Disease Description
Thrombotic thrombocytopenic purpura (TTP) is a rare group of microvascular thrombo-hemorrhagic syndromes that can be caused by a variety of factors or diseases of different nature, with a heterogeneous etiology. The epidemiological statistics of a large series are not yet available.
Patients are mostly adults, especially middle-aged women, and tend to be in their reproductive years. The clinical manifestations can be divided into acute, chronic and recurrent. It can be divided into hereditary and acquired according to the etiology. The incidence of hereditary TTP is extremely low. Acquired TTP is divided into primary and secondary due to the presence or absence of an obvious cause, primary TTP has no specific cause and is prone to recurrent attacks, most cases belong to this type; secondary TTP has a specific cause and the incidence has increased in recent years.
Pathogenesis
TTP mainly affects small terminal arteries and capillaries, where a clear thrombus composed mainly of platelets containing vWF and very small amounts of fibrinogen and fibrin is present. The exact mechanism of thrombosis is not fully understood and may be related to the following factors
1. abnormal von Willbrand factor (vascular hemophilia factor, vWF) formation and vWF cleavage protease (vWFcp) deficiency or defective activity. It is currently believed that abnormal vWF and deficiency and defective activity of vWFcp are central to the pathogenesis of TTP and are the main causes of platelet thrombosis.
2, abnormal vWF factor formation: pathogenic factors damage vascular endothelium, vascular under the action of high shear force, the damaged endothelium can release a large number of vWF mutants in a short period of time, these mutants form large molecular multimers (ULvWFM) in the circulation, whose length is larger than the diameter of platelets, and have higher binding ability with vWF receptors GPIb/IX/V and GPIIb/IIIa on the surface of platelet membrane. ULvWFM has higher binding capacity and acts as a link under the high shear force of microcirculatory fluid, mediating platelet adhesion and aggregation to form microthrombi. The formation of microthrombus not only causes platelet depletion and secondary bleeding, but also causes microvascular stenosis after deposition, which affects the smooth passage of red blood cells, resulting in deformation, damage or even fragmentation of red blood cells and microangiopathic hemolytic anemia, and the narrowing of microvessels also affects blood supply, causing dysfunction and damage to the involved tissues and organs.
3. vWF cleavage protease (vWFcp): Under normal conditions, vWFcp can cleave oversized molecules of vWF (ULvWF), thus preventing ULvWF from entering the blood circulation. This protease has recently been shown to belong to the ADAMTS family member ADAMTS13, a zinc- and calcium-dependent protease with arginine glycine aspartate order (RGD), whose gene is located at 9q34 and is mainly produced by the liver. ADAMTS13 can bind to the endothelial cell surface where ULvWF can be cleaved by ADAMTS13. In addition, TSP1 is another degradation enzyme that has been demonstrated in recent years. Recently, it has been found that ULvWF is present in the plasma of TTP patients but lacks an enzyme that cleaves vWF, namely vWF cleavage protease (vWFcp). tsp1 is reduced in all types of TTP pathogenesis, but it remains to be investigated whether it is the mechanism of TTP pathogenesis. Familial TTP patients lack vWFcp in plasma; the presence of a vWFcp gene defect in TTP patients was further confirmed in studies of familial TTP patients. When vWFCP is deficient, ULvWF cannot be catabolized, leading to the development and progression of the disease. However, studies have also found that patients with congenital protease defects do not necessarily develop the disease, while some patients may develop the disease during pregnancy, which also suggests that simple protease defects may be involved in the pathogenesis of TTP, but are not the decisive factor in causing TTP.
4, vWF cleavage protease activity defect: In patients with acquired TTP, vWFcp can be normal. Studies have found that the presence of autoantibodies (IgG) to vWFcp in the plasma of patients, or its inhibitors, neutralize or inhibit the activity of vWFcp, promoting the formation of microthrombi in circulating platelets, leading to the onset of the disease. After remission of the disease, vWFcp activity may return to normal. Defective lytic protease alone is not a determinant factor in causing TTP. Instead, vascular endothelial cell injury leads to excessive release of ULvWF, when vWFcp deficiency, relative insufficiency or defective activity cannot cleave ULvWF into small molecules, leading to microthrombosis, which is the common cause of morbidity.
