrombosis, even if the patient was negative for this mutation. So that's why thrombosis-predisposing mutations raised a lot of interest. They certainly contributed significantly to our knowledge.

הבנו כיצד פעילות יתר של גורמי קרישה בהשוואה לפעילות חסר בגורמים החשובים בהפרעות קרישה. לכן הנושא טופל על ידי אנשים כמונו, שעסקו בעובדת הקרישה שהיא דימום, אך גם בקרישת יתר, תרומבוזה. אך מוטציות המקדימות תרומבוזה הן למעשה בעלות תועלת מועטה מאוד. אלו מוטציות מאוד מעניינות.

מוטציות פקטור 5 ליידן, חלבון C או חלבון S הן כנראה די שפירות. מוטציות המקדימות תרומבוזה נפוצות מאוד באוכלוסייה הכללית. כנראה שלאנשים עם מוטציות כאלה היה יתרון בגיל צעיר באנושות שלנו. אז האדם הקדמון הסתובב והלחם בחיות מבלי שהפצעים שלו ידממו. אז כנראה שהם עזרו לעצור את הדימום ביתר קלות.

לכן מוטציות אלו ממשיכות להתקיים כי זו הייתה מוטציה מועילה. באותה תקופה, זו כנראה הייתה מוטציה מועילה לנשים קדמוניות מתקופת האבן החדשה בתחילת הלידה. זה היה כך כי, כמובן, נשים רבות מתו בלידה בגלל דימום. ושוב, לכן מוטציות המקדימות תרומבוזה הועברו כי רק לאחרונה, תרומבוזה הפכה לתדירה יותר.

אך שוב, מוטציות אלו לא שינו, לדעתי, את מהלך הטבעי של תסחיף ורידי עמוק ולא את הטיפול בו. אז זו המסר העיקרי שלי. מוטציות מאוד מעניינות. אנו מפרסמים הרבה מאמרים על מוטציות אלו, כפי שאתה יכול לראות מהביבליוגרפיה שלי. אך מה שאני אומר הוא הקונצנזוס הכללי.

לאחר מכן, בדיקת מוטציות פקטור 5 ליידן, חלבון C או חלבון S מתבצעת מאוד frequently, אך mainly because people—וגם זו החוויה שלי—במיוחד young people who develop an event like thrombosis that is not typical for their age. רופאים רוצים לדעת why these young patients developed thrombosis. ולכן השאלה העיקרית שלהם היא: why did I get thrombosis? היא נשאלת more often than this question: what is going to happen in the future?

ולכן sometimes these thrombosis-predisposing mutation tests are done. אך לדעתי, הן די useless.

so there isn't much that a person who is asymptomatic can do about these mutations. אדם may have discovered, for example, through genetic screening, which is becoming more common, of course, because people just want to learn whether they might have some mutations that affect their quality of life. so if that person does the genetic screening and discovers that they have a protein, Factor Five Leiden, Protein C, or Protein S mutations, there isn't much they can do with this information.

well, I don't think it is a good idea to do genetic screening without reason, but only to know. first of all, because I'm not sure you will understand what is there or our destiny is. and think about what I told you. these mutations are a cofactor for developing thrombosis; they are not a reason for not being pregnant. they are not a reason for not taking oral contraceptives.

we did a study on centenarians here in Milan. centenarians, by definition, are the people who are very healthy. they went through pregnancy; the women had trauma sometimes. these are the situations that are associated with a risk of thrombosis. so if a thrombosis-predisposing mutation had some degree of lethality, you would expect to find in them a lower prevalence of Factor Five Leiden, Protein C, or Protein S mutations.

we found a 6% mutation rate for thrombosis-predisposing mutations in a large population of centenarians. it was as frequent a mutation rate as in the general population. so this means, again, if the people with this mutation could reach an age of 100 years, they are not that detrimental. so I would simply not do the screening for thrombosis-predisposing mutations I mentioned.

first of all, because in general, I don't think it would help me a great deal to understand what will be a life-long course of my life, in terms of illnesses. and particularly for this mutation, I will add something. let us say that they did the mutation screening test because they had thrombosis. so at least it is not very cogent, but at least it is a soft reason to do thrombosis-predisposing mutation screening.

and then, of course, patients start to ask you, what about my children? because, you know, the transmission of mutations. so they must have got the mutation either from the mother or the father. and then there is a problem with the children. and we happened to discover this because, of course, you tend to say this: okay, either your father or your mother did transmit the mutation to you.

I usually use this argument because sometimes, the father and the mother are completely asymptomatic. and so I know that this will reassure the patients, because if the father or the mother could have been older than the proband, there could be a thrombosis event. but a person happened to discover that neither the mother nor the father has a thrombosis-predisposing mutation. why is it not a fresh mutation?

probably because the father was not the right one. so that tells you the risks of doing genetic testing. as I said, it applies to the children. think about that. first of all, okay, I have a five-year-old boy. he doesn't need a blood sample. why should I do a mutation analysis? particularly it is worth considering for a boy, and even a girl, you give a tag of a genetic disease.

it is always an unpleasant target, even if you explain that it will not cause any problem, you see. so I think genetic testing is really dangerous because to give somebody a tag of a genetic trait, which is not a disease, but a genetic trait, it is very bad. so I wouldn't do what you said. and I wouldn't do this thrombosis-predisposing mutation test.

