Pediatric von Willebrand Disease
Introduction
Introduction to vascular hemophilia in children Von Willebrand disease (vWD) is a complex hemorrhagic disease with a hemostatic function. In 1926, Erikvon Willebrand first reported the disease, which was thought to be caused by abnormal platelet function or abnormal blood vessels. Pediatric patients are often caused by family heredity, which is a common type of hereditary bleeding disorder, which can be criticized by both men and women. It has been established that von Willebrand Factor (vWF) mass or quantity abnormalities cause vWD with a decrease in Factor VII procoagulant activity (VIII: C). Clinically, there is a tendency to hemorrhage of the skin mucosa, the platelet adhesion is reduced, and the bleeding time is prolonged. Acquired von Willebrand disease can occur on a variety of diseases, and a small number of patients can have no underlying disease. Children are rare. basic knowledge The proportion of illness: 0.001% Susceptible people: children Mode of infection: non-infectious Complications: anemia shock
Cause
Causes of von Willebrand disease in children
(1) Causes of the disease
Vascular hemophilia is a hemorrhagic disease caused by abnormalities in the quality or quantity of von Willebrand factor (vWF). It is currently widely believed that this disease is the most common congenital hemorrhagic disease.
Hereditary von Willebrand disease: Most patients are autosomal dominant, and a few are autosomal recessive. Both men and women can get sick, and both parents can inherit. Among hereditary hemorrhagic diseases, the incidence may be second only to hemophilia, which is about (4~10)/100,000, which is the most common hereditary hemorrhagic disease. However, the incidence of this disease is low in China.
Acquired von Willebrand disease: It is an acquired hemorrhagic disease that can occur on a variety of diseases, and a small number of patients can have no underlying disease. Children are rare, often secondary to lymphatic hyperplasia, acquired gamma globulin and other immune disorders, no family history of bleeding.
(two) pathogenesis
1. Hereditary vascular hemophilia:
vWF is a multimeric glycoprotein regulated by a gene on chromosome 12 and is 180 kb long. It is synthesized by endothelial cells and macrophages, forms vWF dimers from the initially synthesized pre-pre-vWF, and finally forms vWF multimers, which are stored in the Weibel-Palade bodies and platelet alpha particles of endothelial cells. The vWF synthesized by endothelial cells is mostly secreted in a sustained manner, has strong binding ability to the matrix, and plays an important role in the process of platelet adhesion to the vascular endothelium. When vWF is reduced, factor VIII degradation is accelerated and VIII:C activity is affected. In the small arteries with high shear force of the vessel wall, platelets adhere to the damaged endothelial cells and depend on the presence of vWF. vWF plays a role in connecting the platelet membrane surface and the subendothelial connective tissue. When the vWF level is reduced or the function is abnormal, the platelets cannot adhere to the damaged blood vessel wall, and the skin may be spontaneously bleeding or damaged after the injury.
The pathogenesis of vWD is different:
Type 1 is a missense mutation or a nonsense mutation in the vWF gene, causing a decrease in the level of vWF protein. Divided into autosomal recessive or dominant inheritance, the former is less common, and the clinical manifestations are extremely serious.
Type 2A is a missense mutation in the 28 exon of the vWF molecule. Type 2B is a missense mutation due to the site of binding to GPIb on the vWF molecule, and the vWF multimer aggregates with it and is easily cleared in plasma. It is autosomal dominant.
Type 3 mutations are nonsense mutations, gene deletions or defects in mRNA expression. There are few or almost no vWF proteins in plasma and platelets. For autosomal recessive inheritance, the patient's abnormal vWF gene is derived from both parents.
2. Acquired von Willebrand disease
It involves a variety of pathogenesis. The most common is the production of inhibitors with vW activity, mainly IgG, IgA and IgM; secondly, tumor cells adsorb vWF, which reduces plasma vWF.
Prevention
Vascular hemophilia prevention in children
Prevent illness or the birth of a carrier:
According to the genetic pattern of the disease, the family members of the patient are screened to determine the patients and carriers, and they are given genetic counseling about the disease to make them understand the genetic laws. It is best to go to the hospital to check the hemophilia gene before marriage to determine if the offspring are likely to have hemophilia. Prenatal diagnosis should be performed by genetic analysis of pregnant women in the family. The use of PCR technology can detect accurate fetal prenatal diagnosis of extremely serious cases of suspected vWD type II and type I by detecting the water or villus of pregnant women.
For children who are already sick:
It is necessary to develop quiet living habits and strengthen nursing to reduce and avoid traumatic bleeding, avoid trauma and intramuscular injection, and avoid the use of aspirin, non-steroidal anti-infectives and other drugs that affect platelet aggregation. If surgical treatment is required for surgical diseases, attention should be paid to blood transfusion or supplementation of clotting factors before, during and after surgery. If it is acquired, it is necessary to actively treat the primary disease, and treat it according to the specific disease.
Complication
Pediatric vascular hemophilia complications Complications anemia shock
Excessive bleeding can be complicated by anemia; in severe cases, it can be complicated by shock.
Can be complicated by joint soft tissue hemorrhage, joint bleeding can be seen joint swelling, tenderness, movement disorders.
Occasionally hematuria, gastrointestinal bleeding, and intracranial hemorrhage are life-threatening.
