thrombotic thrombocytopenic purpura
Introduction
Introduction to thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura is also called thrombotic microangiopathy hemolytic anemia, platelet thrombosis syndrome and the like. An uncommon thrombotic microangiopathy with microangiopathic hemolytic anemia, clinical features of fever, thrombocytopenic purpura, microangiopathic hemolytic anemia, multiple neurological and renal damage, etc., the cause of which is unknown It may be related to vascular factors, infections, and drug allergies. Most patients are between the ages of 10 and 40, and about 60% are women. The onset is rapid and the condition is serious. Two-thirds of the cases die within 3 months, and a few cases are slow. The course of disease can last from several months to several years. basic knowledge The proportion of illness: 0.005% Susceptible people: no specific population Mode of infection: non-infectious Complications: hemolytic anemia, acute renal failure, myocardial infarction, arrhythmia
Cause
Thrombotic thrombocytopenic purpura
Capillary lesions (35%):
In the capillaries with obvious lesions, the pathological changes of the endothelium before thrombosis can be seen under electron microscope. Microscopic disease can cause erythrocyte lysis due to lesions in the microcirculation, which can aggravate local thrombosis. , can lead to thrombocytopenia, the literature reports that TTP can be associated with discoid or systemic lupus erythematosus, rheumatoid arthritis, rheumatoid spondylitis, multiple nodular arteritis, etc., these diseases have a certain degree of characteristics Vasculitis lesions. It has been found that the lack of a plasminogen activin in the vascular endothelial cell layer of patients with TTP causes local fibrinolytic function to impede thrombosis in small blood vessels. Studies have confirmed that local platelet activation may play a role in the pathogenesis of TTP. Role, some patients with advanced TFP plasma can cause normal human platelet aggregation, but after mixing with normal plasma at 37 ° C, the platelet aggregation activity can be gradually reduced, it is considered that there may be some platelet activating factor (PAF) in the patient's plasma. ), it may also lack the inhibition of platelet activating factor (PAFI) and cause disease. It is reported that the obvious aggregation of platelets requires the binding of high molecular vWF polymer to GPIb in the surface structure of platelets, followed by plasma proteins (probably fibrinogen, thrombus) The regulatory protein or fibronectin) binds to the GPIIb-IIIa complex. It is currently believed that vascular endothelial cell injury is one of the pathogenic factors of TTP. Thrombomodulin (TM) is a high-affinity thrombin receptor in the trophoblast and platelet of vascular endothelial cells. In 1991, Takahashi et al. In 13 patients with acute TTP, the results showed that 8 patients had elevated TM concentrations; TM patients with SLE were higher than those without SLE, TM concentrations were associated with tissue plasminogen activin (t-PA) and VWF: Ag. Significantly related, but regardless of the number of platelets, there was no significant difference in TM concentration in patients with acute TTP regardless of whether the condition was relieved.
Disseminated intravascular coagulation (30%):
The main pathological change of this disease is thrombosis in the microcirculation. Some people think that the essence of this disease is DIC. Takahashi et al tested plasma thrombin-antithrombin III complex (TAT) and plasmin in 10 patients with acute TTP. -2-antiplasmin complex (PAP), the patient's TAT and PAP values were higher than the normal control, but there was no correlation between the two, and the PAP and TAT values of the 5 patients were significantly decreased after remission. However, other abnormal blood coagulation indicators were not abnormal. The authors believe that TTP patients do have increased thrombin and plasmin production, and most patients have no consumptive coagulation. 3. Prostaglandin (PGI2) synthesis is reduced or there is a lack of plasma. Some factors that prevent PGI2 degradation, about 60% of patients with TTP can be relieved with whole blood or plasma. If treated with 5% albumin, the condition deteriorates. After study, the patient's PGI2 production is normal, but its degradation rate is accelerated, suggesting normal plasma. There is a factor that prevents the rapid degradation of PGI2. It does not exist in albumin. The half-life of this factor is 2 weeks, which can prolong the biological activity of PGI2. Its deficiency can lead to a decrease in PGI2, accompanied by microvascular thrombosis, Hensby et al. (1979) reported a decrease in plasma 6-keto-PGF1a in patients with TTP, further confirming this doctrine.