5, vascular endothelial cell injury Vascular endothelial cells are an important component unit of the body to maintain the balance of the coagulation and anticoagulation system. Some pathogenic factors (infection or inflammation, immune abnormalities, pregnancy, drugs and genetic abnormalities) causing systemic vascular endothelial cell injury are also involved in the pathogenesis of the disease from other aspects. (i) Platelets aggregate at the site of injury and cause local deposition of fibrin, resulting in the formation of a fibrin mesh, which ruptures red blood cells and platelets in the blood stream when they are mechanically impressed by the fibrin mesh. ②In recent years, Mitra et al [10] found that the plasma of patients could cause apoptosis of endothelial cells, and Dang et al [11] also confirmed the apoptosis of microvascular endothelial cells in the spleen of patients, suggesting that the apoptosis of vascular endothelial cells may also be related to the pathogenesis. (3) AECA is a marker of endothelial cell injury, and its increase is commonly seen in immune-related diseases, and it is increased in various TTP, which may have significance for the pathogenesis of TTP.
6, increased platelet aggregation factor and anti-platelet aggregation factor deficiency ① Some factors present in the blood of TTP patients such as platelet aggregation factor 37kD protein, calpain, cathepain, etc. have been found to contribute to the role of platelet aggregation. (ii) Tissue fibrinogen activator (tPA) activity is reduced in patients, and high levels of tissue fibrinogen activator inhibitor (PAI1) are also present, resulting in reduced fibrin degradation and microthrombus formation in the injured area. (iii) Vascular endothelial cells can synthesize prostacyclin (PGI2), which, under normal conditions, can inhibit platelet adhesion and aggregation. Some authors reported that in TTP patients, the level of PGI2 is significantly reduced, which strengthens platelet aggregation and adhesion, thus promoting the deposition of platelets in the damaged capillary wall and the onset of disease.
7, genetic factors The incidence of hereditary TTP is extremely low, and it is currently known that: ① peripheral blood has a large molecular weight vWF; ② the ADAMTS13 gene is defective, the patient’s activity is <5%, there is no inhibitor of the enzyme in the blood, and the parents have decreased activity of the enzyme.
Other factors involved in the pathogenesis may be the role of anti-microvascular endothelial cells or anti-platelet antibodies.
Pathological changes.
The typical pathological changes are widespread hyaline thrombosis in the small vessels, resulting in small vessel obstruction and ischemic changes in the corresponding blood supplying tissues and organs. Plasma exchange therapy is still the treatment of choice. Most of the patients have an acute and dangerous onset with high early mortality, but if the diagnosis and treatment are timely, the prognosis can be significantly improved. In recent years, great progress has been made in the pathogenesis, diagnosis and treatment of TTP. The following is a brief overview of recent developments in these areas to improve the understanding of the disease.
Patient presentation.
TTP occurs mostly in young people but can develop at any age, with a median age of onset of 26-46 years and a higher incidence in women than in men (female:male=3:2). The onset of the disease is rapid, with a few starting more slowly, and there may be muscle and joint pain and other preexisting symptoms. The typical clinical presentation is often a “triad of signs”: microvascular hemolytic anemia (100%), progressive thrombocytopenia (100%), and neurological abnormalities (63%) or a “quintuad of signs”: triad of signs plus fever (24%) and renal damage (59%). 59%).
Hemorrhage is mainly due to thrombocytopenia. It is manifested by skin bruises and bruises, and others such as nasal bleeding, gastrointestinal bleeding, hematuria, retinal bleeding, etc. Patients may develop severe hemolysis and yellowing of the bleeding skin.
Neurological abnormalities may include headache, confusion, delirium, coma, etc.
renal lesions may manifest as proteinuria, hematuria, and renal failure.
In addition some patients may present with lower abdominal pain, myocardial ischemia, cardiac arrest or respiratory failure.