Symptom
Symptoms of von Willebrand disease in children Common symptoms Bleeding tendency Gingival bleeding Repeated bleeding Bleeding intracranial hemorrhage Skin mucosal bleeding
1. Clinical features
Most children have bleeding tendency since childhood. The severity of bleeding is related to the type of disease, abnormality of vWF quality or quantity, mostly skin mucosa, especially nasal, gingival hemorrhage, trauma, surgery such as tooth extraction, after tonsillectomy Excessive bleeding, women may have menorrhagia during puberty, type 3 vWD children may have joints, soft tissue hemorrhage, very few due to intracranial hemorrhage and life-threatening, repeated bleeding children easily lead to iron deficiency anemia, bleeding tendency with age can be Reduce yourself.
2. Clinical classification
According to the results of vWF cross-immunoelectrophoresis, vWD is divided into quantitative or qualitative abnormalities. The former is type 1 and the latter is type 2, and type 2 is divided into 4 subtypes: 2A is the type of large and medium-sized multimer in plasma; Lack of majority polymer and increased affinity for platelet GPI b to type 2B. The binding capacity of vWF to platelet GPI b was reduced to 2M type; the decrease in binding ability to factor VIII was 2N type, and the multimers in plasma and platelets of type 3 vWD patients were usually not detected or only low concentration levels.
Examine
Examination of vascular hemophilia in children
Some patients with vWD are completely normal. The same patient may have different test results at different times, so it is necessary to repeat the test.
1. Platelet morphology and counts are normal. A small number of patients (type 2 vWD) may have thrombocytopenia.
2. The time of partial thromboplastin in white clay is slightly prolonged, and the production of thromboplastin is poor.
3. The bleeding time (Ivy method) is prolonged, and the bleeding time of the light patient can be normal, and repeated examinations are required.
4. Blood coagulation factor test vWF: Ag decreased or normal, factor VIII decreased, and some type 2 vWD was normal. Polymers of different molecular weights of Factor VIIIR:Ag can be analyzed by radioimmunoelectrophoresis and SDS poly-propionyl gel electrophoresis.
5. Platelet function test platelet adhesion rate decreased or normal, vWF: RcoF decreased, 2N type was more normal.
6. The platelet retention test uses the Bowie method for abnormal results, while other methods are normal.
7. Aspirin tolerance test was positive. That is, BT was measured 2 hours and 4 hours after oral administration of aspirin 0.6g more than 2 minutes before taking the drug.
8. Classification check
(1) vWF cross-immunoelectrophoresis, except for type 1, other types of abnormal immunoprecipitation patterns may occur.
(2) The ristocetin-induced platelet aggregation response (RIPA) is reduced, and the severe cases are hardly aggregated. Type 2B is increased. It can be used as a diagnostic method for the mild or subclinical type of the disease.
(3) Analysis of vWF:Ag multimer in plasma and platelets: type 1 is normal for multimer distribution, type 2A is lacking for large and medium size multimers, type 2B is lacking for multimers, but some are medium and large Polymers, 2M and 2N are normal for multimer analysis and lack of type 3 multimers.
9. Select the necessary tests according to the clinical, such as B-ultrasound and X-ray examination.
Diagnosis
Diagnosis and diagnosis of vascular hemophilia in children
diagnosis
According to the history of skin mucosal bleeding, there is a tendency of excessive bleeding during trauma or surgery. Girls have a history of menstruation, and family history has the rules of autosomal inheritance. The possibility of this disease should be considered. Further laboratory tests such as platelet morphology and normal counting The activated partial thromboplastin time is normal or prolonged, the bleeding time (Ivy method) is prolonged, the aspirin tolerance test is positive, the platelet adhesion rate is decreased, the ristocetin-induced aggregation reaction is reduced or not aggregated, vWF: Ag is reduced or Normal, factor VIII is reduced or normal, vWF:RcoF is reduced or normal can be clearly diagnosed, RIPA, vWF cross-immunoelectrophoresis and vWF:Ag multimer analysis contribute to vWD typing.
Differential diagnosis
1. Platelet-type vWD (Pseudo-vWD): due to increased platelet GPIb receptor abnormality and vWF binding, reducing vWF in plasma, moderate platelet count reduction, bleeding time prolonged, factor VIII and vWF: Ag decreased, mostly The lack of polymer, RIPA enhanced, this type is similar to type 2B vWD, but the latter platelet count is normal.
2. Acquired vWD: rare in children, multiple secondary to lymphatic proliferative diseases, acquired gamma globulin and other immune disorders, no family history of bleeding, the patient's blood produces antibodies that neutralize vWF activity and There is a tendency to hemorrhage, Ristocetin cofactor activity of vWF (vWF: RcoF), decreased activity of vWF: Ag and factor VII, prolonged bleeding time, and often have symptoms of primary disease.
3. Hemophilia A: X-linked recessive inheritance, mainly muscle and joint hemorrhage, normal bleeding time, prolonged clotting time, decreased factor VIII: C, normal vWF: Ag, identification with vWD depends on the laboratory an examination.
4. Giant platelet syndrome: Due to the lack of platelet membrane GPIb, thrombocytopenia is characterized by large platelets of peripheral blood smear, vWF: As is normal, and bleeding time is prolonged.
