Hemophilia is caused byCoagulation factor ⅧOr coagulation factor Ⅸ gene defectX chromosomeLinked recessive hereditary hemorrhagic disease.There are two main types: hemophilia A (F Ⅷ deficiency) and hemophilia B (F Ⅸ deficiency).The disease can occur at the birth of the patient and may accompany the patient for a lifetime.If standard and standard treatment is not available, there will be a high disability and mortality rate.Abnormal coagulation function makes patients prone to bleeding all their lives.The majority of hemophilia patients are male, and female hemophilia patients are rare.The incidence of hemophilia in men is 1/5000 (hemophilia A) and 1/25000 (hemophilia B).
The main clinical manifestations of hemophilia are bleeding and bleeding related symptoms, such as pain at the bleeding site, mobility disorders, etc.Complications mainly include injuries caused by repeated bleeding, such as joint disease, joint disability orPseudotumor。
The main way to treat hemophilia isAlternative treatmentTo control and prevent bleeding events by infusion of missing coagulation factors.The prognosis of hemophilia depends on the degree and effect of treatment.Early detection and active treatment can significantly improve the quality of life and life expectancy of patients.In order to prevent bleeding events, hemophiliacs should avoid activities and behaviors that may lead to trauma.
The first record of hemophilia appeared in the second century A.DTalmudIn the 19th century, hemophilia appeared in many European royal families due to intermarriage between royal families.Interestingly, we now know that hemophilia B is prevalent among European royal families.According to the prevalence rate in China, it is estimated that the total number of hemophiliacs in China is about 40000.
The deficiency of coagulation factor Ⅷ (F Ⅷ) gene or coagulation factor Ⅸ (F Ⅸ) gene in the body leads to the deficiency of F Ⅷ or F Ⅸ, resulting in abnormal coagulation function of the patient for life.
According to the type of coagulation factor deficiency in patients, it can be divided into:Hemophilia AorHemophilia A(F Ⅷ deficiency) andHemophilia BorHemophilia B(Lack of F Ⅸ).In history, F XI deficiency was once called hemophilia C or hemophilia C, but because its genetic mode is completely different from hemophilia A or B, it is not used now.
Among all hemophilia patients, hemophilia A accounts for 80%~85%, and hemophilia B accounts for 15%~20%.Female hemophilia patients are rare.
According to the residual F Ⅷ activity (F Ⅷ: C) and F Ⅸ activity (F Ⅸ: C) in patients, hemophilia can be divided into: severe (activity<1%), intermediate (1%~5%) and mild (5%~40%). Patients with different levels of factor activity have different bleeding manifestations, which is also the basis for deciding what treatment plan patients need to take.
pathogeny
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If the human body is compared to a factory to produce various products we need, such as coagulation factors F Ⅷ and F Ⅸ, then there are drawings of various products in the body, which we can callgene。Once the drawing is abnormal or missing, the machine body will not be able to produce normal products.Hemophilia is precisely due to the mutation of the "drawings" for the production of F Ⅷ and F Ⅸ in the body, that is, the genes of F Ⅷ and F Ⅸ, which leads to the lack of "correct drawings for the production of F Ⅷ or F Ⅸ" in the body of hemophilia patients, and the inability to produce normal F Ⅷ or F Ⅸ, thus resulting in the lack of F Ⅷ: C or F Ⅸ: C.
Pathogenesis
F Ⅷ and F Ⅸ genes are located on the X chromosome, and X and Y chromosomes determine individual sex.Each individual has twoSex chromosomeAmong them, the X chromosome must be inherited from the mother, while the X or Y chromosome can be inherited from the father.
The male sex chromosome is XY. At this time, when the F Ⅷ or F Ⅸ gene in the only X chromosome of the male is abnormal, the male will lose the only set of "correct drawings", resulting in the decrease of F Ⅷ: C or F Ⅸ: C and become a hemophilic patient.
Women have two reasonsX chromosome(20) Therefore, when one X chromosome contains abnormal F Ⅷ or F Ⅸ genes, in addition, the normal F Ⅷ and F Ⅸ genes contained in X chromosome can maintain normal F Ⅷ: C and F Ⅸ: C in most cases, so there is no disease.This kind of women with abnormal genes, known as "hemophilia carriers", are likely toDefective geneWhen the defective gene is passed on to the offspring, it is a new hemophilia carrier when it is passed on to the girl, and a new hemophilia patient when it is passed on to the boy.
In a few cases, female hemophilia carriers may also become hemophilic patients due to non random inactivation of X chromosome or reduction of F Ⅷ: C or F Ⅸ: C, which is called homozygous patients. Therefore, female patients are extremely rare.