Clinical diagnosis
There is no clinical “gold standard” for the diagnosis of TTP, and the disease is not fatal when all 5 signs are present at the same time in the early stages. In view of the urgency of plasma replacement and the impact of early treatment on the prognosis of this disease, it is considered that the diagnosis can be made as long as there is intravascular hemolytic anemia and thrombocytopenia without other clinical symptoms and signs, but other causes of thrombocytopenic purpura such as idiopathic thrombocytopenic purpura, Evens syndrome, autoimmune hemolytic anemia, systemic lupus erythematosus, DIC, hemolytic-uremic syndrome must be excluded. uremic syndrome. The presence or absence of red blood cell debris on blood smear is therefore important, and recent clinical practice suggests that the presence of thrombocytopenia, lytic erythrocytosis, and abnormally high lactate dehydrogenase is sufficient for the diagnosis of TTP. pathological biopsy reveals homogeneous hyaline thrombi in small arteries and capillaries to aid in the diagnosis. Recently, it has been suggested that detection of vWFcp activity in plasma is also helpful in the diagnosis of TTP and can be used to monitor disease recurrence.
Treatment of patients.
The improved understanding of the pathogenesis of the disease in recent years has also contributed to the development of treatment, which is now mainly adopted as follows.
Plasma exchange Plasma exchange (PE) is currently the preferred and main treatment for this disease. PE should be arranged within 24 h of consultation, too long delay can lead to treatment failure, if renal function, consciousness impairment or coma should be activated immediately, otherwise it is detrimental to regression and overall survival. If plasma exchange therapy is not available to the patient within 24 h, plasma infusion (PI) [at least 25 ml/(kg?d)] therapy should be initiated while preparing for plasma exchange. Half of the deaths occur within the first week of illness. Plasma exchange has a rapid efficacy, with fast results within minutes of exchange, generally within a week, and complete remission within 3 weeks, but the mechanism is not fully understood.
The mechanism of its effective action may be:
(i) removal of pathogenic substances from plasma, such as ULvWFM, vWcp antibodies and inhibitors, platelet aggregation factors, etc.
(ii) Supplementation of substances lacking in plasma: such as small molecular weight vWF, vWFcp, PGI2, etc.
③The amount of plasma used in this therapy is much larger than that of plasma transfusion alone, which may also be the reason for superior efficacy.
④Other: such as inhibition of vWF release, inhibition of endothelial cell apoptosis, etc.
The specific treatment protocol has not been unified, but the recommended protocol is plasma replacement in the amount of 30-40 ml/(kg?d), with fresh frozen plasma as the preferred replacement plasma, once/day until platelets recover, hemoglobin is stable, and serum lactate dehydrogenase level is normal, then gradually reduce the replacement volume until it is stopped. The American Association of Blood Transfusion (AABB) recommends daily plasma exchange until the platelet count reaches 150×109/L for 2-3 d. If immediate plasma exchange is not available, plasma transfusion therapy can be performed at the recommended dosage of 15-30 ml/(kg?d). The treatment of hereditary TTP is based on regular (3-4 weeks) prophylactic transfusions of fresh frozen plasma.
The following supplements are available for plasma replacement: ①fresh frozen plasma (FFP), the most commonly used. ② Plasma cold supernatant: FFP contains large molecules of vWF multimers, therefore, it may be more effective to treat TTP patients with plasma cold supernatant that removes the large vWF multimers, fibrinogen and fibronectin. ③ 5% albumin: It has been suggested that this may be better than FFP alone for the first half of the exchange. ④ Moake et al. treated plasma treated with organic solvents and decontaminants (SDTP) for TTP, which may be safer and more effective because of the inactivation of the virus and the removal of some of the large molecular weight of vWF. Most of the complications are related to intravenous cannulation.
Adverse effects of PE include: (i) catheter-related complications, such as pneumothorax, bleeding, infection, and thrombosis. ②Plasma-related complications: a metabolic reactions, such as hypoxemia, hypotension, serum sickness, urticaria; b alkalosis, manifested as hand and foot convulsions, nausea, vomiting and diarrhea; c blood volume loss, manifested as hypotension, syncope, etc.; d infection, caused by transfusion-transmitted virus. Platelet count and LDH are the most sensitive objective indicators to monitor the efficacy of treatment.
