Thrombotic microangiopathy is a polysyndromic pathology that combines thrombocytopenia, hemolytic anemia, arteriole occlusion with the development of ischemic organ lesions. Clinically, it proceeds with fever, bleeding, neurological disorders, abdominal syndrome. Possible development of TIA, myocardial and kidney infarction, hepatitis, mesenteric ischemia. Diagnosis is based on the study of blood (UAC, platelets, LDH, metalloproteinase activity), kidney biopsies, skin, bone marrow. Treatment involves the use of disaggregants, anticoagulants, glucocorticoids; plasmapheresis, plasma transfusion, according to indications – hemodialysis.
31.1 Thrombotic microangiopathy. Thrombotic thrombocytopenic purpura
A clinical case of an unknown disease, including anemia, fever, hemorrhagic purpura, ischemic stroke, acute heart failure and multiple thrombosis, was first described in 1924 by the American pathologist E. Moshkovits. Later, the disease was named after him, later other terms were introduced into clinical practice: thrombotic thrombocytopenic purpura (TTP), thrombotic microangiopathy, hemolytic anemia with microangiothrombosis. The frequency of the syndrome is 1.5-6 cases per 1 million population. Mostly people aged 30-40 get sick, of which women are 2 times more likely.
Causes of thrombotic microangiopathy
The etiology of thrombotic microangiopathy remains the subject of research in hematology. An important breakthrough of the last decades in this matter is the identification of the connection of TTP with the insufficiency of the enzyme ADAMTS-13 – metalloprotease, which cleaves the Willebrand factor. Violation of enzyme activity can be caused by both congenital and acquired causes:
- Congenital. They include mutations in the ADAMTS-13 gene, leading to a deficiency of disintegrin-like metalloprotease-13 with a repeat of type 1 thrombospondin. To date, more than 80 mutations have been studied that cause the development of a hereditary form of Midge disease.
- Purchased. They are mainly associated with the presence of antibodies that inhibit ADAMTS-13. Such conditions can occur with autoimmune diseases (AFS, SLE, scleroderma), HELLP syndrome, after a viral infection, vaccination, bone marrow transplantation. Also, a decrease in the activity of ADAMTS-13 is noted in DIC syndrome, uremia, cirrhosis of the liver, sepsis, oncopathology. Approximately half of the cases of thrombotic microangiopathy are regarded as idiopathic.
Deficiency or inhibition of ADAMTS-13 leads to increased activity of VWF (von Willebrand factor), which begins to stimulate uncontrolled intravascular platelet aggregation and thrombosis in the microcirculatory bed. The number of circulating platelets decreases, thrombocytopenia develops.
At the same time, the proliferation of the endothelium of small vessels occurs, which causes an additional narrowing of their lumen. Mechanical obstruction of blood flow and the release of various endothelial factors contributes to the fragmentation of red blood cells with the development of intravascular hemolysis.
Platelet aggregates cause blockage of arterioles and capillaries of the brain, heart, kidneys, lungs. Hemorrhagic purpura appears on the skin and mucous membranes, internal organs increase, hemosiderin deposits are found in them. Against the background of microangiopathy, ischemic and necrotic tissue changes are formed, infarctions of the heart muscle, cerebral tissue, and renal parenchyma occur.
In terms of the influence of etiological factors, thrombotic microangiopathy is divided into hereditary and acquired variants. These groups (especially the acquired form) are extremely heterogeneous, differ in the time of the debut, the quality of the course, the prognosis:
1. Hereditary. It is represented by Upshaw-Shulman syndrome with an autosomal recessive mechanism of hereditary transmission. It manifests more often in childhood, but episodes of the onset of the disease are known at the age of 35. The course is chronic, recurrent.
2. Acquired forms of TTP.
- Idiopathic TTP. It can be acute (with a lightning-fast course) and recurrent. In the second case, relapses can be either single or multiple.
- Secondary TTP. They may be associated with pregnancy and childbirth, taking drugs (sulfonamides, antibiotics, COCs, immunosuppressants). They are often provoked by autoimmune pathology (lupus, systemic scleroderma, AFS, RA, Sjogren’s syndrome, nodular periarteritis), infections (intestinal, HIV), malignant tumors (more often gastric adenocarcinoma). The association of Midge disease with organ and bone marrow transplants was noted.
Symptoms of thrombotic microangiopathy
In most cases, the disease manifests acutely and suddenly. A cold-like prodromal condition is often noted. The clinic is developing rapidly. The classical form of thrombotic microangiopathy is characterized by a pentad of signs: severe trobocytopenia, hemolytic anemia, neurological disorders, fever and renal syndrome.