It is common for hemophiliacs to have a history of bleeding in their families.Hemophilia generally affects men on the mother's side;However, new mutations are easy to occur in F Ⅷ and F Ⅸ genes, and as many as 1/3 of patients may not have a family history of this disease.
Predisposing factors
There is no inducing factor for the occurrence of this disease.Because patients have lifelongBleeding tendency, Bleeding can be spontaneous, trauma or surgery can induce bleeding.
symptom
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The symptoms of hemophilia A and hemophilia B are similar, so no distinction is made here.
The symptoms of hemophiliacs include three aspects:
Bleeding and bleeding related symptoms: including pain at the bleeding site, activity disorder, dysfunction, etc.
Symptoms related to injury caused by bleeding: cumulative injury caused by repeated bleeding, such as joint disease, joint disability or pseudotumor caused by repeated joint muscle bleeding.
Treatment related symptoms: complications of hemophilia patients after receiving unsafe treatment or treatment due to their own genes and other factors.Such as blood borne virus infection（hepatitis B、hcv andHIV infectionEtc.)Coagulation factor ⅧAnd Ⅸ inhibitor.
Typical symptoms
Severe patients: F Ⅷ or F Ⅸ activity<1%, characterized by spontaneous muscle or joint bleeding.If the standard preventive treatment is not accepted, the disability rate is high.
Intermediate type patients: the activity of F Ⅷ or F Ⅸ is 1%~5%, with occasional spontaneous bleeding, and severe bleeding after minor surgery and trauma, with the characteristics of delayed bleeding.However, some patients may also have symptoms similar to severe patients with frequent spontaneous bleeding.
Mild patients: the activity of F Ⅷ or F Ⅸ is 5%~40%. Severe bleeding can be caused by major surgery or trauma, and spontaneous bleeding is rare.Many patients are occasionally diagnosed with laboratory abnormalities or excessive bleeding after surgery.
Joint hemorrhage
The most common symptom of hemophilia patients, about 70%~80% of patients will have joint bleeding.It can occur either after trauma or after daily activities, and part of the bleeding occurs after "imperceptible" minor injuries.According to the incidence of joint bleeding from high to low, they are knee (45%), elbow (30%), ankle (15%), shoulder (3%), wrist (3%), hip (2%) and other parts (2%).
Generally speaking, children with severe hemophilia mainly suffer from soft tissue bleeding before learning to walk. After learning to walk, due to the increase of autonomous activities, the joints begin to bear weight, and the frequency of joint bleeding increases.
Muscle hematoma
The characteristic manifestations of hemophilia patients, with an incidence of 10%~20%, are divided into spontaneous and traumatic.The harm caused by muscle hematoma is related to its location. When bleeding compresses important structures around, such as blood vessels and nerves, it will cause serious consequences.Muscle haematomas in the forearm or lower leg can causeOsteofascial compartment syndrome, leading to the formation of artery compressionIschemic contracture。
Abdominal muscle bleeding is also common in hemophilia A. Bleeding inside or around the iliopsoas muscle can cause pain and tenderness.When it occurs on the right side, it can be similar to appendicitis.When the femoral nerve is involved, pain can appear on the surface of the thigh.
Accompanying symptoms
Bleeding in different parts is accompanied by different accompanying symptoms.The patient may have cerebral hemorrhageheadache、Consciousness obstacle、EpilepsyIf not treated in time, the mortality rate will be high.
Joint bleeding will be accompanied by joint swelling and movement disorder. In areas with underdeveloped medical conditions, many patients' joint bleeding symptoms are regarded as the manifestations of arthritis and cannot be diagnosed and treated in time.Long term and repeated joint bleeding will lead to thickening of synovium, proliferation of synovium blood vessels, long-term fluid accumulation, destruction of articular cartilage and bone, joint deformity, decreased range of motion and normal life.
When muscles bleed, if they compress the nerves, they will cause sensory abnormalities and pain in the innervated areas. For example, when iliopsoas muscles bleed, patients often experience pain and abnormalities in the ipsilateral groin and lower limbs. This is because the hematoma compresses the femoral nerve. Improper treatment will cause irreversible damage to the femoral nerve.
Medical treatment
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If the following conditions occur, you should consult the hospital in time to diagnose or exclude hemophilia or other hereditary hemorrhagic diseases.
Minor trauma or bleeding after surgery (such as tooth extraction, circumcision, etc.).
There are hemophiliacs in the family, and his mother is a suspected hemophilia carrier.
The hospital physical examination found abnormal blood coagulation.
Visiting department
In case of acute bleeding, the patient will often go to the emergency department.Routine diagnosis, treatment and follow-up are carried out in the hematology department, hematology department or special hemophilia center.
Relevant inspection
Coagulation screening (PT, APTT, etc.), blood routine examination, activity determination of coagulation factors (including F Ⅷ and F Ⅸ, etc.), vWF: Ag, detection of coagulation factor inhibitor, lupus anticoagulant factor, gene examination.