Immunotherapy is usually used as adjuvant therapy, often in combination with plasma exchange. ①Glucocorticoids: The efficacy of glucocorticoids on TTP is unclear. There are no studies to show whether glucocorticoids in combination with plasma exchange are superior to plasma exchange alone, and there is no uniform understanding of the dose and mode of use. Studies have shown that secondary protease function defects due to circulating subtypes of inhibitory antibodies are an important factor in the pathogenesis of TTP, and in this regard, it seems reasonable to give glucocorticoids to inhibit vWFcp antibodies in every patient. The side effects should be avoided as much as possible during treatment. The recommended dose is 075 mg/kg intravenously, or prednisone 10 mg/kg orally administered once every 12 h. Staphylococcal A protein column immunosorbent therapy: TTP patients who have failed to respond to PE therapy alone can be treated with staphylococcal A protein column (PROSORBA column) immunosorbent therapy as a remedial treatment, and successful results have been reported. The effective mechanism is believed to be its ability to selectively adsorb and remove disease-causing antibodies, immune complexes (CICs) and viruses from plasma to correct or regulate the body’s immune function. It has been suggested that it is suitable for malignant tumors, autoimmune diseases and some hematologic disorders that produce antibodies or CICs. The incidence of common adverse reactions is about 25%, including fever, chills, arthralgia, rash, nausea, tachycardia, respiratory symptoms and blood pressure changes. Generally, they can be reversed with treatment. (iii) Splenectomy: the efficacy is inexact. The mechanism of efficacy may be related to the elimination of autoantibodies to vWF lytic protease and the elimination of vWF-platelet binding sites. It is only occasionally tried in recalcitrant and relapsing cases and is often combined with other treatments.
Anticoagulation and anti-platelet aggregation drugs are controversial in clinical application. 1) The following drugs can be selected according to the anticoagulation index: a heparin: the dose is 100 U/kg, dissolved in 10% glucose solution or 0.9% sodium chloride solution 100 ml intravenously; or low molecular heparin intravenous drip or subcutaneous injection, the dose is 80 IU/kg, once/day; b urokinase: the first loading dose is 6 Urokinase: the first loading dose is 6,000 U, and the subsequent daily maintenance dose is half of the first loading dose. The former is a cyclooxygenase inhibitor, while the latter can inhibit phosphodiesterase and increase plasma cAMP levels. /(kg?d)] can reduce the morbidity and mortality in patients with acute TTP. b Ticlopidine: It can inhibit ADP-induced platelet aggregation and its binding to fibrinogen. Recent studies have favored it as a maintenance drug after remission, with a relapse rate of 6.3% in patients taking ticlopidine and 21.4% in those not taking the drug [19]. However, TTP occurred in some non-TTP patients during the course of the drug, and inhibitory antibodies to vWFcp were detected in patients, 2/3 of whom were men over 60 years of age, 72% of whom were treated with ticlopidine for stroke prevention. Prostacyclin: is a class of natural platelet activation and aggregation inhibitors that act on damaged blood vessels, early found, the patient’s plasma levels of PGI2 and 6 ketone 2PGF1A decreased, may be involved in the pathogenesis of TTP, some studies have shown that early infusion can reduce microvascular hemolysis, the application of late is no significant efficacy.
Fourth, other treatments: for refractory TTP there are treatments with cyclosporine, vincristine (1 mg, 1 time every 3~4 d, applied 4 times; or 2 mg, IV, 1 time a week, applied 4 times), combined chemotherapy (such as CHOP), autologous hematopoietic stem cell transplantation, etc., all of which have been reported to be successful. Recently, the application of anti-B lymphocyte CD20 monoclonal antibody in the treatment of refractory or relapsed TTP has also been successfully reported. There have also been cases of complete remission with the application of high-dose vitamin E therapy. However, high-dose intravenous gammaglobulin infusion has not been reported to be effective. Additional case reports suggest a sudden deterioration of the disease after platelet transfusion and autopsy observations suggest that platelet aggregation is the primary cause of death, but preliminary data suggest that many patients with suspected TTP have received platelet transfusions prior to initiating plasma exchange with few adverse outcomes, and therefore platelet transfusions should not be restricted when massive bleeding occurs. For the treatment of secondary cases, in addition to the treatment options described above, special emphasis should be placed on the correction of the primary condition. Symptomatic and supportive treatment should be given to patients with sequelae, etc.
Prognosis: TTP patients have a poor prognosis, with a short course and an 80% to 90% mortality rate without timely treatment, which is reduced to 10% to 20% with plasma exchange and other effective treatments. The disease may continue to recover completely, some may relapse after 1 month, several months or years of remission, and very few have a persistent course. It has been shown that patients with severely attenuated ADAMTS-13 activity and the presence of immunosuppressive agents have a better prognosis than patients with moderately to mildly attenuated, undetectable immune grafts.