Factor XI deficiency is a clotting disorder. Factor XI is a clotting factor, a part in the clotting cascade that in turn activates other parts, and its failure therefore affects the course of the entire clotting cascade.
What is factor XI deficiency?
Factor XI is a proenzyme of the serine protease factor XIa and plays a role in blood clotting. There, along with prekallikrein, high-molecular-weight kininogen (HMWK), and factor XII, it is at the beginning of the clotting cascade. The enzyme is synthesized in the liver and has a half-life of 52 hours. It circulates in the blood as an inactive form and is present in platelets. In plasma, it is present at a concentration of five milligrams per deciliter. Activation occurs via negatively charged surfaces. In vitro, activation can occur via kaolin or silicon, for example. In the body, it probably occurs via proteoglycans from exposed vessel walls or RNA, but this has not yet been precisely demonstrated. As factor XI circulates in the blood, it is bound to HMWK. This allows binding to negatively charged surfaces, especially the phospholipid surface of activated platelets. In the presence of calcium and phospholipids, factor XIa activates factor IX to factor Xa. In addition, TAFI (thrombin activatable fibrinolysis inhibitor) is activated by factor XIa. Factor XIa in turn is activated by factor XII, thrombin, or it may activate itself. Factor XI is inactivated by antithrombin, alpha-1-antitrypsin, by alpha-2-antiplasmin plasmin inhibitor, C1 inhibitor and protein Z-dependent protease inhibitors (ZPI). If factor XI is not present in sufficient amounts, a coagulation disorder known as factor XI deficiency occurs.
Causes
Factor XI deficiency can be either acquired or congenital. It can be acquired through liver disease, which prevents the liver from adequately synthesizing clotting factors. Likewise, by vitamin K deficiency, which is often caused by anticoagulant drugs. In autoimmune diseases by antibodies to clotting factors or by protein loss in kidney disease. Another cause of deficiency is consumption coagulopathies. A consumption coagulopathy results from intravascular activation of blood clotting. This results in a high consumption of clotting factors and platelets, causing a deficiency. Shock of any kind is a possible trigger, for example due to polytrauma after accidents, as well as obstetric or pregnancy complications such as preeclampsia and eclampsia. Extensive necrosis, for example in burns, can also promote factor XI deficiency. Massive hemolysis, as can occur after a transfusion incident, sepsis caused by gram-negative bacteria, or poisoning from snakebite are also considered causes.
Symptoms, complaints, and signs
Congenital factor XI deficiency is rare but occurs more frequently in certain ethnic groups, such as Ashkenazi Jews or Japanese. The deficiency is inherited in a recessive manner. Gene mutations may occur in the gene responsible for factor XI, or sometimes there may be a complete absence of this gene. This congenital variant is called hemophilia C, PTA deficiency syndrome, or Rosenthal syndrome. Different degrees of severity occur in factor XI deficiency. The normal activity of factor XI is seventy to one hundred fifty percent. In partial deficiency, this value drops to twenty to seventy percent. A partial deficiency is caused by a heterozygous mutation of the corresponding gene. In the case of homozygous inheritance, a severe deficiency occurs. Here the activity of factor XI is sometimes less than fifteen percent. Factor XI deficiency can occur once as type I. This means a reduction in the activity and protein concentration of the clotting factors in the blood. Type II, on the other hand, has the normal protein concentration present, but the activity is decreased. This is called a clotting factor dysfunction.
Diagnosis and progression
Factor XI deficiency leads to an increased tendency to bleed; compared with healthy people, bleeding may occur more easily and quickly. However, the disease can also be completely asymptomatic. If symptoms occur, they are predominantly moderate bleeding.These bleedings usually occur after injuries or surgical procedures. Circumcisions, tooth extractions, and ENT and urogenital procedures in particular are known to have higher bleeding tendencies in this deficiency disorder. Spontaneous bleeding does not usually occur, but women may experience prolonged menstruation. Significant hematomas are occasionally observed after surgical procedures in untreated patients with factor XI deficiency. However, in factor XI deficiency, little correlation can be seen between the severity of bleeding and factor XI levels.
Complications
In general, coagulation is impaired in a patient with factor XI deficiency. This can have a negative impact on health, especially in the case of accidents, and can lead to bleeding that cannot be stopped easily. Even minor injuries can promote relatively severe bleeding in factor XI deficiency. In most cases, there are no further complications with this disease if the patient does not expose himself to special and unnecessary dangers. However, problems may arise when surgery is performed. This is the case, for example, when visiting the dentist, when the bleeding cannot be stopped easily. With proper treatment, however, the disease progresses without further symptoms. Only in very rare cases the bleeding occurs spontaneously. Women are affected by heavier and longer-lasting menstrual bleeding, which can have a negative impact on everyday life. A proper treatment is usually not carried out. The affected person only has to pay more attention to bleeding and, if necessary, inform doctors if bleeding can occur during treatment. Factor XI deficiency does not result in a decreased lifespan.