Autoimmune response (10%):
Burns incubated the serum or purified IgG of 3 patients with TTP with cultured human umbilical vein endothelial cells, and confirmed the binding of IgG antibody on the surface of endothelial cells by indirect immunofluorescence. The specific antibody was confirmed by cytotoxicity test and electron microscopy. Inducing progressive lysis of endothelial cells, vascular endothelial cell damage can lead to low PGI2 formation, decreased plasminogen activator, and ultimately lead to microthrombus formation. It has been reported that platelet surface-associated immunoglobulin (PAIgG) is increased in TTP, and is reduced when treatment is improved. When IgG is attached to the surface of platelets, it is easily destroyed by mononuclear macrophage system, resulting in thrombocytopenia in the blood circulation, and circulating immune complex (CIC). It does not play a major role in the pathogenesis of this disease, but in secondary TTP (such as SLE, bacterial endocarditis), complement often decreases, may be related to the development of symptoms.
Prevention
Thrombotic thrombocytopenic purpura prevention
It is necessary to pay attention to the spirit of happiness, living and festivals, pay attention to cold and warm, eat less fat and nourishment products, mild disease, if the bleeding symptoms are light, can be appropriate activities, is conducive to the operation of blood, serious patients should rest properly, or in bed treatment.
The prevention of this disease is fundamentally to prevent the formation or production of blood stasis. Therefore, the main measures are to enhance the body's righteousness, prevent emotional internal injuries, eating disorders and foreign evils, and timely and correctly treat various diseases so as not to enter the human body. And cause this disease.
Complication
Thrombotic thrombocytopenic purpura complications Complications hemolytic anemia acute renal failure myocardial infarction arrhythmia
Can be complicated by severe hemolytic anemia; very few due to renal cortical ischemia and necrosis due to oliguria, urinary closure and acute renal failure, cardiac thrombosis can cause myocardial infarction, involving the heart conduction system can lead to severe arrhythmia, heartbeat Stop and die.
Symptom
Thrombotic thrombocytopenic purpura symptoms Common symptoms Platelet life shortens abdominal pain bleeding tendency fatigue thrombocytopenia vertigo liver splenomegaly severe anemia inflammatory cell infiltration jaundice
Clinical manifestation
The onset is often rapid. Typical cases have fever, fatigue, weakness, a few onsets are slow, and there are prodromal symptoms such as muscle and joint pain. Other symptoms appear quickly afterwards. There are also pleurisy, Raynaud's phenomenon, and women's vaginal bleeding as the initial complaint.
1. Typical clinical manifestations mainly have the following characteristics
(1) Bleeding caused by thrombocytopenia: mainly caused by skin mucosa, manifested as bruises, ecchymosis or purpura, nosebleeds, retinal hemorrhage, genitourinary tract and gastrointestinal bleeding, severe intracranial hemorrhage, the degree of thrombocytopenia Not one.
(2) microangiopathic hemolytic anemia: different degrees of anemia, about 1/2 of cases have jaundice, 20% have hepatosplenomegaly, and in a few cases Raynaud phenomenon.
(3) Neuropsychiatric symptoms: The clinical manifestations of typical cases are first seen in the nervous system, and the severity often determines the prognosis of the disease. 151 of 168 cases reported by Silverstein have neurological symptoms (90%), which are characterized by symptoms. The change is uncertain, the initial is transient, 50% can be improved, it can be repeated, patients have different levels of consciousness disorder, 30% have headaches and/or aphasia, unclear, dizziness, convulsions, paralysis, paresthesia, Visual impairment, sensory disturbance, disorientation, confusion, paralysis, lethargy, coma, cranial nerve palsy, 45% have convulsions, sometimes hemiplegia, can recover within hours, the variability of nervous system manifestations One of these manifestations is related to cerebral circulation disorders.
(4) Kidney damage: Most of the kidney damage, but to a lesser extent, mild hematuria, proteinuria, tubular urine, 50% of patients with mild nitrogen retention, very few due to renal cortical ischemia and necrosis Urine, urinary closure and acute renal failure, gross hematuria is not common, and severe cases of acute renal failure eventually occur.
(5) Fever: more than 90% of patients have fever, can be fever in different stages, mostly moderate, the cause is unknown, may be related to the following factors: 1 secondary infection, but blood culture results are negative; 2 hypothalamic body temperature Regulatory dysfunction; 3 tissue necrosis; 4 release of hemolysate; 5 antigen-antibody reaction damages macrophages and granulocytes, and releases endogenous pyrogens.
(6) Others: multifocal hemorrhagic necrosis of the myocardium, microthrombus formation in the myocardium, concomitant heart failure or sudden death, electrocardiogram repolarization abnormalities or various arrhythmias, autopsy as acute myocardial infarction, pulmonary insufficiency reported Performance, thought due to pulmonary small blood vessel involvement, hepatosplenomegaly, abdominal pain symptoms, the reason is due to thrombotic occlusion of pancreatic arterioles, pancreatitis caused by pancreatic embolism, serum amylase can be increased, gastrointestinal lesions are due to A few patients have mild lymph nodes, various types of rash, malignant hypertension, extensive necrosis of skin and subcutaneous tissue, periarteritis, and no gamma globulinemia.