I can tell you that even very recently I was approached by a company from Switzerland. they wanted to develop a genetic testing system to offer to women deciding to take oral contraceptives. but it was an algorithm that included many other things. I was not very favorable to that idea. but in any way, they included the gain-of-function mutation testing, but only those mutations were included in testing.

so in a sense, in the end, they gave a risk score for thrombosis. and this again, I wouldn't have done that. I would not recommend that. but at least, risk assessment was not only based on the thrombosis-predisposing mutations. there are around this country and elsewhere, there are several kits that have genetic tests for thrombosis risk.

by the way, genetic testing kits include also testing for thrombosis-related mutations that have not been shown convincingly to be associated with the risk of venous thrombosis and arterial thrombosis. so my private practice has been made larger by people coming with this panel of tests. obviously, they had heterozygosity and homozygosity for mutations that have never been shown to be associated with thrombosis.

Factor Five Leiden, Protein C, or Protein S mutations at least are solid risk factors. but they are risk factors, not causes of thrombosis.

Dr. Anton Titov, MD: אם נוכל לחשוב על מקרה תיאורטי. נניח שזה גבר בשנות ה-40 שלו, שנוסע בגלל העבודה בטיסות מאוד ארוכות מסביב לעולם, שמונה שעות, 12 שעות. והוא הולך ועושה את הבדיקה הגנטית ומגלה שיש לו מוטציית פקטור 5 ליידן. הוא גם מגלה שיש לו פולימורפיזם של נוקלאוטיד בודד שיש לאנשים עם פוליציטמיה ורה. אז ברור, זה לא אומר שיש לו פוליציטמיה ורה. אבל יש מוטציה שלאנשים שיש להם פוליציטמיה ורה יש את המוטציה הזו.

יתר על כן, הוא מסתכל על עשר השנים של בדיקות הדם שלו. ועכשיו הוא שם לב שהכדוריות האדומות שלו תמיד מעל הגבול העליון של הנורמה, וההמטוקריט שלו מעל 50%. אז זה תמיד מעט מעל הטווח הנורמלי, בעקביות. אז עכשיו הוא יכול לשאול את השאלה: האם אני צריך לעשות הפארין במשקל מולקולרי נמוך כשאני טס בטיסה של 12 שעות או 18 שעות לאוסטרליה או למזרח התיכון? האם我应该 просто להתעלם מתוצאות הבדיקה? עכשיו יש לי מוטציית פקטור 5 ליידן; יש לי המטוקריט גבוה, יש לי כדוריות אדומות גבוהות יותר. האם יש משהו לעשות?

האם יש לו סוג דם A או B?

Dr. Anton Titov, MD: ובכן, בסדר, זה מאוד מעניין. אז סוג הדם—איך זה obviously משפיע על הסיכונים לתרומבוזה? so, what would you say to such a person?

Dr. Pier Mannucci, MD: first of all, I would do no tests. but suppose you do none of these tests. I would know that I am at risk of thrombosis as much as I'm a risk because I'm older, as much as other people are at risk of thrombosis. after all, they have some other condition that facilitates the thrombosis risk. in other words, this is what I would do. I would not take any heparin. I would not take any aspirin.

I would simply try not to drink too much on the plane. I will try to get a lot of non-alcoholic drinks, a lot of water, no sugar, no alcohol drinks. and I would monitor and be ready to go very often to the lavatory, which is unpleasant when you sleep. but this is something they should do. and I will do nothing.

there is nobody recommending, even with a lot of risks, to do any preventive low molecular weight heparin injections before a long-haul flight. so that is the general recommendation. this stems from people like Dr. Frits Rosendaal in the Netherlands, who tackled this issue in a clinical study. this, of course, doesn't deny the situations reported in the media.

there was the case of a young nurse who arrived from Australia. she was on oral contraceptives. she was coming from Australia, from abroad, on a 24-hour flight arriving at Heathrow. she fell with a pulmonary embolism and died. but this is not a reason to do the prevention therapy with what may be dangerous. 'drug' is a Greek word that means something positive. but it also, as we will come to discuss in polypharmacy, 'drug' means 'venom.'

so I would simply do nothing of what you mentioned. I would realize, if you have all these risk factors for thrombosis, you have to try to have a decent life, do exercise to avoid stasis. you can avoid immobility during the long-haul flight and walk in the plane's cabin. that's what I would do if I had a risk factor for thrombosis and being old.

I would never take any medications for this. I don't think I have any thrombosis-predisposing mutation because, at the time of the early study, I served as a volunteer to develop the method by my laboratory. but even if I weren't, I would advise nothing. right. so that is my point of view. I think this is consistent with the recommendation of the literature.

they review articles that you cited. but also you would find it difficult to find recommendations different from mine. if you ask other experts, experts, of course, may have different opinions on many aspects. but I don't think on this they would differ. I don't want to be dogmatic and blatant. but I don't think everybody will tell things much different from what I am telling you.