When should you see a doctor?
A visit to a doctor is always necessary when factor XI deficiency is present. The doctor should be seen if the patient suffers from a markedly increased tendency to bleed. In this case, even very minor injuries or cuts can lead to severe bleeding. The bleeding itself can be difficult to stop and lasts for a very long time. A woman’s long and heavy menstrual bleeding can also indicate Factor XI deficiency and should always be investigated. As a rule, the doctor should be consulted when the symptoms are first recognized. Since the disease cannot be treated causally or etiologically, it is only alleviated with the help of medication. This can be used to stop the bleeding directly. In emergencies, an emergency physician can also be called. In the case of Factor XI deficiency, an attending physician should always be warned when surgery is required to avoid complications. Diagnosis and treatment of the disease can usually be done by a pediatrician or a general practitioner. Furthermore, visits to the doctor are usually not necessary if bleeding can be prevented.
Treatment and therapy
To detect factor XI deficiency, factor XI levels must be checked. Prolongation of the activated partial thromboplastin time (aPTT) leads in the same direction. In a severe deficiency, the factor XI level is below twenty units per deciliter. A partial deficiency is diagnosed when the level is between twenty and seventy units per deciliter. The diagnosis must be distinguished from diagnoses of deficiencies of the other coagulation factors, II, V, VII, VIII, IX, X, or XIII; combined deficiencies of factor V and VIII; von Willebrand syndrome; and platelet dysfunction.
Prospect and Prognosis
Factor XI deficiency can be treated very well by administration of tranexamic acid, aminocaproic acid, and other antifibrinolytic agents. Provided there are no concomitant diseases, recovery is likely. The prognosis is worse if the patient has autoimmune deficiency or a skin condition concomitant with the factor XI deficiency. This can promote internal and external bleeding and thus worsen the prognosis. The prognosis is also generally somewhat worse in children, pregnant women, and elderly people, as well as patients who are exposed to an increased risk of accidents at work. Since Factor XI deficiency occurs predominantly after tooth extractions and surgical procedures, the risk of bleeding can be specifically reduced by prescribing the appropriate drugs after such procedures and by having the patient closely monitored by a physician.This can improve the prognosis in the long term. Since spontaneous bleeding does not usually occur in factor XI deficiency, serious complications are unlikely. Life expectancy is not reduced by factor XI deficiency. The responsible internist can make the diagnosis on the basis of a medical history and regular follow-up. In general, the prospect of recovery is good because bleeding symptoms are mostly moderate.
Prevention
Permanent treatment is not necessary because spontaneous bleeding does not occur. In the event of bleeding or situations where bleeding is expected, treatment is required. Prior to tooth extraction or surgery, patients with factor XI deficiency are treated with factor XI concentrate or fresh frozen plasma. Sometimes, antifibrinolytics such as aminocaproic acid and tranexamic acid are also given because factor XI deficiency results in a hyperfibrinolytic status.
Follow-up
In factor XI deficiency, the options for follow-up are very limited in most cases. In this regard, the affected person is primarily dependent on medical examination and treatment of this disease to prevent further complications. As a rule, the affected person should always point out the factor XI deficiency to the doctor during medical examinations so that severe bleeding does not occur. The treatment itself is carried out by administering medication that can alleviate the symptoms. Care must be taken to ensure that the correct dosage is given and that the medication is taken regularly in order to properly counteract the factor XI deficiency. Special complications usually do not occur and there is no reduced life expectancy if Factor XI deficiency is treated correctly and in time. It is also advisable to carry a card indicating Factor XI deficiency, so that in case of accidents or other severe injuries, doctors are also notified about the disease. The affected person should protect himself from bleeding and from other injuries, and parents in particular should take special care of their children with factor XI deficiency. Contact with others affected by the disease may also be useful.
Here’s what you can do yourself
The more detailed the social environment of the affected person is informed about hemophilia C, the more natural it is to deal with it on a daily basis. Family members, friends or teachers and colleagues should be educated about the disease. In an emergency, this enables all those involved to act in a routine and level-headed manner. For example, school children with hemophilia C are at risk of joint and muscle bleeding in physical education classes. A privy physical education teacher knows when administration of factor medications is indicated or cooling is sufficient. Regular endurance sports such as swimming, cycling or hiking are suitable for people with factor XI deficiency, as this way muscles and joints are strengthened evenly. The risk of spontaneous bleeding is reduced. It is not advisable to take part in sports that put a lot of strain on muscles and joints or involve a risk of injury. These include team sports with frequent physical contact such as basketball or soccer. When traveling, the hemophilia ID card carried with the patient is a prerequisite for ensuring that the doctor called will treat the patient correctly in an emergency. When traveling abroad, the international patient ID card serves to improve communication. The shelf life of factor preparations is guaranteed when traveling if they are transported refrigerated. Medications ready to hand at all times increase safety, and a supply of at least one week is recommended.