The typical laboratory examination of hemophilia patients showed that APTT was prolonged, FVIII: C or FIX: C was reduced, vWF: Ag was normal, and the number of platelets was normal.
Because autoantibodies destroy F Ⅷ or F Ⅸ, bleeding is not caused by genetic defect and inheritance.
Deficiency of other coagulation factors
The lack of other coagulation factors besides F Ⅷ and F Ⅸ can also cause bleeding, but most of them areAutosomal recessive inheritanceTherefore, the incidence is low.The deficiency of other coagulation factors can be either single coagulation factor deficiency or combined factor deficiency (such as FV and F Ⅷ combined deficiency).
treatment
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Hemophilia is a rare disease, and its diagnosis and treatment are very complicated.The best management of such patients, especially severe patients, requires more than just treatment and prevention of acute bleeding.More importantly, we should improve our health and quality of life.Key points include:
Prevention of bleeding.
Long term management of joint and muscle injuries and other bleeding sequelae.
Virus infection caused by long-term transfusion of blood products.
These are the management objectives that can be achieved by the medical and health professional team of comprehensive prevention and treatment.Hemophiliacs should receive diagnosis, treatment and follow-up from the comprehensive care team in the hemophilia clinic.In case of acute bleeding, in order to avoid delay in treatment, you can receive treatment in a nearby medical institution under the guidance of the comprehensive care team or inject yourself at home.
Home treatment allows patients to inject immediatelyCoagulation factorThe most ideal early treatment can reduce pain, dysfunction and long-term disability, and significantly reduce hospitalization due to complications.Family therapy must be closely supervised by the comprehensive care team and can only be started after the patient and his family have received adequate education and training.
Acute treatment
When patients suffer from acute bleeding, they should immediately judge the bleeding site and give coagulation factor infusion as soon as possible to stop bleeding.And take appropriate adjuvant treatment.The most commonly used auxiliary measure for joint hemorrhage is RICE method, as follows:
"R" - Rest rest: rest the affected joint (>12~24 hours), and brake in the functional position.
"I" - Ice compress: 10-15 minutes each time, once every 2 hours.
"C" - Compression compression: bandage the bleeding joint with elastic bandage.
"E" - Elevation: Lift the affected limb beyond the heart.
Generally speaking, patients withArthralgiaOr the pain in other parts will be relieved quickly after effective factor infusion, but for some patients who have too long the interval from bleeding to factor infusion, or have serious chronic injury to their own joints, the pain relief may be relatively slow.At this time, pain can be relieved by taking some pain relievers, such as acetaminophen, but it is important not to take aspirin, which can be inhibitedplateletFunctional drugs.
General treatment
Hemophiliacs should avoid intramuscular injection and trauma.
Do not take aspirin and other drugs that may inhibit platelet function.
Patients should try to avoid all kinds of operations and the examination and treatment that may cause bleeding. If surgery is necessary, adequate alternative treatment should be carried out.
medication
The main treatment for hemophilia patients is to supplement the lacking coagulation factors, that is, replacement therapy.According to the different time of coagulation factor used, it can be divided into on-demand treatment and preventive treatment.
Drug selection and dose calculation method
Replacement therapy for hemophilia A
The alternative treatment of hemophilia A is preferred to gene recombinant F Ⅷ preparation (rF Ⅷ) or virus inactivated blood derived F Ⅷ preparation (PdF Ⅷ), which can only be selected in the absence of the above conditionsCold precipitationorFresh Frozen Plasma(FFP), etc.Each infusion of 1 IU/kg of F Ⅷ can increase F Ⅷ ∶ C in the body by 2 IU/dl. The half-life of F Ⅷ in the body is 8~12 hours. To keep F Ⅷ in the body at a certain level, it needs to be infused once every 8~12 hours.
The formula for calculating the infusion dose of F Ⅷ for hemophilia A patients is: required F Ⅷ dose (IU)=(expected F Ⅷ: C-basic F Ⅷ: C) x body weight (Kg)/2.
Replacement therapy for hemophilia B
For alternative treatment of hemophilia B, gene recombinant F Ⅸ preparation or virus inactivated blood derived prothrombin complex is preferred, and fresh frozen plasma (FFP), etc. can be selected in the absence of the above conditions.Each infusion of 1IU/kg weight of F Ⅸ can increase the ratio of F Ⅸ to C by 1IU/dl. The half-life of F Ⅸ in the body is about 24 hours. To keep F Ⅸ in the body at a certain level, it needs to be infused once a day.
The formula for calculating the infusion dose of F Ⅸ for hemophilia B patients is: the required F Ⅸ dose (IU)=(expected F Ⅸ: C-base F Ⅸ: C) x body weight (Kg).