At the onset of TTP, 35% of patients have abdominal syndrome: vomiting, severe abdominal pain, indicating mesenteric ischemia. Fever is typical. Hepatitis, pancreatitis, jaundice, splenomegaly may be detected. Sometimes the disease manifests with myocardial infarction, ARDS, rhabdomyolysis, gangrene.
Thrombocytopenia is accompanied by the appearance of petechial rash on the skin, bleeding of varying severity and localization (gingival, nasal, menorrhagia, melena, hemoptysis, hemorrhage in the subarachnoid space). Cerebral and renal disorders reflect ischemic organ damage. In the neurological status, cephalgia, convulsions, and disorders of consciousness are noted. Paresis and hemiplegia, ataxia, and aphatic disorders may occur. In severe cases, coma is possible.
Signs of renal syndrome are massive edema, arterial hypertension, hematuria. The increase in oliguria, electrolyte imbalance and azotemia indicates the development of acute renal failure. More often, the disease of the Midge is acute or subacute. A recurrent course is possible.
Without an emergency appointment of adequate treatment, the mortality rate from Midge disease is 85-100%. Fatal outcomes are caused by ischemic damage to target organs (acute myocardial infarction, ACVA, kidney infarction), hemorrhagic syndrome (cerebral hemorrhages, internal bleeding), organ dysfunction (AFRF, HF). Cases of sudden cardiac death associated with fatal arrhythmias, cardiogenic shock are described. In the later stages, DIC syndrome develops.
Diagnostics of thrombotic microangiopathy
The difficulty of recognizing thrombotic microangiopathy is explained by the absence of a pathognomonic clinical picture. Patients are often admitted to a hospital with a clinic for stroke, acute coronary insufficiency, abdominal ischemia and are unsuccessfully treated for the corresponding syndromes. Meanwhile, along with the examination of a neurologist, cardiologist, nephrologist, patients need to consult a hematologist:
- Objective status. Upon examination of the admitted patient, pallor and jaundice of the skin, fine–spotted hemorrhages on the skin (purpura), sometimes splenomegaly, increased blood pressure are noted. The patient may be disoriented, agitated, delirium and hallucinations are not uncommon, confusion of consciousness. Typical complaints are abdominal pain, headaches.
- Clinical laboratory diagnostics. Characteristic changes in the hemogram in thrombotic microangiopathy are anemia, reticulocytosis, pronounced thrombocytopenia (microhematuria, cylindruria, proteinuria.
- Biochemical laboratory diagnostics. The Coombs test is negative. The detection of Willebrand factor macromolecules in the blood is characteristic. A sharp increase in LDH levels indicates tissue ischemia and hemolysis. A special study determines a decrease in metalloproteinase activity, the presence of antibodies to ADAMTS-13, antiphospholipid At.
- Biopsy. To clarify the morphological changes in the tissues, a biopsy of the skin, muscles, gum mucosa, kidneys, and bone marrow is performed. The myelogram is characterized by normoblastic hematopoiesis with an increase in megaloblasts, suppression of white and irritation of the erythroid germ.
- Instrumental diagnostics. CT or MRI scanning of the head reveals cerebral ischemic foci, hemorrhages. With hemoptysis, CT of the lungs, fibrobronchoscopy is indicated; with gastrointestinal bleeding, EDG. Ischemic changes in organs are diagnosed using an ECG, ultrasound of the abdominal cavity, kidneys.
Based on laboratory and instrumental data, differential diagnosis of thrombotic microangiopathy is carried out with:
- Evans-Fisher syndrome (autoimmune hemolytic anemia + thrombocytopenia);
- hemolytic-uremic syndrome;
- Werlhof ‘s disease;
- paroxysmal nocturnal hemoglobinuria;
- collagenoses , etc .
Treatment of thrombotic microangiopathy
- Basic therapy. It should be started on the first day after the appearance of clinical symptoms. It includes infusions of large doses of freshly frozen or cryosupernatant plasma, the appointment of antiplatelet agents (aspirin, dipyridamole), anticoagulants (heparin), glucocorticosteroids (prednisone, dexamethasone)
- Extracorporeal hemocorrection. Plasmapheresis is considered the most effective method of therapy for thrombotic microangiopathy, since it allows the removal of metalloprotease inhibitors from the blood. Patients with KF need renal replacement therapy – hemodialysis, peritoneal dialysis
- Auxiliary treatment. With severe anemia syndrome, transfusions of erythrocytes are used. Platelet transfusion is carried out only with life-threatening bleeding. A number of clinicians recommend prescribing folic acid to all patients.