2. Classification
(1) acute type: more rapid progress, explosive, 7 to 14 days of symptoms, about 75% of patients died within 3 months after the onset of the disease, common causes of death are bleeding, cerebrovascular accident, or heart and lung Functional failure.
1 Chronic: rare, relief and deterioration occur one after another, the course of disease can last for months or years.
2 repeated episodes: due to treatment progress, can be repeated 1 to 5 times, the average survival of 9 months to 12 years, the median survival period of 5.1 years.
3 congenital type: TTP occurs in identical twins.
(2) secondary hair: pregnancy with TTP, most of which occurs in eclampsia, pre-eclampsia or pre-eclampsia, can also occur in the first week after production, the pathogenesis may be related to increased circulating immune complexes, a literature report There were 151 cases of TTP in the group, of which 23 cases had SLE at the same time. Another report was that autoimmune hemolytic anemia eventually caused TTP, immune whole blood cell reduction occurred simultaneously with TTP, and TTP occurred after 4 months of ITP interval, and tumor could cause TTP. Such as lymphoma, TTP can occur after 2 to 6 months.
Examine
Examination of thrombotic thrombocytopenic purpura
Laboratory inspection
The normal half-life of normal red blood cells marked with 51Cr in TTP patients is only 3 days (normal 25 to 26 days), and the indirect bilirubin is elevated, which is characterized by proteinuria, microscopic hematuria and tubular urine, 40% to 80% light. Nitrogenemia, decreased creatinine clearance.
1. Peripheral blood: patients have anemia, positive cells are pigmented, 1/3 of patients with hemoglobin <60g / L, hematocrit <0.2, visible red blood cells and debris in the blood picture accounted for 95%, and can be seen Spherical red blood cells, nucleated red blood cells and reticulocytes were significantly increased (>30%), and also reported to decrease first and then increase, median value of 6.6% to 19%, persistent thrombocytopenia 92%, median (8 ~40.4) × 10 9 /L, white blood cell increase accounted for 60%, leukemia-like reaction is rare, but there may be a significant left shift, and immature granulocytes can be seen.
2. Bone marrow: The red blood cell system is significantly proliferated, the number of megakaryocytes is normal or increased, and most of them are naive megakaryocytes, which are mature obstacles.
3. Coagulation examination: normal bleeding time, poor blood clot contraction, positive beam arm test, prolonged prothrombin time, accounting for 20%, partial thromboplastin time prolonged, accounting for 8%, fibrinogen can be reduced, less than 1.5g / L, accounting for 7%, fibrinogen survival and conversion are mostly normal, a few mildly shortened, FDP positive accounted for 70%, thrombin time prolonged, accounting for 48%, but generally no typical DIC laboratory changes, Factor V, VIII is normal, PGI2 is decreased, TM, PAIgG is increased, and it decreases with the improvement of the disease. When HIV-1 infection, endothelial cells damage PAI, V W factor increases, and PS decreases.
4. Hemolysis index examination: direct Coombs test is negative, but a small number of secondary can be positive, serum bilirubin increased, 17 ~ 307.8mol / L (1 ~ 18mg / dl), mild bilirubinemia accounted for 84 % ~ 100%, free hemoglobin increased, combined with decreased globin and hemoglobinuria, suggesting intravascular hemolysis.
5. Immune serological examination: 10% to 20% of patients with SLE cells can be positive, anti-nuclear factor 50% positive, a few rheumatoid factor positive, most of the complement is normal, a few such as SLE, subacute bacterial endocarditis, Chronic nephritis with TTP can be reduced, subacute bacterial endocarditis secondary TTP can increase circulating immune complexes, LDH 100% increase parallel to clinical course and severity, platelet particles and endothelial cells secrete soluble P selection Plasma plasma levels are elevated, and platelet membrane glycoprotein CD36 is found in patients with TTP.
6. The pressure of the effusion and the protein are slightly increased, the number of cells is normal, and the subarachnoid hemorrhage is rare.