Alternatives
On-demand treatment
After the patient has bleedingCoagulation factorIt can stop bleeding, thus relieving pain, saving lives, reducing injuries and promoting functional recovery.However, it is impossible to prevent the occurrence and development of joint diseases, and eventually hemophilic arthropathy will occur.When treatment is needed, it is necessary to raise F Ⅷ: C or F Ⅸ: C to the desired hemostatic level.In general, when educating hemophiliacs, hospitals will issue some materials related to therapeutic dose for patients and their families to use.
Preventive treatment
Preventive treatment refers to the improvement of F Ⅷ: C and F Ⅸ: C in patients by regular infusion of coagulation factors before the occurrence of bleeding events, so as to prevent bleeding.Compared with on-demand treatment, preventive treatment can prevent bleeding, avoid joint damage, and thus avoid disability of patients.The specific prevention and treatment plan needs to be formulated by the doctor according to the patient's corresponding condition. Once the plan is determined, patients and their families should strictly follow the plan, and return regularly to obtain the best effect.
Treatment after producing F Ⅷ or F Ⅸ inhibitor
About 30% of hemophilia A patients and 5% of hemophilia B patients will produce neutralizing antibodies against F Ⅷ or F Ⅸ, also known as inhibitors, after receiving F Ⅷ and F Ⅸ replacement treatment.The inhibitor can destroy the F Ⅷ or F Ⅸ transfused, thus reducing the hemostatic effect or even rendering it ineffective.At present, the main factors of inhibitor production include genetic factors and non genetic factors.The former mainly includes gene mutation type, race and family history.The latter includes trauma history, exposure day, high-intensity treatment, etc.
At present, the generation of inhibitors cannot be accurately predicted.The content of the inhibitor is expressed in BU/ml, the inhibitor>5BU/ml is a high titer inhibitor, and the inhibitor<5BU/ml is a low titer inhibitor.Once the inhibitor is produced, it is necessary to use bypass agents to stop bleeding, including recombinant human activation Ⅶ (rF Ⅶ a) orProthrombin complex（PCC）。
It should be noted that the production of F Ⅸ inhibitor in hemophilia B patients is often accompanied by anaphylaxis. When continuing to contact F Ⅸ (gene recombination or PCC), anaphylaxis may continue to occur, and some patients will have irreversible nephrotic syndrome.The main scheme of inhibitor elimination is immune tolerance induction therapy (ITI). Due to its high specialty and huge cost, it needs to be treated under the guidance of doctors.
Other drug treatment
1-Deamino-8-D-arginine vasopressin (DDAVP)
It is suitable for patients with mild hemophilia A, female hemophilia A carriers and type 1 vWD patients, but not effective for patients with severe hemophilia and hemophilia B.
Fibrinolytic inhibitor
The commonly used ones are tranexamic acid and aminocaproic acid.This drug is ineffective as a routine prevention of hemophilia joint bleeding, but it can be used as an auxiliary treatment of hemophilia. It can effectively treat mucosal bleeding (such as epistaxis, oral bleeding) after 5 to 10 days of continuous use, and can reduce the use of coagulation factors after tooth extraction.However, it should be avoided when there is hematuria to avoid urinary tract obstruction.
surgical treatment
When a hemophilic patient has complications such as arthritis or pseudotumorsurgical treatment。The whole operation should be carried out in cooperation with a team experienced in hemophilia treatment.Common surgical treatment schemes include the following:
Synovectomy
It is suitable for patients with chronic synovitis who are difficult to control recurrent bleeding by alternative treatment.
Joint replacement
Applicable toArticular cartilagePatients with complete destruction, even bone destruction, deformity, joint disease in the end stage (Grade IV disease), pain and limited mobility can not be relieved.
Arthrodesis
It is generally applicable to patients with infection after joint replacement and who cannot or do not consider revision surgery due to various reasons.It is especially suitable for hemophilia patients with obvious foot and ankle joint lesions.
Pseudotumor resection
Adult pseudotumor is ineffective for conservative treatment. If it increases progressively or causes compression symptoms to surrounding organs and tissues and blood vessels and nerves, it will affect the function of organs and tissues and joints or appearPathological fractureSurgical resection is required when the risk of.
prognosis
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Patients receiving standard preventive treatment can keep normal to the maximum extentJoint functionAvoid fatal bleeding, and the life expectancy is close to that of normal people.Patients who only receive on-demand treatment can delay the occurrence of hemophilia arthropathy, but cannot completely avoid disability.For patients who have ever suffered from cerebral hemorrhage, under the premise of non preventive treatment, the probability of recurrent cerebral hemorrhage is high, and there is a risk of life-threatening.The chronic attack of hemophilia includes the following points:
