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Understand Childhood Cancers and Blood Disorders

Thrombotic Disorders

Blood coagulation (clotting) is an important and very carefully balanced process occurring within the body. On the one hand, the blood must be thin and fluid enough so it can flow freely throughout the body. On the other hand, it is vital that abnormal bleeding is stopped as soon as it starts so that we do not lose too much blood. These two opposing systems, one that acts to stop bleeding and one that acts to stop clotting, are normally in balance. When overactive clotting occurs, it results in thrombosis (abnormally exaggerated clot).

Thrombosis can happen inside an artery or a vein, and depending where it occurs can be quite dangerous, because it can decrease or fully block the smooth flow of blood. When thrombosis happens in an important artery, such as one leading to the brain, it can cause a stroke.

Thrombosis in the arteries of the legs causes pain upon walking (or even when lying down if the thrombosis is extensive). When the blood flow is blocked totally, leg muscles die and tissues become gangrenous (gangrene is the death or decay of tissues as a result of impaired blood supply). Should this blockade occur in the blood vessels supplying the intestines, gangrene of a part of the bowel will occur. Thrombosis (or blockade) of the arteries to the kidneys can lead to serious (and sometimes permanent) kidney damage.

Thrombosis inside the deep veins of the legs (also called DVT or deep vein thrombosis) causes swelling, redness, and pain in the leg. Worse yet, a small part of such an abnormal leg clot may break off from the main clot and flow within the bloodstream to the lungs. This is called a pulmonary embolism (PE) and can lead to serious breathing problems and even sudden death. In general, the symptoms of thrombosis depend on the specific blood vessels affected as well as the size of the blockade.

Fortunately, thrombotic disorders are quite rare in children, but tend to become more common as we age. Only about seven children in a million develop thrombosis annually. The highest risk is in newborns with 24-51 cases per year. Children with genetically inherited thrombotic disorders have a greater chance of having an abnormal clot at any age. In some instances, even children without such inherited disorders can have thrombosis.

Before describing individual conditions, it is important to understand the general structure and mechanism of blood clotting. When a blood vessel is nicked or injured, it becomes important for the body to "plug" that hole in the vessel in order to prevent excessive blood loss. The first step involves platelets that are present in the blood: those platelets bond to the injured area, recruit more platelets into the process, and stick to the injury, literally 'corking' the hole in the vessel. They do so with the help of a protein called von Willebrand protein (or von Willebrand factor). That is why patients with von Willebrand Disease who have reduced levels of this protein bleed excessively. This initial plug or cork is flimsy and weak but provides a temporary stoppage of the bleeding until additional protein systems get into the act. At about the same time, certain clotting proteins in the blood, called "clotting factors" become activated, and they in turn, activate additional proteins, eventually forming "glue" called fibrin. Fibrin then mixes with the platelet plug and results in a solid, strong, and safe clot. To keep clotting from getting out of hand, there are other proteins called "anti-coagulants" (Protein C, Protein S, Antithrombin III) that make sure the clot is confined only to the injured site and does not continue endlessly. Finally, there is also another system, called the fibrinolytic system, whose role is to gradually dissolve the solid clot as a scar. It is formed at the site of original injury in the blood vessel.

Some thrombotic disorders affect the veins more than the arteries. Some cause more clots, and are more serious. Many of these disorders are inherited in an autosomal-dominant manner, which means that if one parent has it, there is a 50:50 chance that a child will inherit it. A patient is a heterozygote if he or she inherits only one copy of the disease and a homozygote if he or she inherits two copies of the disease. Abnormal clotting can also happen as a result of other conditions (such as severe dehydration) and illnesses (e.g., kidney or liver failure), but that situation is less common in children. Thrombotic disorders are diagnosed with blood tests, while some of the inherited disorders are diagnosed by genetic testing. It is important to test siblings when a child is diagnosed with a specific thrombotic disorder. If a child is diagnosed with more than a single risk factor for abnormal clotting, the risk for abnormal blood clots increases.

Inherited Thrombotic Disorders in Children

  1. High levels of clotting proteins (Factors VIII and IX) - In the last few years it was found that patients who have very high levels of factor VIII or IX have a 2-fold risk for thrombosis.
  2. Prothrombin G20210A or factor II mutation (elevated levels of prothrombin) An individual with too much prothrombin has about a 3-fold increased risk of thrombosis when compared to the general population. It is inherited when a child gets the gene with the mutation from both parents. If a child only has one such copy, there is no increased risk for thrombosis.
  3. Factor V Leiden (factor V-Arg506Gln)- This is the most commonly inherited thrombotic disorder in the world. While five-10 percent of individuals of Northern European origin have one copy of this mutation, it is extremely rare among Asian and African populations. When a patient has this mutation, the process of clotting goes unchecked and results in thrombosis. This happens because one of the "anti-coagulant" proteins (Protein C) cannot control this altered factor V. There is a 7-fold increase in the risk of abnormal clotting in patients with only one copy of the mutation (heterozygotes) versus an 80-fold risk in patients with both copies of the mutation (homozygotes).
  4. Antithrombin III (ATIII) Deficiency - There are two main types of ATIII deficiency. In type 1, the patient has a decreased level of both the amount of protein and its activity level, while in type 2 there is a normal level of the protein but its function is abnormal. All races and ethnic groups are affected equally. Most patients have only one copy of the gene (heterozygotes). Heterozygous antithrombin deficiency is associated with the greatest risk of thrombosis of all inherited thrombotic disorders. As many as one in two individuals with antithrombin deficiency will have a venous thrombosis before the age of 50 years. It is extremely rare for a patient to have two copies of ATIII deficiency; in such cases, severe abnormal clots start much earlier in life (as early as the newborn period).
  5. Protein C (PC) Deficiency - If protein C is deficient in quantity or defective in function, there is an increased risk of thrombosis, mostly in veins. There are two main types of PC deficiency. In type 1, the patient has decreased amount of protein and activity level, while in type 2 there is a normal level of the protein but its function is abnormal. Most patients have only one copy of the illness (heterozygotes). Heterozygous PC deficiency is associated with increased risk of abnormal clotting usually, at or after puberty. It is very rare (less than one in 1,000,000) to inherit both copies of this deficiency, but then it can lead to very severe and sometimes life-threatening complications in the newborn period.
  6. Protein S (PS) Deficiency - If patients do not have enough PS, or when protein S is defective in function, there is increased risk of abnormal clotting, mostly in veins. There are two main types of PS deficiency. In type 1, the patient has a decreased quantity of protein and its activity level, while in type 2 there is a normal quantity of the protein but its function is abnormal. Most patients have only one copy of the illness (heterozygotes). Heterozygous PS deficiency is associated with increased risk of abnormal clotting. It is rare to have both copies of PS deficiency, but then it can lead to very severe and sometimes life-threatening complications in the newborn period.
  7. Dysfibrinogenemia - Fibrinogen is the end product of the full clotting process. It meshes or mixes with the initial platelet plug to strengthen the final blood clot, making it firm and sturdy. Some individuals who inherit an abnormal fibrinogen protein will bleed too much while others can have thrombosis, depending on the specific type of the abnormal protein. This condition is inherited in the autosomal-dominant manner, which means that if one parent has it, there is a 50:50 chance that a child will inherit it.
  8. Abnormal fibrinolytic System - The fibrinolytic system is responsible for dissolving and removing the clot once the injured blood vessel wall is fully repaired and properly scarred. Therefore, if the system does not operate properly, the clot is not removed in time or not removed at all which can lead to further clotting. These disorders are extremely rare and many are still being researched.
  9. MTHFR (C677T) mutation ( also called - Hyperhomocysteinemia) - Homocysteine is an amino acid (a protein building block) that, if present at a high level within the blood, can lead to an increased risk of abnormal clotting in arteries or veins. This condition is known as hyperhomocysteinemia and the name of the mutation is MTHFR (or C677T). It is believed that high blood levels of homocysteine may damage the lining of the blood vessels and that is what starts a chain of events leading to clotting. A patient may inherit one copy of this mutation from one parent or inherit two abnormal mutations (one from each parent). But the highest risk of abnormal clotting is much more related to the level of homocysteine in the blood (done by a simple blood test on an empty stomach in the morning). In some individuals, the high levels of homocysteine in the blood can actually be also related to nutritional deficiencies (the vitamins -folic acid, B6, and B12). In these rare cases, a patient can be given vitamin supplements in order to reduce the risk for such abnormal clotting.
In addition to inherited clotting disorders, there are also several acquired clotting disorders that can develop at any time in the life of a patient. These conditions are uncommon in children and include:
  1. Myeloproliferative Disorders (MPD) - there are several disorders in this category, but two specifically increase the risk for abnormal clotting -
    1. Polycythemia Vera (PV) - is a condition where a person simply has too many red blood cells (the exact opposite of anemia). This thickens the blood considerably and can lead to abnormal clotting. It rarely occurs in children.
    2. Essential Thrombocythemia (ET) - in this condition, the individual has too many platelets making the blood likelier to clot abnormally. This condition is extremely rare in patients younger than 40-60 years of age and tends to run a milder course in children.
  2. Paroxysmal Nocturnal Hemoglobinuria (PNH) - This very rare condition is a bone marrow disorder and abnormal clotting is often a complication of the disease. Most abnormal blood clots happen in the veins of the liver and brain.
  3. Antiphospholipid Syndrome (APS) - this syndrome has become more recognized and diagnosed during the past several years. In this condition, there are antibodies against substances called phospholipids (fatty compounds that are found in walls of living cells). This condition often occurs in patients with Systemic Lupus Erythematosus. In adult patients major clots can block large and small arteries and lead to frequent miscarriages and lost pregnancies as well as strokes and other serious complications. It is common for patients to have repeated clots in the same area.

What can I do if my child is diagnosed with a Thrombotic Disorder

  • If the condition is inherited, have your other children tested and alert other family members of the finding.
  • Children should be encouraged to live a normal and active lifestyle.
  • On long trips, especially long airline flights, it is strongly recommended that affected individuals walk often in the aisles of the airplane and stretch their calves; while seated imitate a motion as though one is pressing on the gas pedal of a car.
  • Smoking can compound the condition and should be avoided.
  • Any oral contraceptives or hormonal replacement therapies must be discussed with both the gynecologist and hematologist (It is safest to avoid contraceptives altogether).
  • If pregnancy is planned, the risk of abnormal clotting should be mentioned to the obstetrician and hematologist. If there is a history of previously lost pregnancies, the doctors should be alerted.
  • Avoid long periods of staying flat in bed, either at home, or, especially after surgery.
  • If surgery is planned, especially one that will result in long bed-rests (such as orthopedic surgery), the surgeons and doctors should be alerted about an abnormal clotting risk.
  • Excessive weight and obesity make abnormal clotting likelier because mobility is limited and blood flow is slower. Therefore, proper nutrition is of importance.
  • Any child taking a medication to prevent abnormal clotting should be taking the medication under a doctor's supervision, with parents supervising the dosage and compliance.

Examples of medications and devices used in patients at risk of abnormal clotting

  • Coumadin (or Warfarin) - this is a medication that is given orally (tablets). It should be taken at about the same time daily, and foods rich in vitamin K (such as spinach, parsley, etc) or vitamin supplements with vitamin K in them should be avoided. To ensure the correct dose of Coumadin, blood will have to be checked periodically.
  • Heparin or Low-Molecular-Weight Heparin (LMWH) - heparin is given as an intravenous infusion or subcutaneously. Low-Molecular-Weight Heparin is given subcutaneously (injections under the skin) once or twice a day, depending on the circumstances. If one is receiving regular heparin, frequent blood tests will be necessary to make sure that the blood is getting thinner appropriately. With LMWH, blood tests will be done very infrequently. The choice of heparin depends very much on the specific condition as well as recommendations given by other doctors (for example - vascular surgeons).
  • Aspirin (ASA) - Aspirin works by making the platelets work inefficiently. Since any process of thrombosis starts with platelets attaching to one another, we can interrupt that process with Aspirin. Aspirin can cause serious stomach problems and should be given with food and occasionally antacids.
  • Tissue Plasminogen Activator (t-PA, or Alteplase) - This medication is sometimes used to dissolve clots that have already formed. Much like other medications, the use of t-PA is dictated by not only the hematologist, but also often by vascular surgeons and, at times, also intensive care doctors.
It is important to know that all the medications mentioned above can cause abnormal bleeding because their goal is to thin the blood and limit clotting. That is why doctors need to monitor the situation carefully with blood tests. It is also very important to notify the doctors about missed doses of any of the above medications.
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