7. Pathological examination: The main lesions are small arteries and capillary lumens. The deposition of transparent glass-like substances with PAS staining is observed. The deposition of this substance is sometimes under the endothelium. Immunohistochemistry and electron microscopy confirm that the substance is mainly composed of fibers. Protein and platelet composition, endothelial cells near the thrombus can proliferate, electron microscopically visible microthrombus containing cellulose, accumulated platelets, occasionally red, white blood cells, microthrombotic lesions are different from immune small vasculitis, no small blood vessels around the single Nuclear cell infiltration, glomerular involvement is lighter than HUS, granular eosinophilic thrombus in the small arterioles, endothelial proliferation, lipid-containing macrophages in the endothelium, and occasional fibrin in the glomerular capillaries Thrombosis (Figure 1), systemic fibrotic thrombosis is more serious than HUS, but also in the heart, brain, pancreas, adrenal glands and lymph nodes.
Skin biopsy is the safest pathological diagnosis method. The 1/2 case in the stasis area is positive, the bone marrow clot slice is 60% positive, and the autopsy pathological examination is only 44% positive, so the negative can not rule out the disease.
8. Increased TGF1 (transforming growth factor 1) has an inhibitory effect on bone marrow hematopoiesis, that is, clinically observed lack of compensatory hematopoiesis, and some inhibition is still maintained during clinical remission, so that platelet activation is still present.
Film degree exam
1. EEG is normal, or there are diffuse bilateral cortical abnormalities or localized abnormal rhythms.
2. EKG changes in ST-T, and arrhythmia and conduction block are rare.
3. Chest radiographs can be seen in extensive alveolar and interstitial degeneration lesions.
Diagnosis
Diagnosis and identification of thrombotic thrombocytopenic purpura
diagnosis
1. Diagnostic criteria and basis: According to Zhang Zhinan's book "Diagnostic and Efficacy Standards for Blood Diseases", the diagnostic criteria based on relevant literature at home and abroad are as follows. The main diagnostic basis is:
(1) Microangiopathic hemolytic anemia:
1 Anemia is mostly positive cells in the positive pigmentation, severe anemia.
2 microvascular disease hemolysis.
A. Astragalus, dark urine, urinary bilirubin negative, occasional hyperhemoglobinemia, hyperhemoglobinuria and hemosiderinuria.
B. Broken red blood cells in the blood slice > 2%, occasionally there are nuclear red blood cells.
C. Reticulocyte counts are elevated.
D. The bone marrow erythroid hyperplasia, the particle/red ratio decreased.
E. Hyperbilirubinemia, mainly indirect bilirubin.
F. Plasma haptoglobin, reduced hemopexin, and elevated lactate dehydrogenase.
(2) thrombocytopenia and bleeding tendency:
1 platelet count is often significantly reduced, large platelets are visible in the blood.
2 bleeding on the skin and / or other parts.
3 The number of megakaryocytes in the bone marrow is normal or increased, which may be associated with maturity disorders.
4 platelet life is shortened.
(3) neuropsychiatric abnormalities: headaches, personality changes, confusion, abnormal consciousness, language, sensory and motor disorders, convulsions, stupor, positive pathological reflexes, etc., and often transient, repetitive, diverse and diverse Denatured features.
The above three items are also called triplets.
(4) Kidney damage: manifested as abnormal laboratory tests, such as proteinuria, red blood cells in the urine, white blood cells and casts, blood urea nitrogen, elevated creatinine, etc., severe cases can be seen nephrotic syndrome or renal failure.
(5) fever: mostly low, moderate.
2. Auxiliary diagnosis: Histopathological examination can be used as an auxiliary condition for the diagnosis of TTP, including skin, gums, bone marrow, lymph nodes, muscles, kidneys, spleen, lungs, etc., abnormal manifestations of small arteries, uniformity in capillaries "Transparent-like" platelet thrombosis, positive for PAS staining, in addition, there is vascular endothelial cell proliferation, "transparent-like" substance deposition under the endothelium, fibrosis around the small artery, localized embolization may have necrosis, but no inflammatory cell infiltration or inflammation There are several types of reactions and types.
(1) According to the disease type:
1 acute: onset is fast, no recurrence within at least 6 months after cure.
2 Chronic: Can not be completely cured, the course of the disease is long-term.
3 recurrence: recurrence within 6 months after the cure, recurrence within 1 month is a recent recurrence, recurrence after 1 month is a late recurrence.
Chronic and recurrent cases account for approximately 7.5% of the total number of cases.
(2) According to the cause classification:
1 idiopathic: no special cause can be found, most cases belong to this type.
2 secondary: there are specific causes can be found, such as pregnancy, infection, cancer, drugs and so on.
3. Diagnostic evaluation
(1) The typical TTP has five signs: However, many scholars believe that as long as microvascular hemolytic anemia, thrombocytopenia and neuropsychiatric triad can diagnose TTP, even some scholars believe that given the prognosis of this disease, if Microvascular hemolytic anemia and thrombocytopenia should be considered after the exclusion of thrombotic microangiopathy such as DIC, and treatment should begin as soon as possible.
(2) TTP lack of specific experimental diagnostic indicators: only comprehensive clinical manifestations and laboratory examinations can be seen, and other thrombotic microvascular diseases can be excluded before diagnosis can be made. In clinical manifestations, neuropsychiatric abnormalities are the most diagnostic. However, its performance is diverse, and can be transient, need to be carefully understood, neuropsychiatric abnormalities can be repeated during the course of the disease, and the performance of each episode is not the same, it should be noted that in various experimental methods, clinicians often ignore Peripheral blood smear red blood cell morphology examination, but this method is simple and easy, the increase of deformed and broken red blood cells is a favorable evidence for hemolysis of microvascular disease, and has a high diagnostic value. In contrast, histopathological examination found in capillaries. Although there are "transparent-like" platelet thrombosis, although it has great diagnostic significance, this method is time-consuming and traumatic, and it does not necessarily lead to positive results. It is difficult to be widely used clinically. Recent studies have found that the incidence of TTP may be related to vWF. Related to the lack of lyase (vwF-CP), the role of vWF-CP is to degrade vWF macromers. When the enzyme is deficient, vWF is large in plasma. Increasing sub-multimers, leading to platelet adhesion and aggregation, thrombus formation slightly transparent, such as to determine the activity of the vWF-CP, the difficult diagnosis of TTP can be used to monitor the recurrence of the disease.
(3) When diagnosing TTP: attention should be paid to finding various predisposing factors, such as infection, drugs, immune dysfunction, etc. With the continuous introduction of various new drugs, reports of drug-induced TTP are gradually increasing, and some theoretically can be used for treatment. TTP drugs, such as ticlopidine, have also been shown to induce TTP and should be especially vigilant.
(4) In the past, TTP and hemolytic uremic syndrome (HUS) were considered to be two different diseases, but recent studies have found that both have the same etiology, pathological manifestations and clinical features, but differ in clinical manifestations. The latter has a relatively young age of onset, and the performance of uremia is more prominent. Generally, fever and neuropsychiatric abnormalities do not occur. Therefore, most scholars believe that the two diseases should be regarded as the same disease, collectively referred to as TTP-HUS, and recently Scholars have found that vWF-CP deficiency is more common in patients with TTP, but less common in patients with HUS. Therefore, it is suggested that there are differences in pathogenesis between the two, and it is considered that the two can be identified accordingly. This view is yet to be accepted.
(5) The domestic literature often sees the term DIC merged with TTP: it is not appropriate. DIC can show all the clinical manifestations of TTP, including almost all laboratory abnormalities of TTP, and many predisposing factors of the two. The same is true, but the pathological processes of the two are different, and the formed microthrombus has a qualitative difference, and generally there is no problem of coexistence of the two.
Differential diagnosis
1. Disseminated intravascular coagulation (DIC): The patient has no severe hemolytic anemia and transient variability of neuropsychiatric symptoms, but severe bleeding, thrombocytopenia, decreased coagulation factors, secondary fibrinolysis Evidence, protein C measurement was significantly reduced, tissue factor antigen was significantly increased, TTP thrombocytopenia, broken red blood cells, coagulation factors generally did not decrease, protein C was normal, FDP did not increase or slightly increase, 3P negative, tissue factor antigen light The degree of decline was not significantly increased 1 month after treatment, and its inhibitor (TFPI) was significantly increased, but sometimes the identification of TTP and DIC was difficult.
2. Evans syndrome: autoimmune hemolytic anemia with immune thrombocytopenic purpura, may have renal dysfunction, Coombs test positive, no deformity and broken red blood cells, no neurological symptoms.
3. Systemic lupus erythematosus (SLE): There are joint symptoms, kidney damage, neurological symptoms, and hemolytic anemia, skin damage, LE cell positive, no abnormalities in the peripheral blood and broken red blood cells.
4. Hemolytic uremic syndrome (HUS): At present, TTP and HUS are two different clinical manifestations of the same disease, a polygenic disease, and belong to thrombotic microangiopathy (TMA). The lesion of HUS is kidney. Most of the damage is mostly children under the age of 4, occasionally seen in adults, often with symptoms of upper respiratory tract infection and gastrointestinal symptoms, with acute renal failure being the most prominent, except microvascular hemolytic and thrombocytopenia, generally no Mental symptoms.
